{"paper_id": "c9f2ba9d8fea3008779442c4ed578dfeb558fb66", "title": "The promise and challenge of high-throughput sequencing of the antibody repertoire NIH Public Access Author Manuscript", "coda_paper_id": 1349, "has_expert_labels": false, "abstract_text": "Efforts to determine the antibody repertoire encoded by B cells in the blood or lymphoid organs using high-throughput DNA sequencing technologies have been advancing at an extremely rapid pace and are transforming our understanding of humoral immune responses . Information gained from high-throughput DNA sequencing of immunoglobulin genes ( Ig-seq ) can be applied to detect B-cell malignancies with high sensitivity , to discover antibodies specific for antigens of interest , to guide vaccine development and to understand autoimmunity . Rapid progress in the development of experimental protocols and informatics analysis tools is helping to reduce sequencing artifacts , to achieve more precise quantification of clonal diversity and to extract the most pertinent biological information . That said , broader application of Ig-seq , especially in clinical settings , will require the development of a standardized experimental design framework that will enable the sharing and meta-analysis of sequencing data generated by different laboratories . A potent adaptive immune system is fundamentally reliant upon the generation of a diverse repertoire of B-lymphocyte antigen receptors ( BCRs , the membrane-bound form of antibodies expressed on the surface of B cells ) . BCRs are assembled by somatic recombination of a large number of immunoglobulin gene segments ( Fig. 1 ) , and the", "gold_segments": [{"segment_text": "Efforts to determine the antibody repertoire encoded by B cells in the blood or lymphoid organs using high-throughput DNA sequencing technologies have been advancing at an extremely rapid pace and are transforming our understanding of humoral immune responses .", "label": "background"}, {"segment_text": "Information gained from high-throughput DNA sequencing of immunoglobulin genes ( Ig-seq ) can be applied to detect B-cell malignancies with high sensitivity ,", "label": "background"}, {"segment_text": "to discover antibodies specific for antigens of interest ,", "label": "background"}, {"segment_text": "to guide vaccine development and to understand autoimmunity .", "label": "background"}, {"segment_text": "Rapid progress in the development of experimental protocols and informatics analysis tools is helping to reduce sequencing artifacts ,", "label": "background"}, {"segment_text": "to achieve more precise quantification of clonal diversity and to extract the most pertinent biological information .", "label": "background"}, {"segment_text": "That said , broader application of Ig-seq ,", "label": "background"}, {"segment_text": "especially in clinical settings , will require the development of a standardized experimental design framework that will enable the sharing and meta-analysis of sequencing data generated by different laboratories .", "label": "finding"}, {"segment_text": "A potent adaptive immune system is fundamentally reliant upon the generation of a diverse repertoire of B-lymphocyte antigen receptors ( BCRs , the membrane-bound form of antibodies expressed on the surface of B cells ) .", "label": "finding"}, {"segment_text": "BCRs are assembled by somatic recombination of a large number of immunoglobulin gene segments ( Fig. 1 ) , and the", "label": "finding"}], "n_segments": 10}
{"paper_id": "7f6d6d5cf7a484c164c955ff15a32758e1ab3943", "title": "An Investigation of the Outcomes of PGY Students' Cognition of and Persistent Behavior in Learning through the Intervention of the Flipped Classroom in Taiwan", "coda_paper_id": 1565, "has_expert_labels": false, "abstract_text": "The Postgraduate Year ( PGY ) Program allows doctors-in-training to learn about the diagnosis , treatment and nursing of various common , general diseases . These items form the core curriculum and are mostly learned through caring for patients and clinical teaching . Doctorsin-training are evaluated for their knowledge through written tests or assignments , based on which the effectiveness of their training is also assessed ; however , this generally produces a negative learning attitude among them . So we introduced the flipped classroom into PGY training program to change PGY students ' learning behavior . Although the flipped classroom is highly valued and has been practiced by teachers in schools of various levels , very few attempts have been made until now to report the learning outcomes achieved through the flipped classroom by means of rigorous research methods . Therefore we tried to employed Ajzen and Fishbein 's ( 1980 ) theory of reasoned action and Bandura 's self-efficacy to predict and explain the participants ' behavioral intention when participating in the core curriculum learning of the flipped classroom and to assess the change in students ' learning behavior and learning effectiveness . From August 2013 to July 2014 , 39 PGY students from the General Surgery of the Tri-Service General Hospital were selected as the participants of this study . The control group included 43 students of the previous year , that is , the year before the intervention of the flipped classroom . A comparative analysis was performed . The questionnaire 's related matrices indicated highest correlation between self-efficacy and behavioral intention ( r = 0.491 , P < 0.01 ) , followed by attitude ( r = 0.365 , P < 0.01 ) and subjective norms ( r = 0.360 , P < 0.01 . ) All three showed positive correlations with behavioral intention ; among attitude , subjective norms , and self-efficacy , the pairwise correlations also reached significance level . The flipped classroom can indeed change PGY students ' the learning behavior from `` passive learning '' to `` active learning . '' PLOS ONE |", "gold_segments": [{"segment_text": "The Postgraduate Year ( PGY ) Program allows doctors-in-training to learn about the diagnosis ,", "label": "background"}, {"segment_text": "treatment and nursing of various common , general diseases .", "label": "background"}, {"segment_text": "These items form the core curriculum and are mostly learned through caring for patients and clinical teaching .", "label": "background"}, {"segment_text": "Doctorsin-training are evaluated for their knowledge through written tests or assignments ,", "label": "background"}, {"segment_text": "based on which the effectiveness of their training is also assessed ; however ,", "label": "background"}, {"segment_text": "this generally produces a negative learning attitude among them .", "label": "background"}, {"segment_text": "So we introduced the flipped classroom into PGY training program to change PGY students ' learning behavior .", "label": "background"}, {"segment_text": "Although the flipped classroom is highly valued and has been practiced by teachers in schools of various levels ,", "label": "background"}, {"segment_text": "very few attempts have been made until now to report the learning outcomes achieved through the flipped classroom by means of rigorous research methods .", "label": "background"}, {"segment_text": "Therefore we tried to employed Ajzen and Fishbein 's ( 1980 ) theory of reasoned action and Bandura 's self-efficacy to predict and explain the participants ' behavioral intention when participating in the core curriculum learning of the flipped classroom and to assess the change in students ' learning behavior and learning effectiveness .", "label": "method"}, {"segment_text": "From August 2013 to July 2014 ,", "label": "background"}, {"segment_text": "39 PGY students from the General Surgery of the Tri-Service General Hospital were selected as the participants of this study .", "label": "background"}, {"segment_text": "The control group included 43 students of the previous year ,", "label": "finding"}, {"segment_text": "that is , the year before the intervention of the flipped classroom .", "label": "method"}, {"segment_text": "A comparative analysis was performed .", "label": "method"}, {"segment_text": "The questionnaire 's related matrices indicated highest correlation between self-efficacy and behavioral intention ( r = 0.491 , P < 0.01 ) ,", "label": "finding"}, {"segment_text": "followed by attitude ( r = 0.365 , P < 0.01 ) and subjective norms ( r = 0.360 , P < 0.01 . )", "label": "finding"}, {"segment_text": "All three showed positive correlations with behavioral intention ; among attitude ,", "label": "finding"}, {"segment_text": "subjective norms , and self-efficacy ,", "label": "finding"}, {"segment_text": "the pairwise correlations also reached significance level .", "label": "finding"}, {"segment_text": "The flipped classroom can indeed change PGY students ' the learning behavior from `` passive learning '' to `` active learning . ''", "label": "finding"}, {"segment_text": "PLOS ONE |", "label": "other"}], "n_segments": 22}
{"paper_id": "e865e9c70482f7137be58b8a0bcefe06b282fa1e", "title": "Synthetic approaches toward stilbenes and their related structures", "coda_paper_id": 1538, "has_expert_labels": false, "abstract_text": "Compounds belonging to the stilbene family have gained remarkable significance in pharmaceutical as well as material chemistry . The current review covers the various synthetic approaches for the syntheses of stilbene scaffold and related structures over last 30 years . In addition , this review also highlights the role of stilbene intermediates used in the synthesis of important molecules with diverse applications in the field of pharmaceutics and material science .", "gold_segments": [{"segment_text": "Compounds belonging to the stilbene family have gained remarkable significance in pharmaceutical as well as material chemistry .", "label": "background"}, {"segment_text": "The current review covers the various synthetic approaches for the syntheses of stilbene scaffold and related structures over last 30 years .", "label": "background"}, {"segment_text": "In addition , this review also highlights the role of stilbene intermediates used in the synthesis of important molecules with diverse applications in the field of pharmaceutics and material science .", "label": "finding"}], "n_segments": 3}
{"paper_id": "ee6d70a53e3262cea6f85bd8b226f6b4c8b5f64b", "title": "Pandemic Influenza Due to pH1N1/2009 Virus: Estimation of Infection Burden in Reunion Island through a Prospective Serosurvey, Austral Winter 2009", "coda_paper_id": 1948, "has_expert_labels": false, "abstract_text": "Background : To date , there is little information that reflects the true extent of spread of the pH1N1/2009v influenza pandemic at the community level as infection often results in mild or no clinical symptoms . This study aimed at assessing through a prospective study , the attack rate of pH1N1/2009 virus in Reunion Island and risk factors of infection , during the 2009 season . Methodology/Principal Findings : A serosurvey was conducted during the 2009 austral winter , in the frame of a prospective population study . Pairs of sera were collected from 1687 individuals belonging to 772 households , during and after passage of the pandemic wave . Antibodies to pH1N1/2009v were titered using the hemagglutination inhibition assay ( HIA ) with titers $ 1/40 being considered positive . Seroprevalence during the first two weeks of detection of pH1N1/2009v in Reunion Island was 29.8 % in people under 20 years of age , 35.6 % in adults ( 20-59 years ) and 73.3 % in the elderly ( $ 60 years ) ( P ,0.0001 ) . Baseline corrected cumulative incidence rates , were 42.9 % , 13.9 % and 0 % in these age groups respectively ( P ,0.0001 ) . A significant decline in antibody titers occurred soon after the passage of the epidemic wave . Seroconversion rates to pH1N1/2009 correlated negatively with age : 63.2 % , 39.4 % and 16.7 % , in each age group respectively ( P ,0.0001 ) . Seroconversion occurred in 65.2 % of individuals who were seronegative at inclusion compared to 6.8 % in those who were initially seropositive . Conclusions : Seroincidence of pH1N1/2009v infection was three times that estimated from clinical surveillance , indicating that almost two thirds of infections occurring at the community level have escaped medical detection . People under 20 years of age were the most affected group . Pre-epidemic titers $ 1/40 prevented seroconversion and are likely protective against infection . A concern was raised about the long term stability of the antibody responses .", "gold_segments": [{"segment_text": "Background : To date , there is little information that reflects the true extent of spread of the pH1N1/2009v influenza pandemic at the community level as infection often results in mild or no clinical symptoms .", "label": "background"}, {"segment_text": "This study aimed at assessing through a prospective study ,", "label": "purpose"}, {"segment_text": "the attack rate of pH1N1/2009 virus in Reunion Island and risk factors of infection , during the 2009 season .", "label": "purpose"}, {"segment_text": "Methodology/Principal Findings : A serosurvey was conducted during the 2009 austral winter ,", "label": "method"}, {"segment_text": "in the frame of a prospective population study .", "label": "method"}, {"segment_text": "Pairs of sera were collected from 1687 individuals belonging to 772 households ,", "label": "method"}, {"segment_text": "during and after passage of the pandemic wave .", "label": "method"}, {"segment_text": "Antibodies to pH1N1/2009v were titered using the hemagglutination inhibition assay ( HIA ) with titers $ 1/40 being considered positive .", "label": "method"}, {"segment_text": "Seroprevalence during the first two weeks of detection of pH1N1/2009v in Reunion Island was 29.8 % in people under 20 years of age ,", "label": "method"}, {"segment_text": "35.6 % in adults ( 20-59 years ) and 73.3 % in the elderly ( $ 60 years ) ( P ,0.0001 ) .", "label": "method"}, {"segment_text": "Baseline corrected cumulative incidence rates ,", "label": "finding"}, {"segment_text": "were 42.9 % , 13.9 % and 0 % in these age groups respectively ( P ,0.0001 ) .", "label": "finding"}, {"segment_text": "A significant decline in antibody titers occurred soon after the passage of the epidemic wave .", "label": "finding"}, {"segment_text": "Seroconversion rates to pH1N1/2009 correlated negatively with age : 63.2 % ,", "label": "finding"}, {"segment_text": "39.4 % and 16.7 % ,", "label": "finding"}, {"segment_text": "in each age group respectively ( P ,0.0001 ) .", "label": "finding"}, {"segment_text": "Seroconversion occurred in 65.2 % of individuals who were seronegative at inclusion compared to 6.8 % in those who were initially seropositive .", "label": "finding"}, {"segment_text": "Conclusions : Seroincidence of pH1N1/2009v infection was three times that estimated from clinical surveillance ,", "label": "finding"}, {"segment_text": "indicating that almost two thirds of infections occurring at the community level have escaped medical detection .", "label": "finding"}, {"segment_text": "People under 20 years of age were the most affected group .", "label": "finding"}, {"segment_text": "Pre-epidemic titers $ 1/40 prevented seroconversion and are likely protective against infection .", "label": "finding"}, {"segment_text": "A concern was raised about the long term stability of the antibody responses .", "label": "finding"}], "n_segments": 22}
{"paper_id": "0899d745009fa75954f75b381c040aebd927832a", "title": "The evolution of disease: anthropological perspectives on epidemiologic transitions", "coda_paper_id": 1549, "has_expert_labels": false, "abstract_text": "Background : The model of epidemiologic transitions has served as a guiding framework for understanding relationships between patterns of human health and disease and economic development for the past several decades . However , epidemiologic transition theory is infrequently employed in epidemiology . Objective : Moving beyond Omran 's original formulation , we discuss critiques and modifications of the theory of epidemiologic transitions and highlight some of the ways in which incorporating epidemiologic transition theory can benefit theory and practice in epidemiology . Design : We focus on two broad contemporary trends in human health that epidemiologic transition theory is useful for conceptualizing : the increased incidence of chronic inflammatory diseases ( CIDs ) , such as allergic and autoimmune diseases , and the emergence and reemergence of infectious disease . Results : Situating these trends within epidemiologic transition theory , we explain the rise in CIDs with the hygiene hypothesis and the rise in emerging and reemerging infections with the concept of a third epidemiologic transition . Conclusions : Contextualizing these trends within epidemiologic transition theory reveals implications for clinical practice , global health policies , and future research within epidemiology .", "gold_segments": [{"segment_text": "Background : The model of epidemiologic transitions has served as a guiding framework for understanding relationships between patterns of human health and disease and economic development for the past several decades .", "label": "background"}, {"segment_text": "However , epidemiologic transition theory is infrequently employed in epidemiology .", "label": "background"}, {"segment_text": "Objective : Moving beyond Omran 's original formulation ,", "label": "purpose"}, {"segment_text": "we discuss critiques and modifications of the theory of epidemiologic transitions and highlight some of the ways in which incorporating epidemiologic transition theory can benefit theory and practice in epidemiology .", "label": "purpose"}, {"segment_text": "Design : We focus on two broad contemporary trends in human health that epidemiologic transition theory is useful for conceptualizing : the increased incidence of chronic inflammatory diseases ( CIDs ) ,", "label": "method"}, {"segment_text": "such as allergic and autoimmune diseases ,", "label": "method"}, {"segment_text": "and the emergence and reemergence of infectious disease .", "label": "method"}, {"segment_text": "Results : Situating these trends within epidemiologic transition theory ,", "label": "finding"}, {"segment_text": "we explain the rise in CIDs with the hygiene hypothesis and the rise in emerging and reemerging infections with the concept of a third epidemiologic transition .", "label": "finding"}, {"segment_text": "Conclusions : Contextualizing these trends within epidemiologic transition theory reveals implications for clinical practice ,", "label": "finding"}, {"segment_text": "global health policies , and future research within epidemiology .", "label": "finding"}], "n_segments": 11}
{"paper_id": "c1a08ce8f2c5d5311b19822c3df5aa9d25c4d93c", "title": "", "coda_paper_id": 1621, "has_expert_labels": false, "abstract_text": "Findings : Of the 213 cases ( 108 men and 105 women ) , 88 ( 41 % ) had exposure to Wuhan . The median age was 48 years ( range,2-88 years ; IQR,35-58.5 ) . Thirty-three severe patients with a median age of 66 years ( range,33-82 years , IQR , 57-76 ) were treated in intensive care units ; out of these patients , 66.7 % ( 22 ) were men and 19 ( 57.5 % ) had chronic diseases , including hypertension , diabetes , heart failure , stroke , and renal insufficiency . Under the controlled measures , the number of new patients gradually decreased and nearly disappeared after 20 days . Interpretation : All people are susceptible to the COVID-19 , but older males and those with comorbid conditions are more likely to have severe symptoms . Even though COVID-19 is highly contagious , control measures have proven to be very effective .", "gold_segments": [{"segment_text": "Findings : Of the 213 cases ( 108 men and 105 women ) ,", "label": "finding"}, {"segment_text": "88 ( 41 % ) had exposure to Wuhan .", "label": "finding"}, {"segment_text": "The median age was 48 years ( range,2-88 years ; IQR,35-58.5 ) .", "label": "finding"}, {"segment_text": "Thirty-three severe patients with a median age of 66 years ( range,33-82 years , IQR , 57-76 ) were treated in intensive care units ; out of these patients ,", "label": "finding"}, {"segment_text": "66.7 % ( 22 ) were men and 19 ( 57.5 % ) had chronic diseases ,", "label": "finding"}, {"segment_text": "including hypertension , diabetes , heart failure ,", "label": "finding"}, {"segment_text": "stroke , and renal insufficiency .", "label": "finding"}, {"segment_text": "Under the controlled measures , the number of new patients gradually decreased and nearly disappeared after 20 days .", "label": "finding"}, {"segment_text": "Interpretation : All people are susceptible to the COVID-19 ,", "label": "finding"}, {"segment_text": "but older males and those with comorbid conditions are more likely to have severe symptoms .", "label": "finding"}, {"segment_text": "Even though COVID-19 is highly contagious ,", "label": "finding"}, {"segment_text": "control measures have proven to be very effective .", "label": "finding"}], "n_segments": 12}
{"paper_id": "5b13e81ee4495ff3eccaeea21f955ebc5e5cbde1", "title": "Using autoregressive integrated moving average (ARIMA) models to predict and monitor the number of beds occupied during a SARS outbreak in a tertiary hospital in Singapore", "coda_paper_id": 1954, "has_expert_labels": false, "abstract_text": "The main objective of this study is to apply autoregressive integrated moving average ( ARIMA ) models to make real-time predictions on the number of beds occupied in Tan Tock Seng Hospital , during the recent SARS outbreak . Methods : This is a retrospective study design . Hospital admission and occupancy data for isolation beds was collected from Tan Tock Seng hospital for the period 14 th March 2003 to 31 st May 2003 . The main outcome measure was daily number of isolation beds occupied by SARS patients . Among the covariates considered were daily number of people screened , daily number of people admitted ( including observation , suspect and probable cases ) and days from the most recent significant event discovery . We utilized the following strategy for the analysis . Firstly , we split the outbreak data into two . Data from 14 th March to 21 st April 2003 was used for model development . We used structural ARIMA models in an attempt to model the number of beds occupied . Estimation is via the maximum likelihood method using the Kalman filter . For the ARIMA model parameters , we considered the simplest parsimonious lowest order model . We found that the ARIMA ( 1,0,3 ) model was able to describe and predict the number of beds occupied during the SARS outbreak well . The mean absolute percentage error ( MAPE ) for the training set and validation set were 5.7 % and 8.6 % respectively , which we found was reasonable for use in the hospital setting . Furthermore , the model also provided three-day forecasts of the number of beds required . Total number of admissions and probable cases admitted on the previous day were also found to be independent prognostic factors of bed occupancy . Conclusion : ARIMA models provide useful tools for administrators and clinicians in planning for real-time bed capacity during an outbreak of an infectious disease such as SARS . The model could well be used in planning for bed-capacity during outbreaks of other infectious diseases as well .", "gold_segments": [{"segment_text": "The main objective of this study is to apply autoregressive integrated moving average ( ARIMA ) models to make real-time predictions on the number of beds occupied in Tan Tock Seng Hospital ,", "label": "purpose"}, {"segment_text": "during the recent SARS outbreak .", "label": "purpose"}, {"segment_text": "Methods : This is a retrospective study design .", "label": "method"}, {"segment_text": "Hospital admission and occupancy data for isolation beds was collected from Tan Tock Seng hospital for the period 14 th March 2003 to 31 st May 2003 .", "label": "method"}, {"segment_text": "The main outcome measure was daily number of isolation beds occupied by SARS patients .", "label": "method"}, {"segment_text": "Among the covariates considered were daily number of people screened ,", "label": "method"}, {"segment_text": "daily number of people admitted ( including observation , suspect and probable cases ) and days from the most recent significant event discovery .", "label": "method"}, {"segment_text": "We utilized the following strategy for the analysis .", "label": "method"}, {"segment_text": "Firstly , we split the outbreak data into two .", "label": "method"}, {"segment_text": "Data from 14 th March to 21 st April 2003 was used for model development .", "label": "method"}, {"segment_text": "We used structural ARIMA models in an attempt to model the number of beds occupied .", "label": "method"}, {"segment_text": "Estimation is via the maximum likelihood method using the Kalman filter .", "label": "method"}, {"segment_text": "For the ARIMA model parameters ,", "label": "method"}, {"segment_text": "we considered the simplest parsimonious lowest order model .", "label": "method"}, {"segment_text": "We found that the ARIMA ( 1,0,3 ) model was able to describe and predict the number of beds occupied during the SARS outbreak well .", "label": "finding"}, {"segment_text": "The mean absolute percentage error ( MAPE ) for the training set and validation set were 5.7 % and 8.6 % respectively ,", "label": "finding"}, {"segment_text": "which we found was reasonable for use in the hospital setting .", "label": "finding"}, {"segment_text": "Furthermore , the model also provided three-day forecasts of the number of beds required .", "label": "finding"}, {"segment_text": "Total number of admissions and probable cases admitted on the previous day were also found to be independent prognostic factors of bed occupancy .", "label": "finding"}, {"segment_text": "Conclusion : ARIMA models provide useful tools for administrators and clinicians in planning for real-time bed capacity during an outbreak of an infectious disease such as SARS .", "label": "finding"}, {"segment_text": "The model could well be used in planning for bed-capacity during outbreaks of other infectious diseases as well .", "label": "finding"}], "n_segments": 21}
{"paper_id": "844c47b00a34c67630729df40422dfa1a9a61700", "title": "Archives of Virology Mouse Hepatitis Virus Strain 3 Infection of C57, A/Sn and A/J Strain Mice and Their Maerophafles Brief Report", "coda_paper_id": 1326, "has_expert_labels": false, "abstract_text": "Mouse hepatitis virus strain 3 replicated in C57 , A/Sn and A/J strain mouse macrophages with the production of a clear cytopathic effect , although only C57 and A/Sn strains of mice were ki ) led with similar MHV3 dilutions . We could not confirm a previous report showing that in vitro cultured macrophages from A/J strain mice were resistant to MHV3 infection . , Mouse hepatitis virus ( MHV ) exists in several closely related serotypes with varying degrees of pathogenicity in mice ( 8 ) . A number of studies have shown a correlation between the pathogenicity of a certain type of virus and its ability to grow in cultured maeroph ~ ges ( 3 , 9 ) . Thus , the non-pathogenic MHV 1 does not replicate in mouse macrophages ( 1 ) , whereas the pathogenie types MHV2 and MHV3 readily infect mouse peritoneal macrophages ( 2 , 7 , 11 , 12 ) . Most strains of mice can be infected with MHV3 with the development of fu ) minant hepatitis . Previous studies using A/J strain mice showed that these mice were resistant to MHV3 infection , with only a mild disease occurring with large doses of virus ( 4 , 12 ) . During the first four days of infection virus was recovered from infected mice although there were only minimal changes to their livers ( 4 ) . However , young A/J strain mice were susceptible up to 3 weeks of age ( 4 ) . Other mouse strains , including the C57 strain ( 4 , 5 , 12 ) and the A/Sn strain ( 5 ) were sensitive to MHV3 infection . Furthermore , VIaELIZIER and ALLISON ( 12 ) have reported that there was no detectable growth of MHV3 in macrophagcs from A/J mice ; whilst MHV3 replicated in maerophages from C57 strain mice . We were interested in analysing this reported resistance of A/J strain mouse macrophages to MHV3 infection and attempted to repeat this observation by comparing the effect of MHV3 infection on C57 , A/Sn and A/J strain mice and their macrophages .", "gold_segments": [{"segment_text": "Mouse hepatitis virus strain 3 replicated in C57 ,", "label": "background"}, {"segment_text": "A/Sn and A/J strain mouse macrophages with the production of a clear cytopathic effect ,", "label": "background"}, {"segment_text": "although only C57 and A/Sn strains of mice were ki ) led with similar MHV3 dilutions .", "label": "background"}, {"segment_text": "We could not confirm a previous report showing that in vitro cultured macrophages from A/J strain mice were resistant to MHV3 infection .", "label": "background"}, {"segment_text": ",", "label": "other"}, {"segment_text": "Mouse hepatitis virus ( MHV ) exists in several closely related serotypes with varying degrees of pathogenicity in mice ( 8 ) .", "label": "background"}, {"segment_text": "A number of studies have shown a correlation between the pathogenicity of a certain type of virus and its ability to grow in cultured maeroph ~ ges ( 3 , 9 ) .", "label": "background"}, {"segment_text": "Thus , the non-pathogenic MHV 1 does not replicate in mouse macrophages ( 1 ) ,", "label": "background"}, {"segment_text": "whereas the pathogenie types MHV2 and MHV3 readily infect mouse peritoneal macrophages ( 2 , 7 , 11 , 12 ) .", "label": "background"}, {"segment_text": "Most strains of mice can be infected with MHV3 with the development of fu ) minant hepatitis .", "label": "background"}, {"segment_text": "Previous studies using A/J strain mice showed that these mice were resistant to MHV3 infection ,", "label": "background"}, {"segment_text": "with only a mild disease occurring with large doses of virus ( 4 , 12 ) .", "label": "background"}, {"segment_text": "During the first four days of infection virus was recovered from infected mice although there were only minimal changes to their livers ( 4 ) .", "label": "background"}, {"segment_text": "However , young A/J strain mice were susceptible up to 3 weeks of age ( 4 ) .", "label": "background"}, {"segment_text": "Other mouse strains , including the C57 strain ( 4 , 5 , 12 ) and the A/Sn strain ( 5 ) were sensitive to MHV3 infection .", "label": "background"}, {"segment_text": "Furthermore , VIaELIZIER and ALLISON ( 12 ) have reported that there was no detectable growth of MHV3 in macrophagcs from A/J mice ; whilst MHV3 replicated in maerophages from C57 strain mice .", "label": "background"}, {"segment_text": "We were interested in analysing this reported resistance of A/J strain mouse macrophages to MHV3 infection and attempted to repeat this observation by comparing the effect of MHV3 infection on C57 ,", "label": "purpose"}, {"segment_text": "A/Sn and A/J strain mice and their macrophages .", "label": "finding"}], "n_segments": 18}
{"paper_id": "2e0eef7888633184f85b8afd59c032c90c7892d8", "title": "Identification of a novel canine norovirus", "coda_paper_id": 1016, "has_expert_labels": false, "abstract_text": "By screening a collection of fecal samples from young dogs from different European countries , noroviruses ( NoVs ) were found in 13/294 ( 4.4 % ) animals with signs of enteritis whilst they were not detected in healthy dogs ( 0/42 ) . An informative portion of the genome ( 3.4 kb at the 3 ′ end ) was generated for four NoV strains . In the capsid protein VP1 region , strains 63.15 / 2015/ITA and FD53/2007/ITA were genetically related to the canine GVI .2 strain C33/Viseu/2007 / PRT ( 97.4-98.6 % nt and 90.3-98.6 % aa ) . Strain FD210/2007/ITA displayed the highest identity to the GVI .1 canine strain Bari/91/2007 / ITA ( 88.0 % nt and 95.0 % aa ) . Strain 5010/2009/ITA displayed only 66.6-67.6 % nt and 75.5-81.6 % aa identities to the GVI .1 canine strains FD210/2007/ITA and Bari/91/2007 / ITA and the GVI feline strain M49-1 / 2012/JPN . Identity to the other canine/feline NoVs strains in the VP1 was lower than 67.6 % nt and 62.7 % aa . Based on the full-length VP1 amino acid sequence and the criteria proposed for distinction of NoV genotypes , the canine NoV 5010/2009/ITA could represent the prototype of a third GVI genotype , thus providing further evidence for the genetic heterogeneity of NoVs in carnivores .", "gold_segments": [{"segment_text": "By screening a collection of fecal samples from young dogs from different European countries ,", "label": "method"}, {"segment_text": "noroviruses ( NoVs ) were found in 13/294 ( 4.4 % ) animals with signs of enteritis whilst they were not detected in healthy dogs ( 0/42 ) .", "label": "finding"}, {"segment_text": "An informative portion of the genome ( 3.4 kb at the 3 ′ end ) was generated for four NoV strains .", "label": "finding"}, {"segment_text": "In the capsid protein VP1 region ,", "label": "finding"}, {"segment_text": "strains 63.15 / 2015/ITA and FD53/2007/ITA were genetically related to the canine GVI .2 strain C33/Viseu/2007 / PRT ( 97.4-98.6 % nt and 90.3-98.6 % aa ) .", "label": "finding"}, {"segment_text": "Strain FD210/2007/ITA displayed the highest identity to the GVI .1 canine strain Bari/91/2007 / ITA ( 88.0 % nt and 95.0 % aa ) .", "label": "finding"}, {"segment_text": "Strain 5010/2009/ITA displayed only 66.6-67.6 % nt and 75.5-81.6 % aa identities to the GVI .1 canine strains FD210/2007/ITA and Bari/91/2007 / ITA and the GVI feline strain M49-1 / 2012/JPN .", "label": "finding"}, {"segment_text": "Identity to the other canine/feline NoVs strains in the VP1 was lower than 67.6 % nt and 62.7 % aa .", "label": "finding"}, {"segment_text": "Based on the full-length VP1 amino acid sequence and the criteria proposed for distinction of NoV genotypes ,", "label": "finding"}, {"segment_text": "the canine NoV 5010/2009/ITA could represent the prototype of a third GVI genotype ,", "label": "finding"}, {"segment_text": "thus providing further evidence for the genetic heterogeneity of NoVs in carnivores .", "label": "finding"}], "n_segments": 11}
{"paper_id": "d3361db032c5bd76e9fb45c2178249b55e72fc62", "title": "The complete sequence of the bovine torovirus genome", "coda_paper_id": 1772, "has_expert_labels": false, "abstract_text": "Viruses in the family Coronaviridae have elicited new interest , with the outbreaks caused by SARS-HCoV in 2003 and the recent discovery of a new human coronavirus , HCoV-NL63 . The genus Torovirus , within the family Coronaviridae , is less well characterized , in part because toroviruses can not yet be grown in cell culture ( except for the Berne virus ) . In this study , we determined the sequence of the complete genome of Breda-1 ( BoTV-1 ) , a bovine torovirus . This is the first complete torovirus genome sequence to be reported . BoTV-1 RNA was amplified using long RT-PCR and the amplicons sequenced . The genome has a length of 28.475 kb and consisted mainly of the replicase gene ( ∼ 20.2 kb ) which contains two large overlapping ORFs , ORF1a and ORF1b , encoding polyproteins pp1a and pp1b , respectively . Sequence analysis identified conserved domains within the predicted sequences of pp1a and pp1b . Sequence alignments and protein secondary structure prediction data suggest the presence of a 3C-like serine protease domain with similarity to the arterivirus 3C-like serine protease and a single papain-like cysteine protease domain with similarity to the picornavirus leader protease . The ADRP ( APPR-1 ) domain - unique to the Coronaviridae - was also located in BoTV pp1a . In addition , several hydrophobic domains were identified that are typical of a nidovirus replicase . Within the pp1b sequence the polymerase and helicase domains were identified , as well as sequences predicted to be involved in ribosomal frameshifting , including the conserved slippery sequence UUUAAAC and two potential pseudoknot structures .", "gold_segments": [{"segment_text": "Viruses in the family Coronaviridae have elicited new interest ,", "label": "background"}, {"segment_text": "with the outbreaks caused by SARS-HCoV in 2003 and the recent discovery of a new human coronavirus , HCoV-NL63 .", "label": "background"}, {"segment_text": "The genus Torovirus , within the family Coronaviridae ,", "label": "background"}, {"segment_text": "is less well characterized , in part because toroviruses can not yet be grown in cell culture ( except for the Berne virus ) .", "label": "background"}, {"segment_text": "In this study , we determined the sequence of the complete genome of Breda-1 ( BoTV-1 ) , a bovine torovirus .", "label": "purpose"}, {"segment_text": "This is the first complete torovirus genome sequence to be reported .", "label": "purpose"}, {"segment_text": "BoTV-1 RNA was amplified using long RT-PCR and the amplicons sequenced .", "label": "method"}, {"segment_text": "The genome has a length of 28.475 kb and consisted mainly of the replicase gene ( ∼ 20.2 kb ) which contains two large overlapping ORFs ,", "label": "finding"}, {"segment_text": "ORF1a and ORF1b , encoding polyproteins pp1a and pp1b , respectively .", "label": "finding"}, {"segment_text": "Sequence analysis identified conserved domains within the predicted sequences of pp1a and pp1b .", "label": "finding"}, {"segment_text": "Sequence alignments and protein secondary structure prediction data suggest the presence of a 3C-like serine protease domain with similarity to the arterivirus 3C-like serine protease and a single papain-like cysteine protease domain with similarity to the picornavirus leader protease .", "label": "finding"}, {"segment_text": "The ADRP ( APPR-1 ) domain - unique to the Coronaviridae - was also located in BoTV pp1a .", "label": "finding"}, {"segment_text": "In addition , several hydrophobic domains were identified that are typical of a nidovirus replicase .", "label": "finding"}, {"segment_text": "Within the pp1b sequence the polymerase and helicase domains were identified ,", "label": "finding"}, {"segment_text": "as well as sequences predicted to be involved in ribosomal frameshifting ,", "label": "finding"}, {"segment_text": "including the conserved slippery sequence UUUAAAC and two potential pseudoknot structures .", "label": "finding"}], "n_segments": 16}
{"paper_id": "6aa71c592c9d4b88f0289992efbf5ce7f34bb335", "title": "Influenza A virus infection induces liver injury in mice", "coda_paper_id": 1318, "has_expert_labels": false, "abstract_text": "Respiratory infections such as SARS-CoV in humans are often accompanied by mild and self-limiting hepatitis . As a respiratory disease , influenza A virus ( IAV ) infection can lead to hepatitis , but the mechanism remains unclear . This study aimed to investigate the occurrence of hepatitis by establishing a model for infected mice for three different subtypes of respiratory IAVs ( H1N1 , H5N1 , and H7N2 ) . Histological analysis was performed , and results showed increase serum aminotransferase ( ALT and AST ) levels and evident liver injury on days 3 and 7 , especially on day 5 post infection . Immunohistochemistry ( IHC ) results indicated a wide distribution of IAV 's positive signals in the liver of infected mice . Real-time PCR results further revealed a similar viral titer to IHC that presented a remarkedly positive correlation with histology injury . All these data showed that the mouse model suitably contributed valuable information about the mechanism underlying the occurrence of hepatitis induced by respiratory influenza virus .", "gold_segments": [{"segment_text": "Respiratory infections such as SARS-CoV in humans are often accompanied by mild and self-limiting hepatitis .", "label": "background"}, {"segment_text": "As a respiratory disease , influenza A virus ( IAV ) infection can lead to hepatitis ,", "label": "background"}, {"segment_text": "but the mechanism remains unclear .", "label": "background"}, {"segment_text": "This study aimed to investigate the occurrence of hepatitis by establishing a model for infected mice for three different subtypes of respiratory IAVs ( H1N1 , H5N1 , and H7N2 ) .", "label": "purpose"}, {"segment_text": "Histological analysis was performed , and results showed increase serum aminotransferase ( ALT and AST ) levels and evident liver injury on days 3 and 7 ,", "label": "method"}, {"segment_text": "especially on day 5 post infection .", "label": "method"}, {"segment_text": "Immunohistochemistry ( IHC ) results indicated a wide distribution of IAV 's positive signals in the liver of infected mice .", "label": "finding"}, {"segment_text": "Real-time PCR results further revealed a similar viral titer to IHC that presented a remarkedly positive correlation with histology injury .", "label": "finding"}, {"segment_text": "All these data showed that the mouse model suitably contributed valuable information about the mechanism underlying the occurrence of hepatitis induced by respiratory influenza virus .", "label": "finding"}], "n_segments": 9}
{"paper_id": "9c168a74dca383f46fc14047b00fc38ecd012826", "title": "Recent trends on hydrogels based drug delivery systems for infectious diseases", "coda_paper_id": 1444, "has_expert_labels": false, "abstract_text": "For centuries , the rapid spread and cure of infectious diseases have been a major concern to the progress and survival of humans . These diseases are the global burden and the prominent cause for the worldwide deaths and disability . Nanomedicine has emerged as the most excellent tool to eradicate and halt their spread . Various nanoformulations ( NFs ) using advanced nanotechnology are in demand . Recently , hydrogel and nanogel based drug delivery devices poses new prospects to simulate the natural intelligence of various biological systems . Owing to their unique porous interpenetrating network design , hydrophobic drug incorporation and stimulus sensitivity hydrogels owe excellent potential as targeted drug delivery system . Present review is an attempt to highlight the recent trends of hydrogel based drug delivery systems for the delivery of therapeutic agents and diagnostics for the major infectious diseases including Acquired immune deficiency syndrome ( AIDS ) , Malaria , Tuberculosis , Influenza and Ebola . Future prospective and challenges are also briefed . Nanomedicine actively target locations by the use of various NFs 14 as a DDS which include nanoparticles , 8 polymeric micelles , 15 , 16 nanorods , 17 , 18 nanospheres , 19 , 20 solid lipid nanoparticles , 21 , 22 nanolipososmes , 23 , 24 dendrimers , 25 , 26 metal nanoparticles 27 , 28 , fullerenes and quantum dots . 29 , 30 These NFs have been useful in the development of the various different routes like systemic , oral , pulmonary , transdermal and have been helpful for the drug targeting and On-demand drug delivery techniques . 31 The technologies of Vashist et al. .", "gold_segments": [{"segment_text": "For centuries , the rapid spread and cure of infectious diseases have been a major concern to the progress and survival of humans .", "label": "background"}, {"segment_text": "These diseases are the global burden and the prominent cause for the worldwide deaths and disability .", "label": "background"}, {"segment_text": "Nanomedicine has emerged as the most excellent tool to eradicate and halt their spread .", "label": "background"}, {"segment_text": "Various nanoformulations ( NFs ) using advanced nanotechnology are in demand .", "label": "background"}, {"segment_text": "Recently , hydrogel and nanogel based drug delivery devices poses new prospects to simulate the natural intelligence of various biological systems .", "label": "background"}, {"segment_text": "Owing to their unique porous interpenetrating network design ,", "label": "background"}, {"segment_text": "hydrophobic drug incorporation and stimulus sensitivity hydrogels owe excellent potential as targeted drug delivery system .", "label": "background"}, {"segment_text": "Present review is an attempt to highlight the recent trends of hydrogel based drug delivery systems for the delivery of therapeutic agents and diagnostics for the major infectious diseases including Acquired immune deficiency syndrome ( AIDS ) ,", "label": "purpose"}, {"segment_text": "Malaria , Tuberculosis , Influenza and Ebola .", "label": "purpose"}, {"segment_text": "Future prospective and challenges are also briefed .", "label": "purpose"}, {"segment_text": "Nanomedicine actively target locations by the use of various NFs 14 as a DDS which include nanoparticles ,", "label": "finding"}, {"segment_text": "8 polymeric micelles , 15 ,", "label": "finding"}, {"segment_text": "16 nanorods , 17 , 18 nanospheres ,", "label": "finding"}, {"segment_text": "19 , 20 solid lipid nanoparticles ,", "label": "finding"}, {"segment_text": "21 , 22 nanolipososmes , 23 ,", "label": "finding"}, {"segment_text": "24 dendrimers , 25 , 26 metal nanoparticles 27 ,", "label": "finding"}, {"segment_text": "28 , fullerenes and quantum dots .", "label": "finding"}, {"segment_text": "29 , 30 These NFs have been useful in the development of the various different routes like systemic ,", "label": "finding"}, {"segment_text": "oral , pulmonary , transdermal and have been helpful for the drug targeting and On-demand drug delivery techniques .", "label": "finding"}, {"segment_text": "31 The technologies of Vashist et al. .", "label": "finding"}], "n_segments": 20}
{"paper_id": "ac9c190668aef9289bef4bf4e3c7716b2e334d86", "title": "First detection and molecular identification of Borrelia species in Bactrian camel (Camelus bactrianus) from Northwest China", "coda_paper_id": 1642, "has_expert_labels": false, "abstract_text": "Comprehensive epidemiological surveys for Lyme disease have not been conducted for the Bactrian camel in China . In this study , a total of 138 blood specimens collected from Bactrian camels from Zhangye City in Gansu Province and Yili and Aksu in Xinjiang Province , China , were examined for the presence of Borrelia spp. . Speciesspecificity nested PCR based on the 5S-23S rRNA , OspA , flaB and 16S rRNA genes revealed that the total positive rate of Borrelia spp. was 3.6 % ( 5/138 , 95 % CI = 0.2-17.9 ) . These results were confirmed by sequence analysis of the positive PCR products or positive colonies . This is the first report of Borrelia pathogens in camels in China . Two Borrelia species that cause Lyme disease and one that causes relapsing fever were identified in the camel blood samples by sequencing . The findings of this study indicate that the Bactrian camel may serve as a potential natural host of Lyme disease and/or relapsing fever in China .", "gold_segments": [{"segment_text": "Comprehensive epidemiological surveys for Lyme disease have not been conducted for the Bactrian camel in China .", "label": "background"}, {"segment_text": "In this study , a total of 138 blood specimens collected from Bactrian camels from Zhangye City in Gansu Province and Yili and Aksu in Xinjiang Province ,", "label": "method"}, {"segment_text": "China , were examined for the presence of Borrelia spp. .", "label": "method"}, {"segment_text": "Speciesspecificity nested PCR based on the 5S-23S rRNA ,", "label": "background"}, {"segment_text": "OspA , flaB and 16S rRNA genes revealed that the total positive rate of Borrelia spp. was 3.6 % ( 5/138 , 95 % CI = 0.2-17.9 ) .", "label": "finding"}, {"segment_text": "These results were confirmed by sequence analysis of the positive PCR products or positive colonies .", "label": "finding"}, {"segment_text": "This is the first report of Borrelia pathogens in camels in China .", "label": "finding"}, {"segment_text": "Two Borrelia species that cause Lyme disease and one that causes relapsing fever were identified in the camel blood samples by sequencing .", "label": "finding"}, {"segment_text": "The findings of this study indicate that the Bactrian camel may serve as a potential natural host of Lyme disease and/or relapsing fever in China .", "label": "finding"}], "n_segments": 9}
{"paper_id": "7e5ab55e74c377b2a3bd936030ffe0f92d4c2a78", "title": "Candida auris: A Review of Recommendations for Detection and Control in Healthcare Settings", "coda_paper_id": 1249, "has_expert_labels": false, "abstract_text": "Candida auris is an emerging multidrug-resistant fungal pathogen . Since first reported in 2009 , C. auris has caused healthcare outbreaks around the world , often involving high mortality . Identification of C. auris has been a major challenge as many common conventional laboratory methods can not accurately detect it . Early detection and implementation of infection control practices can prevent its spread . The aim of this review is to describe recommendations for the detection and control of C. auris in healthcare settings . most common misidentifications based on frequently used yeast identification methods ( 5 , 6 ) . However , efforts to improve C. auris identification methods have made substantial progress in the last few years . The development of a high-salt , high-temperature enrichment culture-based method has made it possible to reliably isolate C. auris from complex sample types ( 7 ) ( 8 ) ( 9 ) . Once an isolate is obtained , identification of C. auris can be efficiently accomplished with matrix-assisted laser desorption/ionization time-of-flight ( MALDI-TOF ) mass spectrometry . For MALDI-TOF identification , it is important to ensure C. auris is in the reference database ( 5 , 6 , 10 ) . The Bruker Biotyper ( Bruker Daltonik GmbH , Bremen , Germany ) and the VITEK MS ( bioMérieux , Marcy , L'Etoile , France ) include C. auris in their Research Use Only and certain versions of their FDA-approved system databases ( 3 , 5 , 11 ) . If MALDI-TOF is not available , laboratories can reliably identify an isolate by sequencing the D1-D2 region of the 28s rDNA or the internal transcribed spacer ( ITS ) regions of rDNA ( 12 ) ( 13 ) ( 14 ) .", "gold_segments": [{"segment_text": "Candida auris is an emerging multidrug-resistant fungal pathogen .", "label": "background"}, {"segment_text": "Since first reported in 2009 ,", "label": "background"}, {"segment_text": "C. auris has caused healthcare outbreaks around the world , often involving high mortality .", "label": "background"}, {"segment_text": "Identification of C. auris has been a major challenge as many common conventional laboratory methods can not accurately detect it .", "label": "background"}, {"segment_text": "Early detection and implementation of infection control practices can prevent its spread .", "label": "background"}, {"segment_text": "The aim of this review is to describe recommendations for the detection and control of C. auris in healthcare settings .", "label": "purpose"}, {"segment_text": "most common misidentifications based on frequently used yeast identification methods ( 5 , 6 ) .", "label": "purpose"}, {"segment_text": "However , efforts to improve C. auris identification methods have made substantial progress in the last few years .", "label": "finding"}, {"segment_text": "The development of a high-salt ,", "label": "method"}, {"segment_text": "high-temperature enrichment culture-based method has made it possible to reliably isolate C. auris from complex sample types ( 7 ) ( 8 ) ( 9 ) .", "label": "method"}, {"segment_text": "Once an isolate is obtained ,", "label": "method"}, {"segment_text": "identification of C. auris can be efficiently accomplished with matrix-assisted laser desorption/ionization time-of-flight ( MALDI-TOF ) mass spectrometry .", "label": "method"}, {"segment_text": "For MALDI-TOF identification , it is important to ensure C. auris is in the reference database ( 5 , 6 , 10 ) .", "label": "method"}, {"segment_text": "The Bruker Biotyper ( Bruker Daltonik GmbH , Bremen , Germany ) and the VITEK MS ( bioMérieux , Marcy , L'Etoile , France ) include C. auris in their Research Use Only and certain versions of their FDA-approved system databases ( 3 , 5 , 11 ) .", "label": "finding"}, {"segment_text": "If MALDI-TOF is not available ,", "label": "finding"}, {"segment_text": "laboratories can reliably identify an isolate by sequencing the D1-D2 region of the 28s rDNA or the internal transcribed spacer ( ITS ) regions of rDNA ( 12 ) ( 13 ) ( 14 ) .", "label": "finding"}], "n_segments": 16}
{"paper_id": "c51941cdb6e0b6a2f023a8cfab8627ee78f31241", "title": "Disorders of Movement Key Points", "coda_paper_id": 1095, "has_expert_labels": false, "abstract_text": "Disorders of movement can present to the emergency department as new complaints or as an exacerbation of a known condition . Without a prior diagnosis , the etiologies of movement disorders are diffi cult to differentiate .", "gold_segments": [{"segment_text": "Disorders of movement can present to the emergency department as new complaints or as an exacerbation of a known condition .", "label": "background"}, {"segment_text": "Without a prior diagnosis , the etiologies of movement disorders are diffi cult to differentiate .", "label": "background"}], "n_segments": 2}
{"paper_id": "0cca2b3547f329ac1ade31d793e0aceae8cb7af5", "title": "Epidemiologic features of Kawasaki disease in acute stages in Taiwan, 1997e2010: Effect of different case definitions in claims data analysis", "coda_paper_id": 1646, "has_expert_labels": false, "abstract_text": "Background : Kawasaki disease is the leading cause of pediatric acquired cardiac disease in many industrialized countries . The aim of this study was to estimate the incidence of Kawasaki disease in acute stages in Taiwan , by linking the diagnosis code to medication and comparing the differences in epidemiological features with those of previous reports that used the diagnosis code alone . Methods : We searched the National Health Insurance Research Database from 1997 to 2010 . For the International Classification of Diseases , Ninth Revision ( ICD-9 ) set , all inpatients with a main diagnosis of Kawasaki disease ( ICD-9 , 446.1 ) were retrieved . For the ICD-9 þ intravenous immunoglobulin ( IVIG ) set , Kawasaki disease in acute stages was defined as the disease stages requiring IVIG . The epidemiologic features were calculated and compared by both methods . Results : The incidence rates for children under 5 years ranged from 21.5 to 68.5 per 100,000 person-years ( average 49.1 ) for the ICD-9 þ IVIG set and from 48.5 to 82.8 per 100,000 person-years ( average 74.9 ) for the ICD-9 set . Significant discrepancy in peak season estimation occurred in summer . The 5-year recurrence rate was 1.1 % for the ICD-9 þ IVIG set and 4.5 % for the ICD-9 set . The coronary complication rates were around 7.24 % ( ICD-9 þ IVIG ) and 6.48 % ( ICD-9 ) . Conclusion : Discrepancies occurred when different case definitions were used in claims data analysis . Previous reports might have overestimated the incidence , recurrence rate , and complication rate in older children . The new method might slightly underestimate them . The true incidence might lie in between .", "gold_segments": [{"segment_text": "Background : Kawasaki disease is the leading cause of pediatric acquired cardiac disease in many industrialized countries .", "label": "background"}, {"segment_text": "The aim of this study was to estimate the incidence of Kawasaki disease in acute stages in Taiwan ,", "label": "purpose"}, {"segment_text": "by linking the diagnosis code to medication and comparing the differences in epidemiological features with those of previous reports that used the diagnosis code alone .", "label": "purpose"}, {"segment_text": "Methods : We searched the National Health Insurance Research Database from 1997 to 2010 .", "label": "method"}, {"segment_text": "For the International Classification of Diseases ,", "label": "method"}, {"segment_text": "Ninth Revision ( ICD-9 ) set ,", "label": "method"}, {"segment_text": "all inpatients with a main diagnosis of Kawasaki disease ( ICD-9 , 446.1 ) were retrieved .", "label": "method"}, {"segment_text": "For the ICD-9 þ intravenous immunoglobulin ( IVIG ) set ,", "label": "method"}, {"segment_text": "Kawasaki disease in acute stages was defined as the disease stages requiring IVIG .", "label": "method"}, {"segment_text": "The epidemiologic features were calculated and compared by both methods .", "label": "method"}, {"segment_text": "Results : The incidence rates for children under 5 years ranged from 21.5 to 68.5 per 100,000 person-years ( average 49.1 ) for the ICD-9 þ IVIG set and from 48.5 to 82.8 per 100,000 person-years ( average 74.9 ) for the ICD-9 set .", "label": "finding"}, {"segment_text": "Significant discrepancy in peak season estimation occurred in summer .", "label": "finding"}, {"segment_text": "The 5-year recurrence rate was 1.1 % for the ICD-9 þ IVIG set and 4.5 % for the ICD-9 set .", "label": "finding"}, {"segment_text": "The coronary complication rates were around 7.24 % ( ICD-9 þ IVIG ) and 6.48 % ( ICD-9 ) .", "label": "finding"}, {"segment_text": "Conclusion : Discrepancies occurred when different case definitions were used in claims data analysis .", "label": "finding"}, {"segment_text": "Previous reports might have overestimated the incidence ,", "label": "finding"}, {"segment_text": "recurrence rate , and complication rate in older children .", "label": "finding"}, {"segment_text": "The new method might slightly underestimate them .", "label": "finding"}, {"segment_text": "The true incidence might lie in between .", "label": "finding"}], "n_segments": 19}
{"paper_id": "bb9fa420cb74aed846df2a44a6cbd0991d2b2e59", "title": "A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor", "coda_paper_id": 1804, "has_expert_labels": false, "abstract_text": "Lycorine potently inhibits flaviviruses in cell culture . At 1.2-μM concentration , lycorine reduced viral titers of West Nile ( WNV ) , dengue , and yellow fever viruses by 10 2 - to 10 4 - fold . However , the compound did not inhibit an alphavirus ( Western equine encephalitis virus ) or a rhabdovirus ( vesicular stomatitis virus ) , indicating a selective antiviral spectrum . The compound exerts its antiviral activity mainly through suppression of viral RNA replication . A Val → Met substitution at the 9th amino acid position of the viral 2K peptide ( spanning the endoplasmic reticulum membrane between NS4A and NS4B proteins ) confers WNV resistance to lycorine , through enhancement of viral RNA replication . Initial chemistry synthesis demonstrated that modifications of the two hydroxyl groups of lycorine can increase the compound 's potency , while reducing its cytotoxicity . Taken together , the results have established lycorine as a flavivirus inhibitor for antiviral development . The lycorine-resistance results demonstrate a direct role of the 2K peptide in flavivirus RNA synthesis .", "gold_segments": [{"segment_text": "Lycorine potently inhibits flaviviruses in cell culture .", "label": "background"}, {"segment_text": "At 1.2-μM concentration , lycorine reduced viral titers of West Nile ( WNV ) ,", "label": "background"}, {"segment_text": "dengue , and yellow fever viruses by 10 2 - to 10 4 - fold .", "label": "background"}, {"segment_text": "However , the compound did not inhibit an alphavirus ( Western equine encephalitis virus ) or a rhabdovirus ( vesicular stomatitis virus ) ,", "label": "finding"}, {"segment_text": "indicating a selective antiviral spectrum .", "label": "finding"}, {"segment_text": "The compound exerts its antiviral activity mainly through suppression of viral RNA replication .", "label": "finding"}, {"segment_text": "A Val → Met substitution at the 9th amino acid position of the viral 2K peptide ( spanning the endoplasmic reticulum membrane between NS4A and NS4B proteins ) confers WNV resistance to lycorine ,", "label": "method"}, {"segment_text": "through enhancement of viral RNA replication .", "label": "method"}, {"segment_text": "Initial chemistry synthesis demonstrated that modifications of the two hydroxyl groups of lycorine can increase the compound 's potency , while reducing its cytotoxicity .", "label": "finding"}, {"segment_text": "Taken together , the results have established lycorine as a flavivirus inhibitor for antiviral development .", "label": "finding"}, {"segment_text": "The lycorine-resistance results demonstrate a direct role of the 2K peptide in flavivirus RNA synthesis .", "label": "finding"}], "n_segments": 11}
{"paper_id": "57bbc22ad086f88af0cfe1c98bc66ef7a61c8ae6", "title": "A Consensus Action Agenda for Achieving the National Health Information Infrastructure Consensus Action Agenda for Achieving the NHII", "coda_paper_id": 1193, "has_expert_labels": false, "abstract_text": "A b s t r a c t Background : Improving the safety , quality , and efficiency of health care will require immediate and ubiquitous access to complete patient information and decision support provided through a National Health Information Infrastructure ( NHII ) . Methods : To help define the action steps needed to achieve an NHII , the U.S. Department of Health and Human Services sponsored a national consensus conference in July 2003 . Results : Attendees favored a public-private coordination group to guide NHII activities , provide education , share resources , and monitor relevant metrics to mark progress . They identified financial incentives , health information standards , and overcoming a few important legal obstacles as key NHII enablers . Community and regional implementation projects , including consumer access to a personal health record , were seen as necessary to demonstrate comprehensive functional systems that can serve as models for the entire nation . Finally , the participants identified the need for increased funding for research on the impact of health information technology on patient safety and quality of care . Individuals , organizations , and federal agencies are using these consensus recommendations to guide NHII efforts .", "gold_segments": [{"segment_text": "A b s t r a c t Background : Improving the safety ,", "label": "background"}, {"segment_text": "quality , and efficiency of health care will require immediate and ubiquitous access to complete patient information and decision support provided through a National Health Information Infrastructure ( NHII ) .", "label": "background"}, {"segment_text": "Methods : To help define the action steps needed to achieve an NHII ,", "label": "method"}, {"segment_text": "the U.S. Department of Health and Human Services sponsored a national consensus conference in July 2003 .", "label": "method"}, {"segment_text": "Results : Attendees favored a public-private coordination group to guide NHII activities ,", "label": "finding"}, {"segment_text": "provide education , share resources ,", "label": "finding"}, {"segment_text": "and monitor relevant metrics to mark progress .", "label": "finding"}, {"segment_text": "They identified financial incentives , health information standards ,", "label": "finding"}, {"segment_text": "and overcoming a few important legal obstacles as key NHII enablers .", "label": "finding"}, {"segment_text": "Community and regional implementation projects ,", "label": "finding"}, {"segment_text": "including consumer access to a personal health record ,", "label": "finding"}, {"segment_text": "were seen as necessary to demonstrate comprehensive functional systems that can serve as models for the entire nation .", "label": "finding"}, {"segment_text": "Finally , the participants identified the need for increased funding for research on the impact of health information technology on patient safety and quality of care .", "label": "finding"}, {"segment_text": "Individuals , organizations , and federal agencies are using these consensus recommendations to guide NHII efforts .", "label": "finding"}], "n_segments": 14}
{"paper_id": "71355d22c1570abb0e9d250b892e540b2c0a68f3", "title": "Detection of infectious canine parvovirus type 2 by mRNA real-time RT-PCR", "coda_paper_id": 1632, "has_expert_labels": false, "abstract_text": "A TaqMan real-time RT-PCR assay was developed for detection of RNA transcripts produced by replicating CPV-2 . A pair of primers and a TaqMan probe targeting the spliced NS2 mRNA were designed . A synthetic DNA fragment was constructed to mimic the spliced NS2 mRNA by PCR-based gene assembly and was used for generation of standard RNAs . The detection limit of the assay was 1 × 10 2 RNA copies and standard curve displayed a linear range from 1 × 10 2 to 1 × 10 9 copies and a good reproducibility . The assay was then applied to determine the mRNA loads in the tissues of dogs naturally infected by CPV-2 . mRNA was detected in a variety of tissues , including the central nervous system .", "gold_segments": [{"segment_text": "A TaqMan real-time RT-PCR assay was developed for detection of RNA transcripts produced by replicating CPV-2 .", "label": "method"}, {"segment_text": "A pair of primers and a TaqMan probe targeting the spliced NS2 mRNA were designed .", "label": "method"}, {"segment_text": "A synthetic DNA fragment was constructed to mimic the spliced NS2 mRNA by PCR-based gene assembly and was used for generation of standard RNAs .", "label": "method"}, {"segment_text": "The detection limit of the assay was 1 × 10 2 RNA copies and standard curve displayed a linear range from 1 × 10 2 to 1 × 10 9 copies and a good reproducibility .", "label": "method"}, {"segment_text": "The assay was then applied to determine the mRNA loads in the tissues of dogs naturally infected by CPV-2 .", "label": "method"}, {"segment_text": "mRNA was detected in a variety of tissues ,", "label": "finding"}, {"segment_text": "including the central nervous system .", "label": "finding"}], "n_segments": 7}
{"paper_id": "cf01ed843b6e8860b8a87c629852805514d149ae", "title": "Mycobacterium tuberculosis pili (MTP), a putative biomarker for a tuberculosis diagnostic test", "coda_paper_id": 1278, "has_expert_labels": false, "abstract_text": "Point of care test Pili Mycobacterial pili Biomarker s u m m a r y Novel biomarkers are urgently needed for point of care TB diagnostics . In this study , we investigated the potential of the pilin subunit protein encoded by the mtp gene as a diagnostic biomarker . BLAST analysis of the mtp gene on published genome databases , and amplicon sequencing were performed in Mycobacterium tuberculosis Complex ( MTBC ) strains and other organisms . The protein secondary structure of the amino acid sequences of non-tuberculous Mycobacteria that partially aligned with the mtp sequence was analysed with PredictProtein software . The mtp gene and corresponding amino acid sequence of MTBC were 100 % homologous with H37Rv , in contrast to the partial alignment of the non-tuberculous Mycobacteria . The mtp gene was present in all 91 clinical isolates of MTBC . Except for 2 strains with point mutations , the sequence was 100 % conserved among the clinical strains . The mtp gene could not be amplified in all non-tuberculous Mycobacteria and respiratory organisms . The predicted MTP protein structure of Mycobacterium avium , Mycobacterium ulcerans and Mycobacterium abscessus differed significantly from that of the M. tuberculosis , which was similar to Mycobacterium marinum . The absence of the mtp gene in non-tuberculous Mycobacteria and other respiratory bacteria suggests that its encoded product , the pilin subunit protein of M. tuberculosis may be a suitable marker for a point of care TB test .", "gold_segments": [{"segment_text": "Point of care test Pili Mycobacterial pili Biomarker s u m m a r y", "label": "background"}, {"segment_text": "Novel biomarkers are urgently needed for point of care TB diagnostics .", "label": "background"}, {"segment_text": "In this study , we investigated the potential of the pilin subunit protein encoded by the mtp gene as a diagnostic biomarker .", "label": "purpose"}, {"segment_text": "BLAST analysis of the mtp gene on published genome databases ,", "label": "method"}, {"segment_text": "and amplicon sequencing were performed in Mycobacterium tuberculosis Complex ( MTBC ) strains and other organisms .", "label": "method"}, {"segment_text": "The protein secondary structure of the amino acid sequences of non-tuberculous Mycobacteria that partially aligned with the mtp sequence was analysed with PredictProtein software .", "label": "method"}, {"segment_text": "The mtp gene and corresponding amino acid sequence of MTBC were 100 % homologous with H37Rv ,", "label": "finding"}, {"segment_text": "in contrast to the partial alignment of the non-tuberculous Mycobacteria .", "label": "finding"}, {"segment_text": "The mtp gene was present in all 91 clinical isolates of MTBC .", "label": "finding"}, {"segment_text": "Except for 2 strains with point mutations ,", "label": "finding"}, {"segment_text": "the sequence was 100 % conserved among the clinical strains .", "label": "finding"}, {"segment_text": "The mtp gene could not be amplified in all non-tuberculous Mycobacteria and respiratory organisms .", "label": "finding"}, {"segment_text": "The predicted MTP protein structure of Mycobacterium avium ,", "label": "finding"}, {"segment_text": "Mycobacterium ulcerans and Mycobacterium abscessus differed significantly from that of the M. tuberculosis ,", "label": "finding"}, {"segment_text": "which was similar to Mycobacterium marinum .", "label": "finding"}, {"segment_text": "The absence of the mtp gene in non-tuberculous Mycobacteria and other respiratory bacteria suggests that its encoded product ,", "label": "finding"}, {"segment_text": "the pilin subunit protein of M. tuberculosis may be a suitable marker for a point of care TB test .", "label": "finding"}], "n_segments": 17}
{"paper_id": "5a63d131a9fdbdb837c56458c72d6e29942c1fb9", "title": "Cytokine Immunopathogenesis of Enterovirus 71 Brain Stem Encephalitis", "coda_paper_id": 1525, "has_expert_labels": false, "abstract_text": "Enterovirus 71 ( EV71 ) is one of the most important causes of herpangina and hand , foot , and mouth disease . It can also cause severe complications of the central nervous system ( CNS ) . Brain stem encephalitis with pulmonary edema is the severe complication that can lead to death . EV71 replicates in leukocytes , endothelial cells , and dendritic cells resulting in the production of immune and inflammatory mediators that shape innate and acquired immune responses and the complications of disease . Cytokines , as a part of innate immunity , favor the development of antiviral and Th1 immune responses . Cytokines and chemokines play an important role in the pathogenesis EV71 brain stem encephalitis . Both the CNS and the systemic inflammatory responses to infection play important , but distinctly different , roles in the pathogenesis of EV71 pulmonary edema . Administration of intravenous immunoglobulin and milrinone , a phosphodiesterase inhibitor , has been shown to modulate inflammation , to reduce sympathetic overactivity , and to improve survival in patients with EV71 autonomic nervous system dysregulation and pulmonary edema .", "gold_segments": [{"segment_text": "Enterovirus 71 ( EV71 ) is one of the most important causes of herpangina and hand ,", "label": "background"}, {"segment_text": "foot , and mouth disease .", "label": "background"}, {"segment_text": "It can also cause severe complications of the central nervous system ( CNS ) .", "label": "background"}, {"segment_text": "Brain stem encephalitis with pulmonary edema is the severe complication that can lead to death .", "label": "background"}, {"segment_text": "EV71 replicates in leukocytes , endothelial cells ,", "label": "background"}, {"segment_text": "and dendritic cells resulting in the production of immune and inflammatory mediators that shape innate and acquired immune responses and the complications of disease .", "label": "background"}, {"segment_text": "Cytokines , as a part of innate immunity ,", "label": "background"}, {"segment_text": "favor the development of antiviral and Th1 immune responses .", "label": "background"}, {"segment_text": "Cytokines and chemokines play an important role in the pathogenesis EV71 brain stem encephalitis .", "label": "background"}, {"segment_text": "Both the CNS and the systemic inflammatory responses to infection play important ,", "label": "background"}, {"segment_text": "but distinctly different , roles in the pathogenesis of EV71 pulmonary edema .", "label": "background"}, {"segment_text": "Administration of intravenous immunoglobulin and milrinone ,", "label": "finding"}, {"segment_text": "a phosphodiesterase inhibitor , has been shown to modulate inflammation ,", "label": "finding"}, {"segment_text": "to reduce sympathetic overactivity , and to improve survival in patients with EV71 autonomic nervous system dysregulation and pulmonary edema .", "label": "finding"}], "n_segments": 14}
{"paper_id": "745f78dadf6e5a2feb79900688cd5fb9ead4d72e", "title": "Evaluation of Anti-Toxoplasma gondii Effect of Ursolic Acid as a Novel Toxoplasmosis Inhibitor", "coda_paper_id": 1776, "has_expert_labels": false, "abstract_text": "This study was carried out to evaluate the anti-parasitic effect of ursolic acid against Toxoplasma gondii ( T. gondii ) that induces toxoplasmosis , particularly in humans . The anti-parasitic effects of ursolic acid against T. gondii-infected cells and T. gondii were evaluated through different specific assays , including immunofluorescence staining and animal testing . Ursolic acid effectively inhibited the proliferation of T. gondii when compared with sulfadiazine , and consistently induced anti-T . gondii activity/effect . In particular , the formation of parasitophorous vacuole membrane ( PVM ) in host cells was markedly decreased after treating ursolic acid , which was effectively suppressed . Moreover , the survival rate of T. gondii was strongly inhibited in T. gondii group treated with ursolic acid , and then 50 % inhibitory concentration ( IC 50 ) against T. gondii was measured as 94.62 µg/mL . The T. gondii-infected mice treated with ursolic acid indicated the same survival rates and activity as the normal group . These results demonstrate that ursolic acid causes anti-T . gondii action and effect by strongly blocking the proliferation of T. gondii through the direct and the selective T. gondii-inhibitory ability as well as increases the survival of T. gondii-infected mice . This study shows that ursolic acid has the potential to be used as a promising anti-T . gondii candidate substance for developing effective anti-parasitic drugs .", "gold_segments": [{"segment_text": "This study was carried out to evaluate the anti-parasitic effect of ursolic acid against Toxoplasma gondii ( T. gondii ) that induces toxoplasmosis , particularly in humans .", "label": "purpose"}, {"segment_text": "The anti-parasitic effects of ursolic acid against T. gondii-infected cells and T. gondii were evaluated through different specific assays ,", "label": "method"}, {"segment_text": "including immunofluorescence staining and animal testing .", "label": "method"}, {"segment_text": "Ursolic acid effectively inhibited the proliferation of T. gondii when compared with sulfadiazine , and consistently induced anti-T .", "label": "finding"}, {"segment_text": "gondii activity/effect .", "label": "finding"}, {"segment_text": "In particular , the formation of parasitophorous vacuole membrane ( PVM ) in host cells was markedly decreased after treating ursolic acid , which was effectively suppressed .", "label": "finding"}, {"segment_text": "Moreover , the survival rate of T. gondii was strongly inhibited in T. gondii group treated with ursolic acid ,", "label": "finding"}, {"segment_text": "and then 50 % inhibitory concentration ( IC 50 ) against T. gondii was measured as 94.62 µg/mL .", "label": "finding"}, {"segment_text": "The T. gondii-infected mice treated with ursolic acid indicated the same survival rates and activity as the normal group .", "label": "finding"}, {"segment_text": "These results demonstrate that ursolic acid causes anti-T .", "label": "finding"}, {"segment_text": "gondii action and effect by strongly blocking the proliferation of T. gondii through the direct and the selective T. gondii-inhibitory ability as well as increases the survival of T. gondii-infected mice .", "label": "finding"}, {"segment_text": "This study shows that ursolic acid has the potential to be used as a promising anti-T .", "label": "finding"}, {"segment_text": "gondii candidate substance for developing effective anti-parasitic drugs .", "label": "finding"}], "n_segments": 13}
{"paper_id": "9e31c7e67f3b134791cbe0adf9f4c636540a2656", "title": "Molecular characterization of the spike gene of the porcine epidemic diarrhea virus in Mexico, 2013-2016", "coda_paper_id": 1178, "has_expert_labels": false, "abstract_text": "In Mexico , the first outbreaks suggestive of the circulation of the porcine epidemic diarrhea virus ( PEDV ) were identified at the beginning of July 2013 . To identify the molecular characteristics of the PEDV Spike ( S ) gene in Mexico , 116 samples of the intestine and diarrhea of piglets with clinical signs of porcine epidemic diarrhea ( PED ) were obtained . Samples were collected from 14 farms located in six states of Mexico ( Jalisco , Puebla , Sonora , Veracruz , Guanajuato , and Michoacán ) from 2013 to 2016 . To identify PEDV , we used real-time RT-PCR to discriminate between non-INDEL and INDEL strains . We chose samples according to state and year to characterize the S gene . After amplification of the S gene , the obtained products were sequenced and assembled . The complete amino acid sequences of the spike protein were used to perform an epitope analysis , which was used to determine null mutations in regions SS2 , SS6 , and 2C10 compared to the sequences of G2 . A phylogenetic analysis determined the circulation of G2b and INDEL strains in Mexico . However , several mutations were recorded in the collagenase equivalent ( COE ) region that were related to the change in polarity and charge of the amino acid residues . The PEDV strain circulating in Jalisco in 2016 has an insertion of three amino acids ( 232 LGL 234 ) and one change in the antigenic site of the COE region , and strains from the years 2015 and 2016 changed the index of the surface probability , which could be related to the re-emergence of disease outbreaks .", "gold_segments": [{"segment_text": "In Mexico , the first outbreaks suggestive of the circulation of the porcine epidemic diarrhea virus ( PEDV ) were identified at the beginning of July 2013 .", "label": "background"}, {"segment_text": "To identify the molecular characteristics of the PEDV Spike ( S ) gene in Mexico ,", "label": "purpose"}, {"segment_text": "116 samples of the intestine and diarrhea of piglets with clinical signs of porcine epidemic diarrhea ( PED ) were obtained .", "label": "method"}, {"segment_text": "Samples were collected from 14 farms located in six states of Mexico ( Jalisco , Puebla , Sonora , Veracruz , Guanajuato , and Michoacán ) from 2013 to 2016 .", "label": "method"}, {"segment_text": "To identify PEDV , we used real-time RT-PCR to discriminate between non-INDEL and INDEL strains .", "label": "method"}, {"segment_text": "We chose samples according to state and year to characterize the S gene .", "label": "method"}, {"segment_text": "After amplification of the S gene ,", "label": "method"}, {"segment_text": "the obtained products were sequenced and assembled .", "label": "method"}, {"segment_text": "The complete amino acid sequences of the spike protein were used to perform an epitope analysis ,", "label": "method"}, {"segment_text": "which was used to determine null mutations in regions SS2 ,", "label": "method"}, {"segment_text": "SS6 , and 2C10 compared to the sequences of G2 .", "label": "method"}, {"segment_text": "A phylogenetic analysis determined the circulation of G2b and INDEL strains in Mexico .", "label": "finding"}, {"segment_text": "However , several mutations were recorded in the collagenase equivalent ( COE ) region that were related to the change in polarity and charge of the amino acid residues .", "label": "finding"}, {"segment_text": "The PEDV strain circulating in Jalisco in 2016 has an insertion of three amino acids ( 232 LGL 234 ) and one change in the antigenic site of the COE region ,", "label": "finding"}, {"segment_text": "and strains from the years 2015 and 2016 changed the index of the surface probability ,", "label": "finding"}, {"segment_text": "which could be related to the re-emergence of disease outbreaks .", "label": "finding"}], "n_segments": 16}
{"paper_id": "7684a38d0d7d2c6e65a82b43ec39ffa64fda2297", "title": "Age-and gender-related difference of ACE2 expression in rat lung", "coda_paper_id": 1931, "has_expert_labels": false, "abstract_text": "Epidemiologic data suggested that there was an obvious predominance of young adult patients with a slight female proneness in severe acute respiratory syndrome ( SARS ) . The angiotensin-converting enzyme 2 ( ACE2 ) was very recently identified as a functional receptor for SARS virus and is therefore a prime target for pathogenesis and pharmacological intervention . Rats of both genders at three distinct ages ( young-adult , 3 months ; middle-aged , 12 months ; old , 24 months ) were evaluated to determine the characteristic of ACE2 expression in lung and the effect of aging and gender on its expression . ACE2 was predominantly expressed in alveolar epithelium , bronchiolar epithelium , endothelium and smooth muscle cells of pulmonary vessels with similar content , whereas no obvious signal was detected in the bronchiolar smooth muscle cells . ACE2 expression is dramatically reduced with aging in both genders : young-adult vs. old P < 0.001 ( by 78 % in male and 67 % in female , respectively ) and middle-aged vs. old P < 0.001 ( by 71 % in male rats and 59 % in female rats , respectively ) . The decrease of ACE2 content was relatively slight between young-adult and middle-aged groups ( by 25 % in male and 18 % in female , respectively ) . Although there was no gender-related difference of ACE2 in young-adult and middle-aged groups , a significantly higher ACE2 content was detected in old female rats than male . In conclusion , the more elevated ACE2 in young adults as compared to aged groups may contribute to the predominance in SARS attacks in this age group . D", "gold_segments": [{"segment_text": "Epidemiologic data suggested that there was an obvious predominance of young adult patients with a slight female proneness in severe acute respiratory syndrome ( SARS ) .", "label": "background"}, {"segment_text": "The angiotensin-converting enzyme 2 ( ACE2 ) was very recently identified as a functional receptor for SARS virus and is therefore a prime target for pathogenesis and pharmacological intervention .", "label": "background"}, {"segment_text": "Rats of both genders at three distinct ages ( young-adult , 3 months ; middle-aged , 12 months ; old , 24 months ) were evaluated to determine the characteristic of ACE2 expression in lung and the effect of aging and gender on its expression .", "label": "method"}, {"segment_text": "ACE2 was predominantly expressed in alveolar epithelium ,", "label": "finding"}, {"segment_text": "bronchiolar epithelium , endothelium and smooth muscle cells of pulmonary vessels with similar content ,", "label": "finding"}, {"segment_text": "whereas no obvious signal was detected in the bronchiolar smooth muscle cells .", "label": "finding"}, {"segment_text": "ACE2 expression is dramatically reduced with aging in both genders : young-adult vs. old P < 0.001 ( by 78 % in male and 67 % in female , respectively ) and middle-aged vs. old P < 0.001 ( by 71 % in male rats and 59 % in female rats , respectively ) .", "label": "finding"}, {"segment_text": "The decrease of ACE2 content was relatively slight between young-adult and middle-aged groups ( by 25 % in male and 18 % in female , respectively ) .", "label": "finding"}, {"segment_text": "Although there was no gender-related difference of ACE2 in young-adult and middle-aged groups ,", "label": "finding"}, {"segment_text": "a significantly higher ACE2 content was detected in old female rats than male .", "label": "finding"}, {"segment_text": "In conclusion , the more elevated ACE2 in young adults as compared to aged groups may contribute to the predominance in SARS attacks in this age group .", "label": "finding"}, {"segment_text": "D", "label": "other"}], "n_segments": 12}
{"paper_id": "9bd22fc1297bd20710ca26f6e79b6339d576bb74", "title": "Accelerated disease progression and robust innate host response in aged SIVmac239-infected Chinese rhesus macaques is associated with enhanced immunosenescence", "coda_paper_id": 1162, "has_expert_labels": false, "abstract_text": "The elderly population infected with HIV-1 is often characterized by the rapid AIDS progression and poor treatment outcome , possibly because of immunosenescence resulting from both HIV infection and aging . However , this hypothesis remains to be fully tested . Here , we studied 6 young and 12 old Chinese rhesus macaques ( ChRM ) over the course of three months after simian immunodeficiency virus ( SIV ) SIVmac239 infection . Old ChRM showed a higher risk of accelerated AIDS development than did young macaques , owing to rapidly elevated plasma viral loads and decreased levels of CD4 + T cells . The low frequency of naïve CD4 + T cells before infection was strongly predictive of an increased disease progression , whereas the severe depletion of CD4 + T cells and the rapid proliferation of naïve lymphocytes accelerated the exhaustion of naïve lymphocytes in old ChRM . Moreover , in old ChRM , a robust innate host response with defective regulation was associated with a compensation for naïve T cell depletion and a high level of immune activation . Therefore , we suggest that immunosenescence plays an important role in the accelerated AIDS progression in elderly individuals and that SIV-infected old ChRM may be a favorable model for studying AIDS pathogenesis and researching therapies for elderly AIDS patients . Published : xx xx xxxx OPEN www.nature.com/scientificreports/ 2 Scientific RepoRts | 7 : 37 |", "gold_segments": [{"segment_text": "The elderly population infected with HIV-1 is often characterized by the rapid AIDS progression and poor treatment outcome ,", "label": "background"}, {"segment_text": "possibly because of immunosenescence resulting from both HIV infection and aging .", "label": "background"}, {"segment_text": "However , this hypothesis remains to be fully tested .", "label": "background"}, {"segment_text": "Here , we studied 6 young and 12 old Chinese rhesus macaques ( ChRM ) over the course of three months after simian immunodeficiency virus ( SIV ) SIVmac239 infection .", "label": "background"}, {"segment_text": "Old ChRM showed a higher risk of accelerated AIDS development than did young macaques ,", "label": "finding"}, {"segment_text": "owing to rapidly elevated plasma viral loads and decreased levels of CD4 + T cells .", "label": "finding"}, {"segment_text": "The low frequency of naïve CD4 + T cells before infection was strongly predictive of an increased disease progression ,", "label": "finding"}, {"segment_text": "whereas the severe depletion of CD4 + T cells and the rapid proliferation of naïve lymphocytes accelerated the exhaustion of naïve lymphocytes in old ChRM .", "label": "finding"}, {"segment_text": "Moreover , in old ChRM ,", "label": "finding"}, {"segment_text": "a robust innate host response with defective regulation was associated with a compensation for naïve T cell depletion and a high level of immune activation .", "label": "finding"}, {"segment_text": "Therefore , we suggest that immunosenescence plays an important role in the accelerated AIDS progression in elderly individuals and that SIV-infected old ChRM may be a favorable model for studying AIDS pathogenesis and researching therapies for elderly AIDS patients .", "label": "finding"}, {"segment_text": "Published : xx xx xxxx OPEN www.nature.com/scientificreports/ 2 Scientific RepoRts | 7 : 37 |", "label": "finding"}], "n_segments": 12}
{"paper_id": "8cf02f23f08f2b7c8b0e83dcc85d080f9c1cf615", "title": "The Oakville Oil Refinery Closure and Its Influence on Local Hospitalizations: A Natural Experiment on Sulfur Dioxide", "coda_paper_id": 1463, "has_expert_labels": false, "abstract_text": "Background : An oil refinery in Oakville , Canada , closed over 2004Canada , closed over -2005 an opportunity for a natural experiment to examine the effects on oil refinery-related air pollution and residents ' health . Methods : Environmental and health data were collected for the 16 years around the refinery closure . Toronto ( 2.5 million persons ) and the Greater Toronto Area ( GTA , 6.3 million persons ) were used as control and reference populations , respectively , for Oakville ( 160,000 persons ) . We compared sulfur dioxide and age-and season-standardized hospitalizations , considering potential factors such as changes in demographics , socio-economics , drug prescriptions , and environmental variables . Results : The closure of the refinery eliminated 6000 tons/year of SO 2 emissions , with an observed reduction of 20 % in wind direction-adjusted ambient concentrations in Oakville . After accounting for trends , a decrease in cold-season peak-centered respiratory hospitalizations was observed for Oakville ( reduction of 2.2 cases/1000 persons per year , p = 0.0006 ) but not in Toronto ( p = 0.856 ) and the GTA ( p = 0.334 ) . The reduction of respiratory hospitalizations in Oakville post closure appeared to have no observed link to known confounders or effect modifiers . Conclusion : The refinery closure allowed an assessment of the change in community health . This natural experiment provides evidence that a reduction in emissions was associated with improvements in population health . This study design addresses the impact of a removed source of air pollution .", "gold_segments": [{"segment_text": "Background : An oil refinery in Oakville ,", "label": "background"}, {"segment_text": "Canada , closed over 2004Canada ,", "label": "background"}, {"segment_text": "closed over -2005 an opportunity for a natural experiment to examine the effects on oil refinery-related air pollution and residents ' health .", "label": "background"}, {"segment_text": "Methods : Environmental and health data were collected for the 16 years around the refinery closure .", "label": "method"}, {"segment_text": "Toronto ( 2.5 million persons ) and the Greater Toronto Area ( GTA , 6.3 million persons ) were used as control and reference populations ,", "label": "method"}, {"segment_text": "respectively , for Oakville ( 160,000 persons ) .", "label": "method"}, {"segment_text": "We compared sulfur dioxide and age-and season-standardized hospitalizations ,", "label": "method"}, {"segment_text": "considering potential factors such as changes in demographics ,", "label": "method"}, {"segment_text": "socio-economics , drug prescriptions , and environmental variables .", "label": "method"}, {"segment_text": "Results : The closure of the refinery eliminated 6000 tons/year of SO 2 emissions ,", "label": "finding"}, {"segment_text": "with an observed reduction of 20 % in wind direction-adjusted ambient concentrations in Oakville .", "label": "finding"}, {"segment_text": "After accounting for trends , a decrease in cold-season peak-centered respiratory hospitalizations was observed for Oakville ( reduction of 2.2 cases/1000 persons per year , p = 0.0006 ) but not in Toronto ( p = 0.856 ) and the GTA ( p = 0.334 ) .", "label": "finding"}, {"segment_text": "The reduction of respiratory hospitalizations in Oakville post closure appeared to have no observed link to known confounders or effect modifiers .", "label": "finding"}, {"segment_text": "Conclusion : The refinery closure allowed an assessment of the change in community health .", "label": "finding"}, {"segment_text": "This natural experiment provides evidence that a reduction in emissions was associated with improvements in population health .", "label": "finding"}, {"segment_text": "This study design addresses the impact of a removed source of air pollution .", "label": "finding"}], "n_segments": 16}
{"paper_id": "5d98d889c1739957886a3c27dc6552e695fee2f7", "title": "current Review Rhinitis in children less than 6 years of age: current knowledge and challenges", "coda_paper_id": 1758, "has_expert_labels": false, "abstract_text": "Rhinitis is a disease of the upper airway characterized by runny and/or blocked nose and/or sneezing . Though not viewed as a life threatening condition , it is also recognized to impose significant burden to the quality of life of sufferers and their caretakers and imposes an economic cost to society . Through a PubMed online search of the literature from 2006 to September 2011 , this paper aims to review the published literature on rhinitis in young children below the age of 6 years . It is apparent from epidemiology studies that rhinitis in this age group is a relatively common problem . The condition has a heterogenous etiology with classification into allergic and non-allergic rhinitis . Respiratory viral infections may play a role in the pathogenesis of long standing rhinitis , but definitive studies are still lacking . Treatment guidelines for management are lacking for this age group , and is a significant unmet need . Although the consensus is that co-morbidities including otitis media with effusion , adenoidal hypertrophy and asthma , are important considerations of management of these children . Pharmacotherapy is limited for young children especially for those below the age of 2 years . This review underscores the lack of understanding of rhinitis in early childhood and therefore the need for further research in this area . This is an Open Access article distributed under the terms of the creative commons Attribution . Non-commercial License ( http://creativecommons . org/licenses/by-nc / 3.0 / ) which permits unrestricted non-commercial use , distribution , and reproduction in any medium , provided the original work is properly cited . Hardjojo A , et al. . Asia Pacific allergy http://dx .", "gold_segments": [{"segment_text": "Rhinitis is a disease of the upper airway characterized by runny and/or blocked nose and/or sneezing .", "label": "background"}, {"segment_text": "Though not viewed as a life threatening condition ,", "label": "background"}, {"segment_text": "it is also recognized to impose significant burden to the quality of life of sufferers and their caretakers and imposes an economic cost to society .", "label": "background"}, {"segment_text": "Through a PubMed online search of the literature from 2006 to September 2011 ,", "label": "background"}, {"segment_text": "this paper aims to review the published literature on rhinitis in young children below the age of 6 years .", "label": "background"}, {"segment_text": "It is apparent from epidemiology studies that rhinitis in this age group is a relatively common problem .", "label": "background"}, {"segment_text": "The condition has a heterogenous etiology with classification into allergic and non-allergic rhinitis .", "label": "background"}, {"segment_text": "Respiratory viral infections may play a role in the pathogenesis of long standing rhinitis ,", "label": "background"}, {"segment_text": "but definitive studies are still lacking .", "label": "background"}, {"segment_text": "Treatment guidelines for management are lacking for this age group ,", "label": "finding"}, {"segment_text": "and is a significant unmet need .", "label": "finding"}, {"segment_text": "Although the consensus is that co-morbidities including otitis media with effusion ,", "label": "finding"}, {"segment_text": "adenoidal hypertrophy and asthma , are important considerations of management of these children .", "label": "finding"}, {"segment_text": "Pharmacotherapy is limited for young children especially for those below the age of 2 years .", "label": "finding"}, {"segment_text": "This review underscores the lack of understanding of rhinitis in early childhood and therefore the need for further research in this area .", "label": "finding"}, {"segment_text": "This is an Open Access article distributed under the terms of the creative commons Attribution .", "label": "finding"}, {"segment_text": "Non-commercial License ( http://creativecommons .", "label": "finding"}, {"segment_text": "org/licenses/by-nc / 3.0 / ) which permits unrestricted non-commercial use ,", "label": "finding"}, {"segment_text": "distribution , and reproduction in any medium ,", "label": "other"}, {"segment_text": "provided the original work is properly cited .", "label": "other"}, {"segment_text": "Hardjojo A , et al. .", "label": "other"}, {"segment_text": "Asia Pacific allergy http://dx .", "label": "other"}], "n_segments": 22}
{"paper_id": "c875abdf0709870107f76e104d39219217b7ba6b", "title": "H1N1 Is Not a Chinese Virus: the Racialization of People and Viruses in Post-SARS China", "coda_paper_id": 1222, "has_expert_labels": false, "abstract_text": "In this article , I trace how the race-making of people , viruses , and the places they share became a powerful means by which Chinese public health professionals made sense of two major infectious outbreaks that threatened to stall or interrupt China 's development : the SARS outbreak of 2003 and the H1N1 influenza pandemic of 2009 . By inscribing geographical stability onto infected bodies in motion through the languages of race and genetics , Chinese public health professionals sought to constrain the mobility of infection and , in doing so , to contain the symbolic and material threats to China 's modernity and development that flu-like infections , and the people who carried and spread them , had come to represent . While SARS in this imaginary became a BChinese ^ or BCantonese ^ disease , H1N1 became a EuroAmerican disease that , when it reached inside China , adhered more easily to those Chinese who did not quite belong . In constructing this imaginary , public health professionals ' racialization of certain groups thought to be infectious joined with the racialization of the infections themselves . H1N1 could not easily infect most Chinese because both the virus and its hosts were racially alien . When the H1N1 influenza pandemic began spreading around the world in April 2009 , I was nearing the end of a year of ethnographic fieldwork at several local , governmentaffiliated public health institutions in and around Tianmai , China . 1 , 2 Tianmai is a large St Comp Int Dev ( 2015 ) 50:500-518", "gold_segments": [{"segment_text": "In this article , I trace how the race-making of people ,", "label": "purpose"}, {"segment_text": "viruses , and the places they share became a powerful means by which Chinese public health professionals made sense of two major infectious outbreaks that threatened to stall or interrupt China 's development : the SARS outbreak of 2003 and the H1N1 influenza pandemic of 2009 .", "label": "purpose"}, {"segment_text": "By inscribing geographical stability onto infected bodies in motion through the languages of race and genetics ,", "label": "background"}, {"segment_text": "Chinese public health professionals sought to constrain the mobility of infection and ,", "label": "background"}, {"segment_text": "in doing so , to contain the symbolic and material threats to China 's modernity and development that flu-like infections ,", "label": "background"}, {"segment_text": "and the people who carried and spread them , had come to represent .", "label": "background"}, {"segment_text": "While SARS in this imaginary became a BChinese ^ or BCantonese ^ disease ,", "label": "background"}, {"segment_text": "H1N1 became a EuroAmerican disease that ,", "label": "background"}, {"segment_text": "when it reached inside China ,", "label": "background"}, {"segment_text": "adhered more easily to those Chinese who did not quite belong .", "label": "background"}, {"segment_text": "In constructing this imaginary , public health professionals ' racialization of certain groups thought to be infectious joined with the racialization of the infections themselves .", "label": "background"}, {"segment_text": "H1N1 could not easily infect most Chinese because both the virus and its hosts were racially alien .", "label": "background"}, {"segment_text": "When the H1N1 influenza pandemic began spreading around the world in April 2009 ,", "label": "background"}, {"segment_text": "I was nearing the end of a year of ethnographic fieldwork at several local ,", "label": "background"}, {"segment_text": "governmentaffiliated public health institutions in and around Tianmai , China .", "label": "background"}, {"segment_text": "1 , 2 Tianmai is a large St Comp Int Dev ( 2015 ) 50:500-518", "label": "background"}], "n_segments": 16}
{"paper_id": "a034fc1a3e926d0e12339678c32e892c37f514cb", "title": "Detecting Differential Transmissibilities That Affect the Size of Self-Limited Outbreaks", "coda_paper_id": 1958, "has_expert_labels": false, "abstract_text": "Our ability to respond appropriately to infectious diseases is enhanced by identifying differences in the potential for transmitting infection between individuals . Here , we identify epidemiological traits of self-limited infections ( i.e. infections with an effective reproduction number satisfying 0vR eff v1 ) that correlate with transmissibility . Our analysis is based on a branching process model that permits statistical comparison of both the strength and heterogeneity of transmission for two distinct types of cases . Our approach provides insight into a variety of scenarios , including the transmission of Middle East Respiratory Syndrome Coronavirus ( MERS-CoV ) in the Arabian peninsula , measles in North America , pre-eradication smallpox in Europe , and human monkeypox in the Democratic Republic of the Congo . When applied to chain size data for MERS-CoV transmission before 2014 , our method indicates that despite an apparent trend towards improved control , there is not enough statistical evidence to indicate that R eff has declined with time . Meanwhile , chain size data for measles in the United States and Canada reveal statistically significant geographic variation in R eff , suggesting that the timing and coverage of national vaccination programs , as well as contact tracing procedures , may shape the size distribution of observed infection clusters . Infection source data for smallpox suggests that primary cases transmitted more than secondary cases , and provides a quantitative assessment of the effectiveness of control interventions . Human monkeypox , on the other hand , does not show evidence of differential transmission between animals in contact with humans , primary cases , or secondary cases , which assuages the concern that social mixing can amplify transmission by secondary cases . Lastly , we evaluate surveillance requirements for detecting a change in the human-to-human transmission of monkeypox since the cessation of cross-protective smallpox vaccination . Our studies lay the foundation for future investigations regarding how infection source , vaccination status or other putative transmissibility traits may affect self-limited transmission .", "gold_segments": [{"segment_text": "Our ability to respond appropriately to infectious diseases is enhanced by identifying differences in the potential for transmitting infection between individuals .", "label": "background"}, {"segment_text": "Here , we identify epidemiological traits of self-limited infections ( i.e. infections with an effective reproduction number satisfying 0vR eff v1 ) that correlate with transmissibility .", "label": "purpose"}, {"segment_text": "Our analysis is based on a branching process model that permits statistical comparison of both the strength and heterogeneity of transmission for two distinct types of cases .", "label": "method"}, {"segment_text": "Our approach provides insight into a variety of scenarios ,", "label": "finding"}, {"segment_text": "including the transmission of Middle East Respiratory Syndrome Coronavirus ( MERS-CoV ) in the Arabian peninsula ,", "label": "finding"}, {"segment_text": "measles in North America , pre-eradication smallpox in Europe ,", "label": "finding"}, {"segment_text": "and human monkeypox in the Democratic Republic of the Congo .", "label": "finding"}, {"segment_text": "When applied to chain size data for MERS-CoV transmission before 2014 ,", "label": "finding"}, {"segment_text": "our method indicates that despite an apparent trend towards improved control ,", "label": "finding"}, {"segment_text": "there is not enough statistical evidence to indicate that R eff has declined with time .", "label": "finding"}, {"segment_text": "Meanwhile , chain size data for measles in the United States and Canada reveal statistically significant geographic variation in R eff ,", "label": "finding"}, {"segment_text": "suggesting that the timing and coverage of national vaccination programs ,", "label": "finding"}, {"segment_text": "as well as contact tracing procedures ,", "label": "finding"}, {"segment_text": "may shape the size distribution of observed infection clusters .", "label": "finding"}, {"segment_text": "Infection source data for smallpox suggests that primary cases transmitted more than secondary cases ,", "label": "finding"}, {"segment_text": "and provides a quantitative assessment of the effectiveness of control interventions .", "label": "finding"}, {"segment_text": "Human monkeypox , on the other hand ,", "label": "finding"}, {"segment_text": "does not show evidence of differential transmission between animals in contact with humans ,", "label": "finding"}, {"segment_text": "primary cases , or secondary cases ,", "label": "finding"}, {"segment_text": "which assuages the concern that social mixing can amplify transmission by secondary cases .", "label": "finding"}, {"segment_text": "Lastly , we evaluate surveillance requirements for detecting a change in the human-to-human transmission of monkeypox since the cessation of cross-protective smallpox vaccination .", "label": "finding"}, {"segment_text": "Our studies lay the foundation for future investigations regarding how infection source ,", "label": "finding"}, {"segment_text": "vaccination status or other putative transmissibility traits may affect self-limited transmission .", "label": "finding"}], "n_segments": 23}
{"paper_id": "f2b0dc500eda0f3738aa080f7491032c6a76d5a5", "title": "", "coda_paper_id": 1662, "has_expert_labels": false, "abstract_text": "Emphases on biomarkers ( e.g. when making diagnoses ) and pharmaceutical / drug methods ( e.g. when researching/disseminating population level interventions ) in primary care evidence philosophies of health ( and healthcare ) that reduce health to the biological level . However , with chronic diseases being responsible for the majority of all cause deaths and being strongly linked to health behavior and lifestyle ; predominantly biological views are becoming increasingly insufficient when discussing this health crisis . A philosophy that integrates biological , behavioral , and social determinants of health could benefit multidisciplinary discussions of healthy publics . This manuscript introduces a Philosophy of Health by presenting its first five principles of health . The philosophy creates parallels among biological immunity , health behavior change , social change by proposing that two general functions-precision and variation-impact population health at biological , behavioral , and social levels . This higher-level of abstraction is used to conclude that integrating functions , rather than separated ( biological ) structures drive healthy publics . A Philosophy of Health provides a framework that can integrate existing theories , models , concepts , and constructs .", "gold_segments": [{"segment_text": "Emphases on biomarkers ( e.g. when making diagnoses ) and pharmaceutical / drug methods ( e.g. when researching/disseminating population level interventions ) in primary care evidence philosophies of health ( and healthcare ) that reduce health to the biological level .", "label": "background"}, {"segment_text": "However , with chronic diseases being responsible for the majority of all cause deaths and being strongly linked to health behavior and lifestyle ; predominantly biological views are becoming increasingly insufficient when discussing this health crisis .", "label": "background"}, {"segment_text": "A philosophy that integrates biological ,", "label": "background"}, {"segment_text": "behavioral , and social determinants of health could benefit multidisciplinary discussions of healthy publics .", "label": "background"}, {"segment_text": "This manuscript introduces a Philosophy of Health by presenting its first five principles of health .", "label": "background"}, {"segment_text": "The philosophy creates parallels among biological immunity ,", "label": "background"}, {"segment_text": "health behavior change , social change by proposing that two general functions-precision and variation-impact population health at biological ,", "label": "background"}, {"segment_text": "behavioral , and social levels .", "label": "background"}, {"segment_text": "This higher-level of abstraction is used to conclude that integrating functions ,", "label": "finding"}, {"segment_text": "rather than separated ( biological ) structures drive healthy publics .", "label": "finding"}, {"segment_text": "A Philosophy of Health provides a framework that can integrate existing theories ,", "label": "finding"}, {"segment_text": "models , concepts , and constructs .", "label": "finding"}], "n_segments": 12}
{"paper_id": "d100406771e2d29572652ae1cbc7469a01c6f193", "title": "Modulation of cell proteome by 25-hydroxycholesterol and 27- hydroxycholesterol: A link between cholesterol metabolism and antiviral defense", "coda_paper_id": 1521, "has_expert_labels": false, "abstract_text": "Physiological cholesterol metabolism implies the generation of a series of oxidized derivatives , whose oxysterols are by far the most investigated ones for their potential multifaceted involvement in human pathophysiology . In this regard , noteworthy is the broad antiviral activity displayed by defined side chain oxysterols , in particular 25-hydroxycholesterol ( 25HC ) and 27-hydroxycholesterol ( 27HC ) . Although their antiviral mechanism ( s ) may vary depending on virus/host interaction , these oxysterols share the common feature to hamper viral replication by interacting with cellular proteins . Here reported is the first analysis of the modulation of a cell proteome by these two oxysterols , that , besides yielding additional clues about their potential involvement in the regulation of sterol metabolism , provides novelinsights about the mechanism underlying the inhibition of virus entry and trafficking within infected cells . We show here that both 25HC and 27HC can down-regulate the junction adhesion molecule-A ( JAM-A ) and the cation independent isoform of mannose-6-phosphate receptor ( MPRci ) , two crucial molecules for the replication of all those viruses that exploit adhesion molecules and the endosomal pathway to enter and diffuse within target cells .", "gold_segments": [{"segment_text": "Physiological cholesterol metabolism implies the generation of a series of oxidized derivatives ,", "label": "background"}, {"segment_text": "whose oxysterols are by far the most investigated ones for their potential multifaceted involvement in human pathophysiology .", "label": "background"}, {"segment_text": "In this regard , noteworthy is the broad antiviral activity displayed by defined side chain oxysterols ,", "label": "background"}, {"segment_text": "in particular 25-hydroxycholesterol ( 25HC ) and 27-hydroxycholesterol ( 27HC ) .", "label": "background"}, {"segment_text": "Although their antiviral mechanism ( s ) may vary depending on virus/host interaction ,", "label": "background"}, {"segment_text": "these oxysterols share the common feature to hamper viral replication by interacting with cellular proteins .", "label": "background"}, {"segment_text": "Here reported is the first analysis of the modulation of a cell proteome by these two oxysterols ,", "label": "finding"}, {"segment_text": "that , besides yielding additional clues about their potential involvement in the regulation of sterol metabolism ,", "label": "finding"}, {"segment_text": "provides novelinsights about the mechanism underlying the inhibition of virus entry and trafficking within infected cells .", "label": "finding"}, {"segment_text": "We show here that both 25HC and 27HC can down-regulate the junction adhesion molecule-A ( JAM-A ) and the cation independent isoform of mannose-6-phosphate receptor ( MPRci ) ,", "label": "finding"}, {"segment_text": "two crucial molecules for the replication of all those viruses that exploit adhesion molecules and the endosomal pathway to enter and diffuse within target cells .", "label": "finding"}], "n_segments": 11}
{"paper_id": "7d37dca746114af4879ecb53c1584fb776d748be", "title": "National post-market surveillance assessment of veterinary medicines in Korea during the past decade", "coda_paper_id": 1077, "has_expert_labels": false, "abstract_text": "Background : Veterinary medicines have been widely used for the prevention and treatment of diseases , growth promotion , and to promote feeding efficacy in livestock . As the veterinary medicine industry has steadily grown , it is crucial to set up a baseline for the quality of medicine as well as the insufficiency or excessiveness of the active ingredients in drug products to ensure the compliance , safety and efficacy of these medicines . Thus , the 10 years data of post-marketing quality control study was summarized to determine the rate and extent of non-compliance of these medicines and to establish baseline data for future quality control measures of veterinary medicine . Results : In this study , 1650 drugs for veterinary use were collected per year from each city and province in Korea and analysed for the quantity of active ingredients according to the `` national post-market surveillance ( NPMS ) system '' over the past decade . The NPMS assessment was performed using liquid and gas chromatography , titration , UV/Vis spectrophotometry , and bioassays . A total of 358 cases were deemed noncompliant , with the average noncompliance rate for all medicine types being 2.0 % . The average noncompliance rates for antibiotics , biologics and other chemical drugs except antibiotics ( OCD ) were 1.1 % , 1.2 % , and 3.0 % , respectively . The first leading cause for noncompliant products was insufficient quantity of major ingredients ( 283 cases ) , and the second leading cause was the existence of excess amount of active ingredients ( 60 cases ) . Tylosin , spiramycin , ampicillin , tetracyclines and penicillins were most frequently found to be noncompliant among antibiotics . Among the OCD , the noncompliance was found commonly in vitamin A. The overall trend presented gradually decreasing violation rates , suggesting that the quality of veterinary medicines has improved . Consistent application of the NPMS assessment and the establishment of the Korea Veterinary Good Manufacturing Practice ( KVGMP ) will help to maintain the good quality of medicine .", "gold_segments": [{"segment_text": "Background : Veterinary medicines have been widely used for the prevention and treatment of diseases ,", "label": "background"}, {"segment_text": "growth promotion , and to promote feeding efficacy in livestock .", "label": "background"}, {"segment_text": "As the veterinary medicine industry has steadily grown ,", "label": "background"}, {"segment_text": "it is crucial to set up a baseline for the quality of medicine as well as the insufficiency or excessiveness of the active ingredients in drug products to ensure the compliance ,", "label": "background"}, {"segment_text": "safety and efficacy of these medicines .", "label": "background"}, {"segment_text": "Thus , the 10 years data of post-marketing quality control study was summarized to determine the rate and extent of non-compliance of these medicines and to establish baseline data for future quality control measures of veterinary medicine .", "label": "method"}, {"segment_text": "Results : In this study ,", "label": "finding"}, {"segment_text": "1650 drugs for veterinary use were collected per year from each city and province in Korea and analysed for the quantity of active ingredients according to the `` national post-market surveillance ( NPMS ) system '' over the past decade .", "label": "finding"}, {"segment_text": "The NPMS assessment was performed using liquid and gas chromatography ,", "label": "finding"}, {"segment_text": "titration , UV/Vis spectrophotometry , and bioassays .", "label": "finding"}, {"segment_text": "A total of 358 cases were deemed noncompliant ,", "label": "finding"}, {"segment_text": "with the average noncompliance rate for all medicine types being 2.0 % .", "label": "finding"}, {"segment_text": "The average noncompliance rates for antibiotics ,", "label": "finding"}, {"segment_text": "biologics and other chemical drugs except antibiotics ( OCD ) were 1.1 % ,", "label": "finding"}, {"segment_text": "1.2 % , and 3.0 % , respectively .", "label": "finding"}, {"segment_text": "The first leading cause for noncompliant products was insufficient quantity of major ingredients ( 283 cases ) ,", "label": "finding"}, {"segment_text": "and the second leading cause was the existence of excess amount of active ingredients ( 60 cases ) .", "label": "finding"}, {"segment_text": "Tylosin , spiramycin , ampicillin ,", "label": "finding"}, {"segment_text": "tetracyclines and penicillins were most frequently found to be noncompliant among antibiotics .", "label": "finding"}, {"segment_text": "Among the OCD , the noncompliance was found commonly in vitamin A.", "label": "finding"}, {"segment_text": "The overall trend presented gradually decreasing violation rates ,", "label": "finding"}, {"segment_text": "suggesting that the quality of veterinary medicines has improved .", "label": "finding"}, {"segment_text": "Consistent application of the NPMS assessment and the establishment of the Korea Veterinary Good Manufacturing Practice ( KVGMP ) will help to maintain the good quality of medicine .", "label": "finding"}], "n_segments": 23}
{"paper_id": "ef7110a9022bac2e50c995b0f6b826ff071e48f8", "title": "Isothermal Amplification Using a Chemical Heating Device for Point-of-Care Detection of HIV-1", "coda_paper_id": 1373, "has_expert_labels": false, "abstract_text": "Background : To date , the use of traditional nucleic acid amplification tests ( NAAT ) for detection of HIV-1 DNA or RNA has been restricted to laboratory settings due to time , equipment , and technical expertise requirements . The availability of a rapid NAAT with applicability for resource-limited or point-of-care ( POC ) settings would fill a great need in HIV diagnostics , allowing for timely diagnosis or confirmation of infection status , as well as facilitating the diagnosis of acute infection , screening and evaluation of infants born to HIV-infected mothers . Isothermal amplification methods , such as reversetranscription , loop-mediated isothermal amplification ( RT-LAMP ) , exhibit characteristics that are ideal for POC settings , since they are typically quicker , easier to perform , and allow for integration into low-tech , portable heating devices . Methodology/Significant Findings : In this study , we evaluated the HIV-1 RT-LAMP assay using portable , non-instrumented nucleic acid amplification ( NINA ) heating devices that generate heat from the exothermic reaction of calcium oxide and water . The NINA heating devices exhibited stable temperatures throughout the amplification reaction and consistent amplification results between three separate devices and a thermalcycler . The performance of the NINA heaters was validated using whole blood specimens from HIV-1 infected patients . The RT-LAMP isothermal amplification method used in conjunction with a chemical heating device provides a portable , rapid and robust NAAT platform that has the potential to facilitate HIV-1 testing in resource-limited settings and POC .", "gold_segments": [{"segment_text": "Background : To date , the use of traditional nucleic acid amplification tests ( NAAT ) for detection of HIV-1 DNA or RNA has been restricted to laboratory settings due to time ,", "label": "background"}, {"segment_text": "equipment , and technical expertise requirements .", "label": "background"}, {"segment_text": "The availability of a rapid NAAT with applicability for resource-limited or point-of-care ( POC ) settings would fill a great need in HIV diagnostics ,", "label": "background"}, {"segment_text": "allowing for timely diagnosis or confirmation of infection status ,", "label": "background"}, {"segment_text": "as well as facilitating the diagnosis of acute infection ,", "label": "background"}, {"segment_text": "screening and evaluation of infants born to HIV-infected mothers .", "label": "background"}, {"segment_text": "Isothermal amplification methods , such as reversetranscription ,", "label": "background"}, {"segment_text": "loop-mediated isothermal amplification ( RT-LAMP ) ,", "label": "background"}, {"segment_text": "exhibit characteristics that are ideal for POC settings ,", "label": "background"}, {"segment_text": "since they are typically quicker ,", "label": "background"}, {"segment_text": "easier to perform , and allow for integration into low-tech , portable heating devices .", "label": "background"}, {"segment_text": "Methodology/Significant Findings : In this study ,", "label": "method"}, {"segment_text": "we evaluated the HIV-1 RT-LAMP assay using portable ,", "label": "method"}, {"segment_text": "non-instrumented nucleic acid amplification ( NINA ) heating devices that generate heat from the exothermic reaction of calcium oxide and water .", "label": "method"}, {"segment_text": "The NINA heating devices exhibited stable temperatures throughout the amplification reaction and consistent amplification results between three separate devices and a thermalcycler .", "label": "method"}, {"segment_text": "The performance of the NINA heaters was validated using whole blood specimens from HIV-1 infected patients .", "label": "method"}, {"segment_text": "The RT-LAMP isothermal amplification method used in conjunction with a chemical heating device provides a portable ,", "label": "finding"}, {"segment_text": "rapid and robust NAAT platform that has the potential to facilitate HIV-1 testing in resource-limited settings and POC .", "label": "finding"}], "n_segments": 18}
{"paper_id": "5e300aa83a729075b7ee62608b647218e7404b52", "title": "8. The Human Antibody Response Against WNV", "coda_paper_id": 1733, "has_expert_labels": false, "abstract_text": "Experimental evidence has shown that antibody responses to West Nile virus ( WNV ) are critical for protection from WNV-mediated disease . Antibody responses are also an important immune correlate of protection for the clinical evaluation of WNV vaccines . However , little direct study has been carried out on the characteristics of the human antibody response to natural WNV infection . Preliminary evidence suggests that there are important differences in the way humans and experimental animals mount humoral responses to WNV . In humans , IgM is remarkably persistent in the serum and specific IgG is slow to appear . In addition , mapping of the IgG response to the functionally relevant E-protein suggests that it directed away from critical protective epitopes and towards weakly neutralizing immunodominant epitopes . These findings have important implications for vaccine design and testing .", "gold_segments": [{"segment_text": "Experimental evidence has shown that antibody responses to West Nile virus ( WNV ) are critical for protection from WNV-mediated disease .", "label": "background"}, {"segment_text": "Antibody responses are also an important immune correlate of protection for the clinical evaluation of WNV vaccines .", "label": "background"}, {"segment_text": "However , little direct study has been carried out on the characteristics of the human antibody response to natural WNV infection .", "label": "background"}, {"segment_text": "Preliminary evidence suggests that there are important differences in the way humans and experimental animals mount humoral responses to WNV .", "label": "finding"}, {"segment_text": "In humans , IgM is remarkably persistent in the serum and specific IgG is slow to appear .", "label": "finding"}, {"segment_text": "In addition , mapping of the IgG response to the functionally relevant E-protein suggests that it directed away from critical protective epitopes and towards weakly neutralizing immunodominant epitopes .", "label": "finding"}, {"segment_text": "These findings have important implications for vaccine design and testing .", "label": "finding"}], "n_segments": 7}
{"paper_id": "963869beb920b86eefb2de2c6ea224da847855c6", "title": "Recombinant Vectors as Influenza Vaccines", "coda_paper_id": 1515, "has_expert_labels": false, "abstract_text": "The antiquated system used to manufacture the currently licensed inactivated influenza virus vaccines would not be adequate during an influenza virus pandemic . There is currently a search for vaccines that can be developed faster and provide superior , long-lasting immunity to influenza virus as well as other highly pathogenic viruses and bacteria . Recombinant vectors provide a safe and effective method to elicit a strong immune response to a foreign protein or epitope . This review explores the advantages and limitations of several different vectors that are currently being tested , and highlights some of the newer viruses being used as recombinant vectors .", "gold_segments": [{"segment_text": "The antiquated system used to manufacture the currently licensed inactivated influenza virus vaccines would not be adequate during an influenza virus pandemic .", "label": "background"}, {"segment_text": "There is currently a search for vaccines that can be developed faster and provide superior ,", "label": "background"}, {"segment_text": "long-lasting immunity to influenza virus as well as other highly pathogenic viruses and bacteria .", "label": "background"}, {"segment_text": "Recombinant vectors provide a safe and effective method to elicit a strong immune response to a foreign protein or epitope .", "label": "background"}, {"segment_text": "This review explores the advantages and limitations of several different vectors that are currently being tested ,", "label": "purpose"}, {"segment_text": "and highlights some of the newer viruses being used as recombinant vectors .", "label": "finding"}], "n_segments": 6}
{"paper_id": "b72e220b6500d2251e103f23d64b2f96f6e082f2", "title": "GenomeLandscaper: Landscape analysis of genome-fingerprints maps assessing chromosome architecture OPEN", "coda_paper_id": 1305, "has_expert_labels": false, "abstract_text": "Assessing correctness of an assembled chromosome architecture is a central challenge . We create a geometric analysis method ( called GenomeLandscaper ) to conduct landscape analysis of genomefingerprints maps ( GFM ) , trace large-scale repetitive regions , and assess their impacts on the global architectures of assembled chromosomes . We develop an alignment-free method for phylogenetics analysis . The human Y chromosomes ( GRCh.chrY , HuRef.chrY and YH.chrY ) are analysed as a proofof-concept study . We construct a galaxy of genome-fingerprints maps ( GGFM ) for them , and a landscape compatibility among relatives is observed . But a long sharp straight line on the GGFM breaks such a landscape compatibility , distinguishing GRCh38p1.chrY ( and throughout GRCh38p7 . chrY ) from GRCh37p13.chrY , HuRef.chrY and YH.chrY . We delete a 1.30-Mbp target segment to rescue the landscape compatibility , matching the antecedent GRCh37p13.chrY . We re-locate it into the modelled centromeric and pericentromeric region of GRCh38p10.chrY , matching a gap placeholder of GRCh37p13.chrY . We decompose it into sub-constituents ( such as BACs , interspersed repeats , and tandem repeats ) and trace their homologues by phylogenetics analysis . We elucidate that most examined tandem repeats are of reasonable quality , but the BAC-sized repeats , 173U1020C ( 176.46 Kbp ) and 5U41068C ( 205.34 Kbp ) , are likely over-repeated . These results offer unique insights into the centromeric and pericentromeric regions of the human Y chromosomes .", "gold_segments": [{"segment_text": "Assessing correctness of an assembled chromosome architecture is a central challenge .", "label": "background"}, {"segment_text": "We create a geometric analysis method ( called GenomeLandscaper ) to conduct landscape analysis of genomefingerprints maps ( GFM ) ,", "label": "method"}, {"segment_text": "trace large-scale repetitive regions , and assess their impacts on the global architectures of assembled chromosomes .", "label": "method"}, {"segment_text": "We develop an alignment-free method for phylogenetics analysis .", "label": "method"}, {"segment_text": "The human Y chromosomes ( GRCh.chrY , HuRef.chrY and YH.chrY ) are analysed as a proofof-concept study .", "label": "method"}, {"segment_text": "We construct a galaxy of genome-fingerprints maps ( GGFM ) for them ,", "label": "method"}, {"segment_text": "and a landscape compatibility among relatives is observed .", "label": "method"}, {"segment_text": "But a long sharp straight line on the GGFM breaks such a landscape compatibility ,", "label": "finding"}, {"segment_text": "distinguishing GRCh38p1.chrY ( and throughout GRCh38p7 .", "label": "finding"}, {"segment_text": "chrY ) from GRCh37p13.chrY , HuRef.chrY and YH.chrY .", "label": "finding"}, {"segment_text": "We delete a 1.30-Mbp target segment to rescue the landscape compatibility , matching the antecedent GRCh37p13.chrY .", "label": "method"}, {"segment_text": "We re-locate it into the modelled centromeric and pericentromeric region of GRCh38p10.chrY ,", "label": "method"}, {"segment_text": "matching a gap placeholder of GRCh37p13.chrY .", "label": "method"}, {"segment_text": "We decompose it into sub-constituents ( such as BACs , interspersed repeats , and tandem repeats ) and trace their homologues by phylogenetics analysis .", "label": "method"}, {"segment_text": "We elucidate that most examined tandem repeats are of reasonable quality ,", "label": "finding"}, {"segment_text": "but the BAC-sized repeats , 173U1020C ( 176.46 Kbp ) and 5U41068C ( 205.34 Kbp ) , are likely over-repeated .", "label": "finding"}, {"segment_text": "These results offer unique insights into the centromeric and pericentromeric regions of the human Y chromosomes .", "label": "finding"}], "n_segments": 17}
{"paper_id": "0d5be5a4268da7c08b478ca36721d46bd67bbe69", "title": "Effect of avian influenza A H5N1 infection on the expression of microRNA-141 in human respiratory epithelial cells", "coda_paper_id": 1719, "has_expert_labels": false, "abstract_text": "Background : Avian influenza remains a serious threat to human health . The consequence of human infection varies markedly among different subtypes of avian influenza viruses . In addition to viral factors , the difference in host cellular response is likely to play a critical role . This study aims at elucidating how avian influenza infection perturbs the host 's miRNA regulatory pathways that may lead to adverse pathological events , such as cytokine storm , using the miRNA microarray approach . Results : The results showed that dysregulation of miRNA expression was mainly observed in highly pathogenic avian influenza A H5N1 infection . We found that miR-21 * , miR-100 * , miR-141 , miR-574-3p , miR-1274a and miR1274b were differentially expressed in response to influenza A virus infection . Interestingly , we demonstrated that miR-141 , which was more highly induced by H5N1 than by H1N1 ( p < 0.05 ) , had an ability to suppress the expression of a cytokine - transforming growth factor ( TGF ) - β2 . This was supported by the observation that the inhibitory effect could be reversed by antagomiR-141 . Conclusions : Since TGF-β2 is an important cytokine that can act as both an immunosuppressive agent and a potent proinflammatory molecule through its ability to attract and regulate inflammatory molecules , and previous report showed that only seasonal influenza H1N1 ( but not the other avian influenza subtypes ) could induce a persistent expression of TGF-β2 , we speculate that the modulation of TGF-β2 expression by different influenza subtypes via miR-141 might be a critical step for determining the outcome of either normal or excessive inflammation progression .", "gold_segments": [{"segment_text": "Background : Avian influenza remains a serious threat to human health .", "label": "background"}, {"segment_text": "The consequence of human infection varies markedly among different subtypes of avian influenza viruses .", "label": "background"}, {"segment_text": "In addition to viral factors ,", "label": "background"}, {"segment_text": "the difference in host cellular response is likely to play a critical role .", "label": "background"}, {"segment_text": "This study aims at elucidating how avian influenza infection perturbs the host 's miRNA regulatory pathways that may lead to adverse pathological events ,", "label": "purpose"}, {"segment_text": "such as cytokine storm , using the miRNA microarray approach .", "label": "purpose"}, {"segment_text": "Results : The results showed that dysregulation of miRNA expression was mainly observed in highly pathogenic avian influenza A H5N1 infection .", "label": "finding"}, {"segment_text": "We found that miR-21 * ,", "label": "finding"}, {"segment_text": "miR-100 * , miR-141 , miR-574-3p ,", "label": "finding"}, {"segment_text": "miR-1274a and miR1274b were differentially expressed in response to influenza A virus infection .", "label": "finding"}, {"segment_text": "Interestingly , we demonstrated that miR-141 ,", "label": "finding"}, {"segment_text": "which was more highly induced by H5N1 than by H1N1 ( p < 0.05 ) ,", "label": "finding"}, {"segment_text": "had an ability to suppress the expression of a cytokine - transforming growth factor ( TGF ) - β2 .", "label": "finding"}, {"segment_text": "This was supported by the observation that the inhibitory effect could be reversed by antagomiR-141 .", "label": "finding"}, {"segment_text": "Conclusions : Since TGF-β2 is an important cytokine that can act as both an immunosuppressive agent and a potent proinflammatory molecule through its ability to attract and regulate inflammatory molecules ,", "label": "finding"}, {"segment_text": "and previous report showed that only seasonal influenza H1N1 ( but not the other avian influenza subtypes ) could induce a persistent expression of TGF-β2 ,", "label": "finding"}, {"segment_text": "we speculate that the modulation of TGF-β2 expression by different influenza subtypes via miR-141 might be a critical step for determining the outcome of either normal or excessive inflammation progression .", "label": "finding"}], "n_segments": 17}
{"paper_id": "6cab413e00675285c0dafb8c2824114a3358b403", "title": "Large-scale production and purification of VLP-based vaccines", "coda_paper_id": 1041, "has_expert_labels": false, "abstract_text": "Virus-like particles ( VLPs ) hold tremendous potential as vaccine candidates . These innovative biopharmaceuticals present the remarkable advantages of closely mimicking the three-dimensional nature of an actual virus while lacking the virus genome packaged inside its capsid . As a result , an equally efficient but safer prophylaxis is anticipated as compared to inactivated or live attenuated viral vaccines . With the advent of successful cases of approved VLP-based vaccines , pharmaceutical companies are indeed redirecting their resources to the development of such products . This paper reviews the current choices and trends of large-scale production and purification of VLP-based vaccines generated through the baculovirus expression vector system using insect cells .", "gold_segments": [{"segment_text": "Virus-like particles ( VLPs ) hold tremendous potential as vaccine candidates .", "label": "background"}, {"segment_text": "These innovative biopharmaceuticals present the remarkable advantages of closely mimicking the three-dimensional nature of an actual virus while lacking the virus genome packaged inside its capsid .", "label": "background"}, {"segment_text": "As a result , an equally efficient but safer prophylaxis is anticipated as compared to inactivated or live attenuated viral vaccines .", "label": "background"}, {"segment_text": "With the advent of successful cases of approved VLP-based vaccines ,", "label": "background"}, {"segment_text": "pharmaceutical companies are indeed redirecting their resources to the development of such products .", "label": "finding"}, {"segment_text": "This paper reviews the current choices and trends of large-scale production and purification of VLP-based vaccines generated through the baculovirus expression vector system using insect cells .", "label": "finding"}], "n_segments": 6}
{"paper_id": "0e1c055e39c45d7cef611b6bd17fb67c249ed742", "title": "Unifying evolutionary and thermodynamic information for RNA folding of multiple alignments", "coda_paper_id": 1013, "has_expert_labels": false, "abstract_text": "Computational methods for determining the secondary structure of RNA sequences from given alignments are currently either based on thermodynamic folding , compensatory base pair substitutions or both . However , there is currently no approach that combines both sources of information in a single optimization problem . Here , we present a model that formally integrates both the energy-based and evolution-based approaches to predict the folding of multiple aligned RNA sequences . We have implemented an extended version of Pfold that identifies base pairs that have high probabilities of being conserved and of being energetically favorable . The consensus structure is predicted using a maximum expected accuracy scoring scheme to smoothen the effect of incorrectly predicted base pairs . Parameter tuning revealed that the probability of base pairing has a higher impact on the RNA structure prediction than the corresponding probability of being single stranded . Furthermore , we found that structurally conserved RNA motifs are mostly supported by folding energies . Other problems ( e.g. RNA-folding kinetics ) may also benefit from employing the principles of the model we introduce . Our implementation , PETfold , was tested on a set of 46 well-curated Rfam families and its performance compared favorably to that of Pfold and RNAalifold .", "gold_segments": [{"segment_text": "Computational methods for determining the secondary structure of RNA sequences from given alignments are currently either based on thermodynamic folding ,", "label": "background"}, {"segment_text": "compensatory base pair substitutions or both .", "label": "background"}, {"segment_text": "However , there is currently no approach that combines both sources of information in a single optimization problem .", "label": "background"}, {"segment_text": "Here , we present a model that formally integrates both the energy-based and evolution-based approaches to predict the folding of multiple aligned RNA sequences .", "label": "purpose"}, {"segment_text": "We have implemented an extended version of Pfold that identifies base pairs that have high probabilities of being conserved and of being energetically favorable .", "label": "method"}, {"segment_text": "The consensus structure is predicted using a maximum expected accuracy scoring scheme to smoothen the effect of incorrectly predicted base pairs .", "label": "method"}, {"segment_text": "Parameter tuning revealed that the probability of base pairing has a higher impact on the RNA structure prediction than the corresponding probability of being single stranded .", "label": "finding"}, {"segment_text": "Furthermore , we found that structurally conserved RNA motifs are mostly supported by folding energies .", "label": "finding"}, {"segment_text": "Other problems ( e.g. RNA-folding kinetics ) may also benefit from employing the principles of the model we introduce .", "label": "finding"}, {"segment_text": "Our implementation , PETfold , was tested on a set of 46 well-curated Rfam families and its performance compared favorably to that of Pfold and RNAalifold .", "label": "finding"}], "n_segments": 10}
{"paper_id": "4302c1662f631c45a9edf8cd7010d35ccc682f62", "title": "Meeting report: 4th ISIRV antiviral group conference: Novel antiviral therapies for influenza and other respiratory viruses", "coda_paper_id": 1818, "has_expert_labels": false, "abstract_text": "The International Society for Influenza and other Respiratory Virus Diseases ( isirv ) held its 4th Antiviral Group Conference at the University of Texas on 2e4 June , 2015 . With emerging resistance to the drugs currently licensed for treatment and prophylaxis of influenza viruses , primarily the neuraminidase inhibitor oseltamivir phosphate ( Tamiflu ) and the M2 inhibitors amantadine and rimantadine , and the lack of effective interventions against other respiratory viruses , the 3-day programme focused on the discovery and development of inhibitors of several virus targets and key host cell factors involved in virus replication or mediating the inflammatory response . Virus targets included the influenza haemagglutinin , neuraminidase and M2 proteins , and both the respiratory syncytial virus and influenza polymerases and nucleoproteins . Therapies for rhinoviruses and MERS and SARS coronaviruses were also discussed . With the emerging development of monoclonal antibodies as therapeutics , the potential implications of antibody-dependent enhancement of disease were also addressed . Topics covered all aspects from structural and molecular biology to preclinical and clinical studies . The importance of suitable clinical trial endpoints and regulatory issues were also discussed from the perspectives of both industry and government . This meeting summary provides an overview , not only for the conference participants , but also for those interested in the current status of antivirals for respiratory viruses .", "gold_segments": [{"segment_text": "The International Society for Influenza and other Respiratory Virus Diseases ( isirv ) held its 4th Antiviral Group Conference at the University of Texas on 2e4 June , 2015 .", "label": "background"}, {"segment_text": "With emerging resistance to the drugs currently licensed for treatment and prophylaxis of influenza viruses ,", "label": "background"}, {"segment_text": "primarily the neuraminidase inhibitor oseltamivir phosphate ( Tamiflu ) and the M2 inhibitors amantadine and rimantadine ,", "label": "background"}, {"segment_text": "and the lack of effective interventions against other respiratory viruses ,", "label": "background"}, {"segment_text": "the 3-day programme focused on the discovery and development of inhibitors of several virus targets and key host cell factors involved in virus replication or mediating the inflammatory response .", "label": "background"}, {"segment_text": "Virus targets included the influenza haemagglutinin ,", "label": "background"}, {"segment_text": "neuraminidase and M2 proteins , and both the respiratory syncytial virus and influenza polymerases and nucleoproteins .", "label": "finding"}, {"segment_text": "Therapies for rhinoviruses and MERS and SARS coronaviruses were also discussed .", "label": "finding"}, {"segment_text": "With the emerging development of monoclonal antibodies as therapeutics ,", "label": "finding"}, {"segment_text": "the potential implications of antibody-dependent enhancement of disease were also addressed .", "label": "finding"}, {"segment_text": "Topics covered all aspects from structural and molecular biology to preclinical and clinical studies .", "label": "finding"}, {"segment_text": "The importance of suitable clinical trial endpoints and regulatory issues were also discussed from the perspectives of both industry and government .", "label": "finding"}, {"segment_text": "This meeting summary provides an overview ,", "label": "finding"}, {"segment_text": "not only for the conference participants ,", "label": "finding"}, {"segment_text": "but also for those interested in the current status of antivirals for respiratory viruses .", "label": "finding"}], "n_segments": 15}
{"paper_id": "c8b1da52eeb1d7dc2ff2f2f20a44ef13160fd626", "title": "Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication", "coda_paper_id": 1458, "has_expert_labels": false, "abstract_text": "Background : Infectious bronchitis virus ( IBV ) is a pathogenic chicken coronavirus . Currently , vaccination against IBV is only partially protective ; therefore , better preventions and treatments are needed . Plants produce antimicrobial secondary compounds , which may be a source for novel anti-viral drugs . Non-cytotoxic , crude ethanol extracts of Rhodiola rosea roots , Nigella sativa seeds , and Sambucus nigra fruit were tested for anti-IBV activity , since these safe , widely used plant tissues contain polyphenol derivatives that inhibit other viruses . Results : Dose-response cytotoxicity curves on Vero cells using trypan blue staining determined the highest non-cytotoxic concentrations of each plant extract . To screen for IBV inhibition , cells and virus were pretreated with extracts , followed by infection in the presence of extract . Viral cytopathic effect was assessed visually following an additional 24 h incubation with extract . Cells and supernatants were harvested separately and virus titers were quantified by plaque assay . Variations of this screening protocol determined the effects of a number of shortened S. nigra extract treatments . Finally , S. nigra extract-treated virions were visualized by transmission electron microscopy with negative staining . Virus titers from infected cells treated with R. rosea and N. sativa extracts were not substantially different from infected cells treated with solvent alone . However , treatment with S. nigra extracts reduced virus titers by four orders of magnitude at a multiplicity of infection ( MOI ) of 1 in a dose-responsive manner . Infection at a low MOI reduced viral titers by six orders of magnitude and pretreatment of virus was necessary , but not sufficient , for full virus inhibition . Electron microscopy of virions treated with S. nigra extract showed compromised envelopes and the presence of membrane vesicles , which suggested a mechanism of action . Conclusions : These results demonstrate that S. nigra extract can inhibit IBV at an early point in infection , probably by rendering the virus non-infectious . They also suggest that future studies using S. nigra extract to treat or prevent IBV or other coronaviruses are warranted .", "gold_segments": [{"segment_text": "Background : Infectious bronchitis virus ( IBV ) is a pathogenic chicken coronavirus .", "label": "background"}, {"segment_text": "Currently , vaccination against IBV is only partially protective ; therefore ,", "label": "background"}, {"segment_text": "better preventions and treatments are needed .", "label": "background"}, {"segment_text": "Plants produce antimicrobial secondary compounds ,", "label": "background"}, {"segment_text": "which may be a source for novel anti-viral drugs .", "label": "background"}, {"segment_text": "Non-cytotoxic , crude ethanol extracts of Rhodiola rosea roots ,", "label": "background"}, {"segment_text": "Nigella sativa seeds , and Sambucus nigra fruit were tested for anti-IBV activity ,", "label": "method"}, {"segment_text": "since these safe , widely used plant tissues contain polyphenol derivatives that inhibit other viruses .", "label": "method"}, {"segment_text": "Results : Dose-response cytotoxicity curves on Vero cells using trypan blue staining determined the highest non-cytotoxic concentrations of each plant extract .", "label": "finding"}, {"segment_text": "To screen for IBV inhibition ,", "label": "finding"}, {"segment_text": "cells and virus were pretreated with extracts ,", "label": "finding"}, {"segment_text": "followed by infection in the presence of extract .", "label": "finding"}, {"segment_text": "Viral cytopathic effect was assessed visually following an additional 24 h incubation with extract .", "label": "finding"}, {"segment_text": "Cells and supernatants were harvested separately and virus titers were quantified by plaque assay .", "label": "finding"}, {"segment_text": "Variations of this screening protocol determined the effects of a number of shortened S. nigra extract treatments .", "label": "finding"}, {"segment_text": "Finally , S. nigra extract-treated virions were visualized by transmission electron microscopy with negative staining .", "label": "finding"}, {"segment_text": "Virus titers from infected cells treated with R. rosea and N. sativa extracts were not substantially different from infected cells treated with solvent alone .", "label": "finding"}, {"segment_text": "However , treatment with S. nigra extracts reduced virus titers by four orders of magnitude at a multiplicity of infection ( MOI ) of 1 in a dose-responsive manner .", "label": "finding"}, {"segment_text": "Infection at a low MOI reduced viral titers by six orders of magnitude and pretreatment of virus was necessary ,", "label": "finding"}, {"segment_text": "but not sufficient , for full virus inhibition .", "label": "finding"}, {"segment_text": "Electron microscopy of virions treated with S. nigra extract showed compromised envelopes and the presence of membrane vesicles ,", "label": "finding"}, {"segment_text": "which suggested a mechanism of action .", "label": "finding"}, {"segment_text": "Conclusions : These results demonstrate that S. nigra extract can inhibit IBV at an early point in infection ,", "label": "finding"}, {"segment_text": "probably by rendering the virus non-infectious .", "label": "finding"}, {"segment_text": "They also suggest that future studies using S. nigra extract to treat or prevent IBV or other coronaviruses are warranted .", "label": "finding"}], "n_segments": 25}
{"paper_id": "2e45e30b65fd34a5727e967dda22436bffc2b57e", "title": "natural selection supports escape from concerted evolution of a recently duplicated CEACAM1 paralog in the ruminant ceA gene family", "coda_paper_id": 1133, "has_expert_labels": false, "abstract_text": "Concerted evolution is often observed in multigene families such as the CEA gene family . As a result , sequence similarity of paralogous genes is significantly higher than expected from their evolutionary distance . Gene conversion , a `` copy paste '' DNA repair mechanism that transfers sequences from one gene to another and homologous recombination are drivers of concerted evolution . Nevertheless , some gene family members escape concerted evolution and acquire sufficient sequence differences that orthologous genes can be assigned in descendant species . Reasons why some gene family members can escape while others are captured by concerted evolution are poorly understood . By analyzing the entire ceA gene family in cattle ( Bos taurus ) we identified a member ( CEACAM32 ) that was created by gene duplication and cooption of a unique transmembrane domain exon in the most recent ancestor of ruminants . CEACAM32 shows a unique , testis-specific expression pattern . Phylogenetic analysis indicated that CEACAM32 is not involved in concerted evolution of CEACAM1 paralogs in ruminants . However , analysis of gene conversion events revealed that CEACAM32 is subject to gene conversion but remarkably , these events are found in the leader exon and intron sequences but not in exons coding for the Ig-like domains . These findings suggest that natural selection hinders gene conversion affecting protein sequences of the mature protein and thereby support escape of CEACAM32 from concerted evolution .", "gold_segments": [{"segment_text": "Concerted evolution is often observed in multigene families such as the CEA gene family .", "label": "background"}, {"segment_text": "As a result , sequence similarity of paralogous genes is significantly higher than expected from their evolutionary distance .", "label": "background"}, {"segment_text": "Gene conversion , a `` copy paste '' DNA repair mechanism that transfers sequences from one gene to another and homologous recombination are drivers of concerted evolution .", "label": "background"}, {"segment_text": "Nevertheless , some gene family members escape concerted evolution and acquire sufficient sequence differences that orthologous genes can be assigned in descendant species .", "label": "background"}, {"segment_text": "Reasons why some gene family members can escape while others are captured by concerted evolution are poorly understood .", "label": "background"}, {"segment_text": "By analyzing the entire ceA gene family in cattle ( Bos taurus ) we identified a member ( CEACAM32 ) that was created by gene duplication and cooption of a unique transmembrane domain exon in the most recent ancestor of ruminants .", "label": "method"}, {"segment_text": "CEACAM32 shows a unique , testis-specific expression pattern .", "label": "finding"}, {"segment_text": "Phylogenetic analysis indicated that CEACAM32 is not involved in concerted evolution of CEACAM1 paralogs in ruminants .", "label": "finding"}, {"segment_text": "However , analysis of gene conversion events revealed that CEACAM32 is subject to gene conversion but remarkably ,", "label": "finding"}, {"segment_text": "these events are found in the leader exon and intron sequences but not in exons coding for the Ig-like domains .", "label": "finding"}, {"segment_text": "These findings suggest that natural selection hinders gene conversion affecting protein sequences of the mature protein and thereby support escape of CEACAM32 from concerted evolution .", "label": "finding"}], "n_segments": 11}
{"paper_id": "cee0724d4b1544eda1581f96962694ecd1f0125b", "title": "Antiviral effect of diammonium glycyrrhizinate and lithium chloride on cell infection by pseudorabies herpesvirus", "coda_paper_id": 1906, "has_expert_labels": false, "abstract_text": "Diammonium glycyrrhizin ( DG ) , a salt from glycyrrhizinate ( GL ) that is a major active component of licorice root extract with various pharmacological activities was investigated for its inhibitory effect on pseudorabies virus ( PrV ) infection . In parallel , lithium chloride ( LiCl ) , a chemical reagent with potential antiviral activity was compared with DG for their inhibitory ability against PrV infection in vitro . Virus plaque-reduction assays , PCR and RT-PCR analysis indicated that both drugs inhibited cell infection by PrV . Moreover , addition of the drugs resulted in fewer apoptotic cells during PrV infection .", "gold_segments": [{"segment_text": "Diammonium glycyrrhizin ( DG ) ,", "label": "background"}, {"segment_text": "a salt from glycyrrhizinate ( GL ) that is a major active component of licorice root extract with various pharmacological activities was investigated for its inhibitory effect on pseudorabies virus ( PrV ) infection .", "label": "background"}, {"segment_text": "In parallel , lithium chloride ( LiCl ) ,", "label": "background"}, {"segment_text": "a chemical reagent with potential antiviral activity was compared with DG for their inhibitory ability against PrV infection in vitro .", "label": "background"}, {"segment_text": "Virus plaque-reduction assays , PCR and RT-PCR analysis indicated that both drugs inhibited cell infection by PrV .", "label": "finding"}, {"segment_text": "Moreover , addition of the drugs resulted in fewer apoptotic cells during PrV infection .", "label": "finding"}], "n_segments": 6}
{"paper_id": "2c9e0077309492d6c2784dc19dc7bfc44a442cb4", "title": "Responsive immunization and intervention for infectious diseases in social networks", "coda_paper_id": 1925, "has_expert_labels": false, "abstract_text": "By using the microscopic Markov-chain approximation approach , we investigate the epidemic spreading and the responsive immunization in social networks . It is assumed that individual vaccination behavior depends on the local information of an epidemic . Our results suggest that the responsive immunization has negligible impact on the epidemic threshold and the critical value of initial epidemic outbreak , but it can effectively inhibit the outbreak of epidemic . We also analyze the influence of the intervention on the disease dynamics , where the vaccination is available only to those individuals whose number of neighbors is greater than a certain value . Simulation analysis implies that the intervention strategy can effectively reduce the vaccine use under the epidemic control . V C 2014 AIP Publishing LLC . ( http://dx . It is well known that the vaccination is very helpful in controlling vaccine preventable disease . When the voluntary vaccination can eradicate the epidemic transmission eventually , two relevant problems are presented : ( i ) whether it is able to decrease the possibility of epidemic outbreak ? ( ii ) how the vaccine should be used at minimum to yield better result ? In this work , we attempt to solve them to some extent . By introducing the responsive immunization based on the local information , we study the impact of the voluntary vaccination on the epidemic threshold . Theoretical analysis and simulation shows that the responsive immunization can not significantly affect the condition of epidemic . We further analyze the intervention strategy based on the targeted immunization and find that it can effectively reduce the vaccine use . These results may allow to gain new insight into the role of the voluntary vaccination in the epidemic control .", "gold_segments": [{"segment_text": "By using the microscopic Markov-chain approximation approach ,", "label": "background"}, {"segment_text": "we investigate the epidemic spreading and the responsive immunization in social networks .", "label": "background"}, {"segment_text": "It is assumed that individual vaccination behavior depends on the local information of an epidemic .", "label": "background"}, {"segment_text": "Our results suggest that the responsive immunization has negligible impact on the epidemic threshold and the critical value of initial epidemic outbreak ,", "label": "finding"}, {"segment_text": "but it can effectively inhibit the outbreak of epidemic .", "label": "finding"}, {"segment_text": "We also analyze the influence of the intervention on the disease dynamics ,", "label": "finding"}, {"segment_text": "where the vaccination is available only to those individuals whose number of neighbors is greater than a certain value .", "label": "finding"}, {"segment_text": "Simulation analysis implies that the intervention strategy can effectively reduce the vaccine use under the epidemic control .", "label": "finding"}, {"segment_text": "V C 2014 AIP Publishing LLC .", "label": "other"}, {"segment_text": "( http://dx .", "label": "other"}, {"segment_text": "It is well known that the vaccination is very helpful in controlling vaccine preventable disease .", "label": "background"}, {"segment_text": "When the voluntary vaccination can eradicate the epidemic transmission eventually ,", "label": "background"}, {"segment_text": "two relevant problems are presented : ( i ) whether it is able to decrease the possibility of epidemic outbreak ?", "label": "background"}, {"segment_text": "( ii ) how the vaccine should be used at minimum to yield better result ?", "label": "background"}, {"segment_text": "In this work , we attempt to solve them to some extent .", "label": "finding"}, {"segment_text": "By introducing the responsive immunization based on the local information ,", "label": "finding"}, {"segment_text": "we study the impact of the voluntary vaccination on the epidemic threshold .", "label": "finding"}, {"segment_text": "Theoretical analysis and simulation shows that the responsive immunization can not significantly affect the condition of epidemic .", "label": "finding"}, {"segment_text": "We further analyze the intervention strategy based on the targeted immunization and find that it can effectively reduce the vaccine use .", "label": "finding"}, {"segment_text": "These results may allow to gain new insight into the role of the voluntary vaccination in the epidemic control .", "label": "finding"}], "n_segments": 20}
{"paper_id": "25c901092dd741d3fceaf534d0af685e8f2324e1", "title": "Itinerant exosomes: emerging roles in cell and tissue polarity", "coda_paper_id": 1633, "has_expert_labels": false, "abstract_text": "Cells use secreted signals ( e.g. chemokines and growth factors ) and sophisticated vehicles such as argosomes , cytonemes , tunneling nanotubes and exosomes to relay important information to other cells , often over large distances . Exosomes , 30-100-nm intraluminal vesicles of multivesicular bodies ( MVB ) released upon exocytic fusion of the MVB with the plasma membrane , are increasingly recognized as a novel mode of cell-independent communication . Exosomes have been shown to function in antigen presentation and tumor metastasis , and in transmitting infectious agents . However , little is known about the biogenesis and function of exosomes in polarized cells . In this review , we discuss new evidence suggesting that exosomes participate in the transport of morphogens and RNA , and thus influence cell polarity and developmental patterning of tissues .", "gold_segments": [{"segment_text": "Cells use secreted signals ( e.g. chemokines and growth factors ) and sophisticated vehicles such as argosomes ,", "label": "background"}, {"segment_text": "cytonemes , tunneling nanotubes and exosomes to relay important information to other cells , often over large distances .", "label": "background"}, {"segment_text": "Exosomes , 30-100-nm intraluminal vesicles of multivesicular bodies ( MVB ) released upon exocytic fusion of the MVB with the plasma membrane ,", "label": "background"}, {"segment_text": "are increasingly recognized as a novel mode of cell-independent communication .", "label": "background"}, {"segment_text": "Exosomes have been shown to function in antigen presentation and tumor metastasis ,", "label": "background"}, {"segment_text": "and in transmitting infectious agents .", "label": "background"}, {"segment_text": "However , little is known about the biogenesis and function of exosomes in polarized cells .", "label": "background"}, {"segment_text": "In this review , we discuss new evidence suggesting that exosomes participate in the transport of morphogens and RNA ,", "label": "finding"}, {"segment_text": "and thus influence cell polarity and developmental patterning of tissues .", "label": "finding"}], "n_segments": 9}
{"paper_id": "bf9a104a0e968123eb292724891eb702f5f32f9a", "title": "Clinical Infectious Diseases Severe Illnesses Associated With Outbreaks of Respiratory Syncytial Virus and Influenza in Adults", "coda_paper_id": 1400, "has_expert_labels": false, "abstract_text": "Background . Recent reports have described the contribution of adult respiratory syncytial virus ( RSV ) infections to the use of advanced healthcare resources and death . Methods . Data regarding patients aged ≥ 18 years admitted to any of Maryland 's 50 acute-care hospitals were evaluated over 12 consecutive years ( 2001 ) ( 2002 ) ( 2003 ) ( 2004 ) ( 2005 ) ( 2006 ) ( 2007 ) ( 2008 ) ( 2009 ) ( 2010 ) ( 2011 ) ( 2012 ) ( 2013 ) . We examined RSV and influenza ( flu ) surveillance data from the US National Respiratory and Enteric Virus Surveillance System and the Centers for Disease Control and Prevention and used this information to define RSV and flu outbreak periods in the Maryland area . Outbreak periods consisted of consecutive individual weeks during which at least 10 % of RSV and/or flu diagnostic tests were positive . We examined relationships of RSV and flu outbreaks to occurrence of 4 advanced medical outcomes ( hospitalization , intensive care unit admission , intubated mechanical ventilation , and death ) due to medically attended acute respiratory illness ( MAARI ) . Results . Occurrences of all 4 MAARI-related hospital advanced medical outcomes were consistently greater for all adult ages during RSV , flu , and combined RSV-flu outbreak periods compared to nonoutbreak periods and tended to be greatest in adults aged ≥ 65 years during combined RSV-flu outbreak periods . Rate ratios for all 4 MAARI-related advanced medical outcomes ranged from 1.04 to 1.38 during the RSV , flu , or combined RSV-flu outbreaks compared to the nonoutbreak periods , with all 95 % lower confidence limits > 1 . Conclusions . Both RSV and flu outbreaks were associated with surges in MAARI-related advanced medical outcomes ( hospitalization , intensive care unit admission , intubated mechanical ventilation , and death ) for adults of all ages . Keywords . respiratory syncytial virus ; influenza , medically attended acute respiratory illness ; advanced medical outcomes . Respiratory syncytial virus ( RSV ) is a well-recognized , common cause of severe lower respiratory tract illness and hospitalization in children ( 1 ) . More recently , the contribution of adult RSV infections to the utilization of advanced healthcare resources , morbidity , and mortality has become increasingly clear ( 2 ) ( 3 ) ( 4 ) ( 5 ) ( 6 ) ( 7 ) .", "gold_segments": [{"segment_text": "Background .", "label": "background"}, {"segment_text": "Recent reports have described the contribution of adult respiratory syncytial virus ( RSV ) infections to the use of advanced healthcare resources and death .", "label": "background"}, {"segment_text": "Methods .", "label": "method"}, {"segment_text": "Data regarding patients aged ≥ 18 years admitted to any of Maryland 's 50 acute-care hospitals were evaluated over 12 consecutive years ( 2001 ) ( 2002 ) ( 2003 ) ( 2004 ) ( 2005 ) ( 2006 ) ( 2007 ) ( 2008 ) ( 2009 ) ( 2010 ) ( 2011 ) ( 2012 ) ( 2013 ) .", "label": "method"}, {"segment_text": "We examined RSV and influenza ( flu ) surveillance data from the US National Respiratory and Enteric Virus Surveillance System and the Centers for Disease Control and Prevention and used this information to define RSV and flu outbreak periods in the Maryland area .", "label": "method"}, {"segment_text": "Outbreak periods consisted of consecutive individual weeks during which at least 10 % of RSV and/or flu diagnostic tests were positive .", "label": "method"}, {"segment_text": "We examined relationships of RSV and flu outbreaks to occurrence of 4 advanced medical outcomes ( hospitalization , intensive care unit admission , intubated mechanical ventilation , and death ) due to medically attended acute respiratory illness ( MAARI ) .", "label": "method"}, {"segment_text": "Results .", "label": "finding"}, {"segment_text": "Occurrences of all 4 MAARI-related hospital advanced medical outcomes were consistently greater for all adult ages during RSV ,", "label": "finding"}, {"segment_text": "flu , and combined RSV-flu outbreak periods compared to nonoutbreak periods and tended to be greatest in adults aged ≥ 65 years during combined RSV-flu outbreak periods .", "label": "finding"}, {"segment_text": "Rate ratios for all 4 MAARI-related advanced medical outcomes ranged from 1.04 to 1.38 during the RSV ,", "label": "finding"}, {"segment_text": "flu , or combined RSV-flu outbreaks compared to the nonoutbreak periods ,", "label": "finding"}, {"segment_text": "with all 95 % lower confidence limits > 1 .", "label": "finding"}, {"segment_text": "Conclusions .", "label": "finding"}, {"segment_text": "Both RSV and flu outbreaks were associated with surges in MAARI-related advanced medical outcomes ( hospitalization , intensive care unit admission , intubated mechanical ventilation , and death ) for adults of all ages .", "label": "finding"}, {"segment_text": "Keywords .", "label": "finding"}, {"segment_text": "respiratory syncytial virus ; influenza ,", "label": "finding"}, {"segment_text": "medically attended acute respiratory illness ; advanced medical outcomes .", "label": "finding"}, {"segment_text": "Respiratory syncytial virus ( RSV ) is a well-recognized ,", "label": "finding"}, {"segment_text": "common cause of severe lower respiratory tract illness and hospitalization in children ( 1 ) .", "label": "finding"}, {"segment_text": "More recently , the contribution of adult RSV infections to the utilization of advanced healthcare resources ,", "label": "finding"}, {"segment_text": "morbidity , and mortality has become increasingly clear ( 2 ) ( 3 ) ( 4 ) ( 5 ) ( 6 ) ( 7 ) .", "label": "finding"}], "n_segments": 22}
{"paper_id": "6cf87a546884756094da0d300e85a061c2cc43ea", "title": "A retrospective study of the clinical characteristics of COVID-19 infection in 26 children", "coda_paper_id": 1217, "has_expert_labels": false, "abstract_text": "Background : The outbreak of novel coronavirus pneumonia in China began in December 2019 . Studies on novel coronavirus disease ( COVID-19 ) were less based on pediatric patients . This study aimed to reveal the clinical characteristics of COVID-19 in children . Method : This study retrospectively analyzed the clinical symptoms , laboratory results , chest CT , and treatment of children with laboratory-confirmed COVID-19 ( ie , with samples that were positive for 2019 novel coronavirus ( 2019-nCoV ) ) who were admitted to Result : Nine patients had no obvious clinical symptom . 11 patients developed fever . Other symptoms , including cough ( in eleven of seventeen patients ) , rhinorrhea ( in two ) , diarrhea ( in two ) , vomiting ( in two ) , were also observed . A small minority of patients had lymphocytopenia . Alanine transaminase or transaminase increased in three cases . According to chest CT scan , 11 patients showed unilateral pneumonia , 8 patients had no pulmonary infiltration . No serious complications such as acute respiratory syndrome and acute lung injury occurred in all patients . Conclusion : The clinical characteristics of 2019-nCoV infection in children were different from adult . The overall condition of children were mild and have a good prognosis .", "gold_segments": [{"segment_text": "Background : The outbreak of novel coronavirus pneumonia in China began in December 2019 .", "label": "background"}, {"segment_text": "Studies on novel coronavirus disease ( COVID-19 ) were less based on pediatric patients .", "label": "background"}, {"segment_text": "This study aimed to reveal the clinical characteristics of COVID-19 in children .", "label": "purpose"}, {"segment_text": "Method : This study retrospectively analyzed the clinical symptoms ,", "label": "method"}, {"segment_text": "laboratory results , chest CT ,", "label": "method"}, {"segment_text": "and treatment of children with laboratory-confirmed COVID-19 ( ie , with samples that were positive for 2019 novel coronavirus ( 2019-nCoV ) ) who were admitted to Result : Nine patients had no obvious clinical symptom .", "label": "finding"}, {"segment_text": "11 patients developed fever .", "label": "finding"}, {"segment_text": "Other symptoms , including cough ( in eleven of seventeen patients ) ,", "label": "finding"}, {"segment_text": "rhinorrhea ( in two ) ,", "label": "finding"}, {"segment_text": "diarrhea ( in two ) ,", "label": "finding"}, {"segment_text": "vomiting ( in two ) , were also observed .", "label": "finding"}, {"segment_text": "A small minority of patients had lymphocytopenia .", "label": "finding"}, {"segment_text": "Alanine transaminase or transaminase increased in three cases .", "label": "finding"}, {"segment_text": "According to chest CT scan ,", "label": "finding"}, {"segment_text": "11 patients showed unilateral pneumonia ,", "label": "finding"}, {"segment_text": "8 patients had no pulmonary infiltration .", "label": "finding"}, {"segment_text": "No serious complications such as acute respiratory syndrome and acute lung injury occurred in all patients .", "label": "finding"}, {"segment_text": "Conclusion : The clinical characteristics of 2019-nCoV infection in children were different from adult .", "label": "finding"}, {"segment_text": "The overall condition of children were mild and have a good prognosis .", "label": "finding"}], "n_segments": 19}
{"paper_id": "f9162c1be900c7bab2cc52de3e8cdef666c4824c", "title": "Microbiota epitope similarity either dampens or enhances the immunogenicity of disease- associated antigenic epitopes", "coda_paper_id": 1840, "has_expert_labels": false, "abstract_text": "The microbiome influences adaptive immunity and molecular mimicry influences T cell reactivity . Here , we evaluated whether the sequence similarity of various antigens to the microbiota dampens or increases immunogenicity of T cell epitopes .", "gold_segments": [{"segment_text": "The microbiome influences adaptive immunity and molecular mimicry influences T cell reactivity .", "label": "background"}, {"segment_text": "Here , we evaluated whether the sequence similarity of various antigens to the microbiota dampens or increases immunogenicity of T cell epitopes .", "label": "purpose"}], "n_segments": 2}
{"paper_id": "058b7249ce7acc1c14c989cb2d8db27435f81363", "title": "Studies on Influenza Virus Transmission between Ferrets: the Public Health Risks Revisited", "coda_paper_id": 1774, "has_expert_labels": false, "abstract_text": "Citation Fouchier RAM . 2015 . Studies on influenza virus transmission between ferrets : the public health risks revisited . mBio 6 ( 1 ) : e02560-14 .", "gold_segments": [{"segment_text": "Citation Fouchier RAM .", "label": "other"}, {"segment_text": "2015 .", "label": "other"}, {"segment_text": "Studies on influenza virus transmission between ferrets : the public health risks revisited .", "label": "background"}, {"segment_text": "mBio 6 ( 1 ) : e02560-14 .", "label": "other"}], "n_segments": 4}
{"paper_id": "2f2921851e825705103320bf3d61f9d76e4c6b45", "title": "Aerosol Sampling in a Hospital Emergency Room Setting: A Complementary Surveillance Method for the Detection of Respiratory Viruses", "coda_paper_id": 1424, "has_expert_labels": false, "abstract_text": "This study aimed to evaluate environmental air sampling as an alternative form of active surveillance for respiratory pathogens in clinical settings . Samples were collected from three locations in the . Of the 44 samples collected , 12 were positive for known respiratory pathogens including influenza A , influenza D , and adenovirus . Results suggest bioaerosol sampling may serve as a complement to active surveillance in clinical settings . Additionally , since respiratory viruses were detected in aerosol samples , our results suggest that hospital infection control measures , including the use of N95 respirators , could be used to limit the spread of infectious viruses in the air .", "gold_segments": [{"segment_text": "This study aimed to evaluate environmental air sampling as an alternative form of active surveillance for respiratory pathogens in clinical settings .", "label": "purpose"}, {"segment_text": "Samples were collected from three locations in the .", "label": "method"}, {"segment_text": "Of the 44 samples collected ,", "label": "finding"}, {"segment_text": "12 were positive for known respiratory pathogens including influenza A ,", "label": "finding"}, {"segment_text": "influenza D , and adenovirus .", "label": "finding"}, {"segment_text": "Results suggest bioaerosol sampling may serve as a complement to active surveillance in clinical settings .", "label": "finding"}, {"segment_text": "Additionally , since respiratory viruses were detected in aerosol samples ,", "label": "finding"}, {"segment_text": "our results suggest that hospital infection control measures ,", "label": "finding"}, {"segment_text": "including the use of N95 respirators ,", "label": "finding"}, {"segment_text": "could be used to limit the spread of infectious viruses in the air .", "label": "finding"}], "n_segments": 10}
{"paper_id": "69ae80f15e2b6e40a90752e801332926b62f6083", "title": "Levels of complexity in pathogen recognition by C-type lectins This review comes from a themed issue on Host-pathogen interactions Edited", "coda_paper_id": 1913, "has_expert_labels": false, "abstract_text": "In pathogen recognition by C-type lectins , several levels of complexity can be distinguished ; these might modulate the immune response in different ways . Firstly , the pathogenassociated molecular pattern repertoire expressed at the microbial surface determines the interactions with specific receptors . Secondly , each immune cell type possesses a specific set of pathogen-recognition receptors . Thirdly , changes in the cell-surface distribution of C-type lectins regulate carbohydrate binding by modulating receptor affinity for different ligands . Crosstalk between these receptors results in a network of multimolecular complexes , adding a further level of complexity in pathogen recognition .", "gold_segments": [{"segment_text": "In pathogen recognition by C-type lectins ,", "label": "background"}, {"segment_text": "several levels of complexity can be distinguished ; these might modulate the immune response in different ways .", "label": "background"}, {"segment_text": "Firstly , the pathogenassociated molecular pattern repertoire expressed at the microbial surface determines the interactions with specific receptors .", "label": "background"}, {"segment_text": "Secondly , each immune cell type possesses a specific set of pathogen-recognition receptors .", "label": "background"}, {"segment_text": "Thirdly , changes in the cell-surface distribution of C-type lectins regulate carbohydrate binding by modulating receptor affinity for different ligands .", "label": "finding"}, {"segment_text": "Crosstalk between these receptors results in a network of multimolecular complexes ,", "label": "finding"}, {"segment_text": "adding a further level of complexity in pathogen recognition .", "label": "finding"}], "n_segments": 7}
{"paper_id": "943576d41ee9cd2a8be3379fa2ff1bc8963a3202", "title": "A comparative study of experimental mouse models of central nervous system demyelination HHS Public Access Author manuscript", "coda_paper_id": 1464, "has_expert_labels": false, "abstract_text": "Several mouse models of multiple sclerosis ( MS ) are now available . We have established a mouse model , in which ocular infection with a recombinant HSV-1 that expresses murine IL-2 constitutively ( HSV-IL-2 ) causes CNS demyelination in different strains of mice . This model differs from most other models in that it represents a mixture of viral and immune triggers . In the present study , we directly compared MOG 35-55 , MBP ( 35 ) ( 36 ) ( 37 ) ( 38 ) ( 39 ) ( 40 ) ( 41 ) ( 42 ) ( 43 ) ( 44 ) ( 45 ) ( 46 ) ( 47 ) models of EAE with our HSV-IL-2-induced MS model . Mice with HSV-IL-2-induced and MOG-induced demyelinating diseases demonstrated a similar pattern and distribution of demyelination in their brain , spinal cord , and optic nerves . In contrast , no demyelination was detected in the optic nerves of MBP-and PLP-injected mice . IFN-β injections significantly reduced demyelination in brains of all groups , in the spinal cords of the MOG and MBP groups , and completely blocked it in the spinal cords of the PLP and HSV-IL-2 groups as well as in optic nerves of MOG and HSV-IL-2 groups . In contrast to IFN-β treatment , IL-12p70 protected the HSV-IL-2 group from demyelination , while IL-4 was not effective at all in preventing demyelination . MOG-injected mice showed clinical signs of paralysis and disease-related mortality whereas mice in the other treatment groups did not . Collectively , the results indicate that the HSV-IL-2 model and the MOG model complement each other and , together , provide unique insights into the heterogeneity of human MS.", "gold_segments": [{"segment_text": "Several mouse models of multiple sclerosis ( MS ) are now available .", "label": "background"}, {"segment_text": "We have established a mouse model ,", "label": "background"}, {"segment_text": "in which ocular infection with a recombinant HSV-1 that expresses murine IL-2 constitutively ( HSV-IL-2 ) causes CNS demyelination in different strains of mice .", "label": "background"}, {"segment_text": "This model differs from most other models in that it represents a mixture of viral and immune triggers .", "label": "background"}, {"segment_text": "In the present study , we directly compared MOG 35-55 ,", "label": "method"}, {"segment_text": "MBP ( 35 ) ( 36 ) ( 37 ) ( 38 ) ( 39 ) ( 40 ) ( 41 ) ( 42 ) ( 43 ) ( 44 ) ( 45 ) ( 46 ) ( 47 ) models of EAE with our HSV-IL-2-induced MS model .", "label": "method"}, {"segment_text": "Mice with HSV-IL-2-induced and MOG-induced demyelinating diseases demonstrated a similar pattern and distribution of demyelination in their brain ,", "label": "background"}, {"segment_text": "spinal cord , and optic nerves .", "label": "background"}, {"segment_text": "In contrast , no demyelination was detected in the optic nerves of MBP-and PLP-injected mice .", "label": "finding"}, {"segment_text": "IFN-β injections significantly reduced demyelination in brains of all groups ,", "label": "finding"}, {"segment_text": "in the spinal cords of the MOG and MBP groups ,", "label": "finding"}, {"segment_text": "and completely blocked it in the spinal cords of the PLP and HSV-IL-2 groups as well as in optic nerves of MOG and HSV-IL-2 groups .", "label": "finding"}, {"segment_text": "In contrast to IFN-β treatment ,", "label": "finding"}, {"segment_text": "IL-12p70 protected the HSV-IL-2 group from demyelination ,", "label": "finding"}, {"segment_text": "while IL-4 was not effective at all in preventing demyelination .", "label": "finding"}, {"segment_text": "MOG-injected mice showed clinical signs of paralysis and disease-related mortality whereas mice in the other treatment groups did not .", "label": "finding"}, {"segment_text": "Collectively , the results indicate that the HSV-IL-2 model and the MOG model complement each other and ,", "label": "finding"}, {"segment_text": "together , provide unique insights into the heterogeneity of human MS.", "label": "finding"}], "n_segments": 18}
{"paper_id": "a85bf11a1e9b9ea361e5478c0bcd938990fff73d", "title": "", "coda_paper_id": 1603, "has_expert_labels": false, "abstract_text": "Hospitalized children < 2 years of age in Amman , Jordan , admitted for fever and/or respiratory symptoms , were tested for Middle East respiratory syndrome coronavirus ( MERS-CoV ) : MERS-CoV by real-time RT-PCR ( rRT-PCR ) . This was a prospective year-round viral surveillance study in children < 2 years of age admitted with acute respiratory symptoms and/or fever from March 2010 to September 2012 and enrolled from a government-run hospital , Al-Bashir in Amman , Jordan . Clinical and demographic data , including antibiotic use , were collected . Combined nasal/throat swabs were collected , aliquoted , and frozen at À80 °C . Specimen aliquots were shipped to Vanderbilt University and the Centers for Disease Control and Prevention ( CDC ) , and tested by rRT-PCR for MERS-CoV . Of the and tested at Vanderbilt , none were positive for MERS-CoV . Our negative findings from a large sample of young Jordanian children hospitalized with fever and/or respiratory symptoms suggest that MERS-CoV was not widely circulating in Amman , Jordan , during the 30-month period of prospective , active surveillance occurring before and after the first documented MERS-CoV outbreak in the Middle East region .", "gold_segments": [{"segment_text": "Hospitalized children < 2 years of age in Amman ,", "label": "background"}, {"segment_text": "Jordan , admitted for fever and/or respiratory symptoms ,", "label": "background"}, {"segment_text": "were tested for Middle East respiratory syndrome coronavirus ( MERS-CoV ) : MERS-CoV by real-time RT-PCR ( rRT-PCR ) .", "label": "background"}, {"segment_text": "This was a prospective year-round viral surveillance study in children < 2 years of age admitted with acute respiratory symptoms and/or fever from March 2010 to September 2012 and enrolled from a government-run hospital ,", "label": "purpose"}, {"segment_text": "Al-Bashir in Amman , Jordan .", "label": "purpose"}, {"segment_text": "Clinical and demographic data , including antibiotic use , were collected .", "label": "method"}, {"segment_text": "Combined nasal/throat swabs were collected ,", "label": "method"}, {"segment_text": "aliquoted , and frozen at À80 °C .", "label": "method"}, {"segment_text": "Specimen aliquots were shipped to Vanderbilt University and the Centers for Disease Control and Prevention ( CDC ) ,", "label": "method"}, {"segment_text": "and tested by rRT-PCR for MERS-CoV .", "label": "method"}, {"segment_text": "Of the and tested at Vanderbilt ,", "label": "finding"}, {"segment_text": "none were positive for MERS-CoV .", "label": "finding"}, {"segment_text": "Our negative findings from a large sample of young Jordanian children hospitalized with fever and/or respiratory symptoms suggest that MERS-CoV was not widely circulating in Amman ,", "label": "finding"}, {"segment_text": "Jordan , during the 30-month period of prospective ,", "label": "finding"}, {"segment_text": "active surveillance occurring before and after the first documented MERS-CoV outbreak in the Middle East region .", "label": "finding"}], "n_segments": 15}
{"paper_id": "c63c4d58d170136b8d3b5a66424b5ac3f73a92d9", "title": "Viral Discovery and Sequence Recovery Using DNA Microarrays", "coda_paper_id": 1620, "has_expert_labels": false, "abstract_text": "Because of the constant threat posed by emerging infectious diseases and the limitations of existing approaches used to identify new pathogens , there is a great demand for new technological methods for viral discovery . We describe herein a DNA microarray-based platform for novel virus identification and characterization . Central to this approach was a DNA microarray designed to detect a wide range of known viruses as well as novel members of existing viral families ; this microarray contained the most highly conserved 70mer sequences from every fully sequenced reference viral genome in GenBank . During an outbreak of severe acute respiratory syndrome ( SARS ) in March 2003 , hybridization to this microarray revealed the presence of a previously uncharacterized coronavirus in a viral isolate cultivated from a SARS patient . To further characterize this new virus , approximately 1 kb of the unknown virus genome was cloned by physically recovering viral sequences hybridized to individual array elements . Sequencing of these fragments confirmed that the virus was indeed a new member of the coronavirus family . This combination of array hybridization followed by direct viral sequence recovery should prove to be a general strategy for the rapid identification and characterization of novel viruses and emerging infectious disease .", "gold_segments": [{"segment_text": "Because of the constant threat posed by emerging infectious diseases and the limitations of existing approaches used to identify new pathogens ,", "label": "background"}, {"segment_text": "there is a great demand for new technological methods for viral discovery .", "label": "background"}, {"segment_text": "We describe herein a DNA microarray-based platform for novel virus identification and characterization .", "label": "purpose"}, {"segment_text": "Central to this approach was a DNA microarray designed to detect a wide range of known viruses as well as novel members of existing viral families ; this microarray contained the most highly conserved 70mer sequences from every fully sequenced reference viral genome in GenBank .", "label": "method"}, {"segment_text": "During an outbreak of severe acute respiratory syndrome ( SARS ) in March 2003 ,", "label": "method"}, {"segment_text": "hybridization to this microarray revealed the presence of a previously uncharacterized coronavirus in a viral isolate cultivated from a SARS patient .", "label": "method"}, {"segment_text": "To further characterize this new virus ,", "label": "method"}, {"segment_text": "approximately 1 kb of the unknown virus genome was cloned by physically recovering viral sequences hybridized to individual array elements .", "label": "method"}, {"segment_text": "Sequencing of these fragments confirmed that the virus was indeed a new member of the coronavirus family .", "label": "finding"}, {"segment_text": "This combination of array hybridization followed by direct viral sequence recovery should prove to be a general strategy for the rapid identification and characterization of novel viruses and emerging infectious disease .", "label": "finding"}], "n_segments": 10}
{"paper_id": "349104eb16d3c08e212c6ee78230d8778621c40f", "title": "Estimation of the reproductive number of novel coronavirus (COVID-19) and the probable outbreak size on the Diamond Princess cruise ship: A data-driven analysis", "coda_paper_id": 1869, "has_expert_labels": false, "abstract_text": "Backgrounds : Up to February 16 , 2020 , 355 cases have been confirmed as having COVID-19 infection on the Diamond Princess cruise ship . It is of crucial importance to estimate the reproductive number ( R0 ) of the novel virus in the early stage of outbreak and make a prediction of daily new cases on the ship . Method : We fitted the reported serial interval ( mean and standard deviation ) with a gamma distribution and applied `` earlyR '' package in R to estimate the R0 in the early stage of COVID-19 outbreak . We applied `` projections '' package in R to simulate the plausible cumulative epidemic trajectories and future daily incidence by fitting the data of existing daily incidence , a serial interval distribution , and the estimated R0 into a model based on the assumption that daily incidence obeys approximately Poisson distribution determined by daily infectiousness . Results : The Maximum-Likelihood ( ML ) value of R0 was 2.28 for COVID-19 outbreak at the early stage on the ship . The median with 95 % confidence interval ( CI ) of R0 values was 2.28 ( 2.06-2.52 ) estimated by the bootstrap resampling method . The probable number of new cases for the next ten days would gradually increase , and the estimated cumulative cases would reach 1514 ( 1384-1656 ) at the tenth day in the future . However , if R0 value was reduced by 25 % and 50 % , the estimated total number of cumulative cases would be reduced to 1081 ( 981-1177 ) and 758 ( 697-817 ) , respectively . Conclusion : The median with 95 % CI of R0 of COVID-19 was about 2.28 ( 2.06-2.52 ) during the early stage experienced on the Diamond Princess cruise ship . The future daily incidence and probable outbreak size is largely dependent on the change of R0 . Unless strict infection management and control are taken , our findings indicate the potential of COVID-19 to cause greater outbreak on the ship .", "gold_segments": [{"segment_text": "Backgrounds : Up to February 16 ,", "label": "background"}, {"segment_text": "2020 , 355 cases have been confirmed as having COVID-19 infection on the Diamond Princess cruise ship .", "label": "background"}, {"segment_text": "It is of crucial importance to estimate the reproductive number ( R0 ) of the novel virus in the early stage of outbreak and make a prediction of daily new cases on the ship .", "label": "background"}, {"segment_text": "Method : We fitted the reported serial interval ( mean and standard deviation ) with a gamma distribution and applied `` earlyR '' package in R to estimate the R0 in the early stage of COVID-19 outbreak .", "label": "method"}, {"segment_text": "We applied `` projections '' package in R to simulate the plausible cumulative epidemic trajectories and future daily incidence by fitting the data of existing daily incidence ,", "label": "method"}, {"segment_text": "a serial interval distribution , and the estimated R0 into a model based on the assumption that daily incidence obeys approximately Poisson distribution determined by daily infectiousness .", "label": "method"}, {"segment_text": "Results : The Maximum-Likelihood ( ML ) value of R0 was 2.28 for COVID-19 outbreak at the early stage on the ship .", "label": "finding"}, {"segment_text": "The median with 95 % confidence interval ( CI ) of R0 values was 2.28 ( 2.06-2.52 ) estimated by the bootstrap resampling method .", "label": "finding"}, {"segment_text": "The probable number of new cases for the next ten days would gradually increase ,", "label": "finding"}, {"segment_text": "and the estimated cumulative cases would reach 1514 ( 1384-1656 ) at the tenth day in the future .", "label": "finding"}, {"segment_text": "However , if R0 value was reduced by 25 % and 50 % ,", "label": "finding"}, {"segment_text": "the estimated total number of cumulative cases would be reduced to 1081 ( 981-1177 ) and 758 ( 697-817 ) , respectively .", "label": "finding"}, {"segment_text": "Conclusion : The median with 95 % CI of R0 of COVID-19 was about 2.28 ( 2.06-2.52 ) during the early stage experienced on the Diamond Princess cruise ship .", "label": "finding"}, {"segment_text": "The future daily incidence and probable outbreak size is largely dependent on the change of R0 .", "label": "finding"}, {"segment_text": "Unless strict infection management and control are taken ,", "label": "finding"}, {"segment_text": "our findings indicate the potential of COVID-19 to cause greater outbreak on the ship .", "label": "finding"}], "n_segments": 16}
{"paper_id": "926d8dc84a667e11dfea30fac3824fd17e175398", "title": "A Crucial Role for Infected-Cell/Antibody Immune Complexes in the Enhancement of Endogenous Antiviral Immunity by Short Passive Immunotherapy", "coda_paper_id": 1912, "has_expert_labels": false, "abstract_text": "Antiviral monoclonal antibodies ( mAbs ) represent promising therapeutics . However , most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization , namely the modulation of the endogenous immune response . As induction of longterm antiviral immunity still remains a paramount challenge for treating chronic infections , we have asked here whether neutralizing mAbs can , in addition to blunting viral propagation , exert immunomodulatory effects with protective outcomes . Supporting this idea , we report here that mice infected with the FrCas E murine retrovirus on day 8 after birth die of leukemia within 4-5 months and mount a non-protective immune response , whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses . Interestingly , the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity ( ADCC ) mechanism . In addition , it forms immune complexes ( ICs ) with infected cells that enhance antiviral CTL responses through FccR-mediated binding to dendritic cells ( DCs ) . Importantly , the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties , allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb . Thus , our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment . They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses . They also indicate that targeting infected cells , and not just viruses , by antibodies can be crucial for elicitation of efficient , long-lasting antiviral T-cell responses . This must be considered when designing antiviral mAb-based immunotherapies .", "gold_segments": [{"segment_text": "Antiviral monoclonal antibodies ( mAbs ) represent promising therapeutics .", "label": "background"}, {"segment_text": "However , most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization ,", "label": "background"}, {"segment_text": "namely the modulation of the endogenous immune response .", "label": "background"}, {"segment_text": "As induction of longterm antiviral immunity still remains a paramount challenge for treating chronic infections ,", "label": "background"}, {"segment_text": "we have asked here whether neutralizing mAbs can ,", "label": "background"}, {"segment_text": "in addition to blunting viral propagation ,", "label": "background"}, {"segment_text": "exert immunomodulatory effects with protective outcomes .", "label": "background"}, {"segment_text": "Supporting this idea , we report here that mice infected with the FrCas E murine retrovirus on day 8 after birth die of leukemia within 4-5 months and mount a non-protective immune response ,", "label": "finding"}, {"segment_text": "whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses .", "label": "finding"}, {"segment_text": "Interestingly , the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity ( ADCC ) mechanism .", "label": "finding"}, {"segment_text": "In addition , it forms immune complexes ( ICs ) with infected cells that enhance antiviral CTL responses through FccR-mediated binding to dendritic cells ( DCs ) .", "label": "finding"}, {"segment_text": "Importantly , the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties ,", "label": "finding"}, {"segment_text": "allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb .", "label": "finding"}, {"segment_text": "Thus , our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment .", "label": "finding"}, {"segment_text": "They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses .", "label": "finding"}, {"segment_text": "They also indicate that targeting infected cells ,", "label": "finding"}, {"segment_text": "and not just viruses , by antibodies can be crucial for elicitation of efficient , long-lasting antiviral T-cell responses .", "label": "finding"}, {"segment_text": "This must be considered when designing antiviral mAb-based immunotherapies .", "label": "finding"}], "n_segments": 18}
{"paper_id": "4d07fa09850cdef43d77e86fc1aa2fca59e5b13c", "title": "Slow, Reversible, Coupled Folding and Binding of the Spectrin Tetramerization Domain", "coda_paper_id": 1724, "has_expert_labels": false, "abstract_text": "Many intrinsically disordered proteins ( IDPs ) are significantly unstructured under physiological conditions . A number of these IDPs have been shown to undergo coupled folding and binding reactions whereby they can gain structure upon association with an appropriate partner protein . In general , these systems display weaker binding affinities than do systems with association between completely structured domains , with micromolar K d values appearing typical . One such system is the association between aand b-spectrin , where two partially structured , incomplete domains associate to form a fully structured , three-helix bundle , the spectrin tetramerization domain . Here , we use this model system to demonstrate a method for fitting association and dissociation kinetic traces where , using typical biophysical concentrations , the association reactions are expected to be highly reversible . We elucidate the unusually slow , two-state kinetics of spectrin assembly in solution . The advantages of studying kinetics in this regime include the potential for gaining equilibrium constants as well as rate constants , and for performing experiments with low protein concentrations . We suggest that this approach would be particularly appropriate for high-throughput mutational analysis of two-state reversible binding processes .", "gold_segments": [{"segment_text": "Many intrinsically disordered proteins ( IDPs ) are significantly unstructured under physiological conditions .", "label": "background"}, {"segment_text": "A number of these IDPs have been shown to undergo coupled folding and binding reactions whereby they can gain structure upon association with an appropriate partner protein .", "label": "background"}, {"segment_text": "In general , these systems display weaker binding affinities than do systems with association between completely structured domains ,", "label": "background"}, {"segment_text": "with micromolar K d values appearing typical .", "label": "background"}, {"segment_text": "One such system is the association between aand b-spectrin ,", "label": "background"}, {"segment_text": "where two partially structured , incomplete domains associate to form a fully structured ,", "label": "background"}, {"segment_text": "three-helix bundle , the spectrin tetramerization domain .", "label": "background"}, {"segment_text": "Here , we use this model system to demonstrate a method for fitting association and dissociation kinetic traces where ,", "label": "purpose"}, {"segment_text": "using typical biophysical concentrations , the association reactions are expected to be highly reversible .", "label": "method"}, {"segment_text": "We elucidate the unusually slow ,", "label": "method"}, {"segment_text": "two-state kinetics of spectrin assembly in solution .", "label": "method"}, {"segment_text": "The advantages of studying kinetics in this regime include the potential for gaining equilibrium constants as well as rate constants ,", "label": "finding"}, {"segment_text": "and for performing experiments with low protein concentrations .", "label": "finding"}, {"segment_text": "We suggest that this approach would be particularly appropriate for high-throughput mutational analysis of two-state reversible binding processes .", "label": "finding"}], "n_segments": 14}
{"paper_id": "a279441c0873b6bfdfbd63cee1220cf9596acaee", "title": "A dose and time response Markov model for the in-host dynamics of infection with intracellular bacteria following inhalation: with application to Francisella tularensis", "coda_paper_id": 1371, "has_expert_labels": false, "abstract_text": "In a novel approach , the standard birth-death process is extended to incorporate a fundamental mechanism undergone by intracellular bacteria , phagocytosis . The model accounts for stochastic interaction between bacteria and cells of the immune system and heterogeneity in susceptibility to infection of individual hosts within a population . Model output is the dose-response relation and the dose-dependent distribution of time until response , where response is the onset of symptoms . The model is thereafter parametrized with respect to the highly virulent Schu S4 strain of Francisella tularensis , in the first such study to consider a biologically plausible mathematical model for early human infection with this bacterium . Results indicate a median infectious dose of about 23 organisms , which is higher than previously thought , and an average incubation period of between 3 and 7 days depending on dose . The distribution of incubation periods is right-skewed up to about 100 organisms and symmetric for larger doses . Moreover , there are some interesting parallels to the hypotheses of some of the classical dose-response models , such as independent action ( single-hit model ) and individual effective dose ( probit model ) . The findings of this study support experimental evidence and postulations from other investigations that response is , in fact , influenced by both in-host and between-host variability .", "gold_segments": [{"segment_text": "In a novel approach , the standard birth-death process is extended to incorporate a fundamental mechanism undergone by intracellular bacteria , phagocytosis .", "label": "background"}, {"segment_text": "The model accounts for stochastic interaction between bacteria and cells of the immune system and heterogeneity in susceptibility to infection of individual hosts within a population .", "label": "background"}, {"segment_text": "Model output is the dose-response relation and the dose-dependent distribution of time until response ,", "label": "background"}, {"segment_text": "where response is the onset of symptoms .", "label": "background"}, {"segment_text": "The model is thereafter parametrized with respect to the highly virulent Schu S4 strain of Francisella tularensis ,", "label": "method"}, {"segment_text": "in the first such study to consider a biologically plausible mathematical model for early human infection with this bacterium .", "label": "method"}, {"segment_text": "Results indicate a median infectious dose of about 23 organisms ,", "label": "finding"}, {"segment_text": "which is higher than previously thought ,", "label": "finding"}, {"segment_text": "and an average incubation period of between 3 and 7 days depending on dose .", "label": "finding"}, {"segment_text": "The distribution of incubation periods is right-skewed up to about 100 organisms and symmetric for larger doses .", "label": "finding"}, {"segment_text": "Moreover , there are some interesting parallels to the hypotheses of some of the classical dose-response models ,", "label": "finding"}, {"segment_text": "such as independent action ( single-hit model ) and individual effective dose ( probit model ) .", "label": "finding"}, {"segment_text": "The findings of this study support experimental evidence and postulations from other investigations that response is ,", "label": "finding"}, {"segment_text": "in fact , influenced by both in-host and between-host variability .", "label": "finding"}], "n_segments": 14}
{"paper_id": "625ebf6fb0e903bee91ebbbf16a9223e3cad7eca", "title": "Prediction of smallpox outbreak and evaluation of control-measure policy in Japan, using a mathematical model", "coda_paper_id": 1113, "has_expert_labels": false, "abstract_text": "Since the September 1 terrorist attacks and moreover , since the anthrax exposure events in 2001 in the United States , bioterrorism attacks seem to be a real threat . Of course , the public health authorities in Japan have started to prepare control measures for such events . We report here our attempts , using a mathematical model , to estimate outbreak size and to examine the most effective measures ; comparing ring vaccination ( contact tracing , isolation , and vaccination among contacts ) and mass vaccination of the susceptible population in the area . The basic framework of the mathematical model follows a model used in previous research . The initial susceptible population is assumed to be 30 million persons . Concerning the important parameters , such as the number of initial-exposure cases , R 0 ( infectious power , or natural history ) and , the starting day of intervention after the initial exposure , we checked the robustness of our conclusions by sensitivity analysis . We found that mass vaccination is preferable to ring vaccination when the values for the initial-exposure cases and R 0 are high and when the start of intervention by public health authorities is delayed . In the base-case situation , the mass vaccination strategy needs almost 30 million vaccine doses . On the other hand , though ring vaccination needs fewer doses , it needs fewer than 50 000 doses in the worst-case scenario , that with larger first exposure , higher R 0 , or later start of public health authority intervention . This mathematical model can measure the prevalence of an infectious disease and can evaluate control measures for it before an outbreak . Especially , it is useful for the planning of the outbreaks of emerging diseases such as severe acute respiratory syndrome ( SARS ) or for bioterrorism attacks involving such diseases as smallpox . In further research , we will have to take into account the population people vaccinated of for smallpox , who account for about 70 % of the total population in Japan .", "gold_segments": [{"segment_text": "Since the September 1 terrorist attacks and moreover ,", "label": "background"}, {"segment_text": "since the anthrax exposure events in 2001 in the United States ,", "label": "background"}, {"segment_text": "bioterrorism attacks seem to be a real threat .", "label": "background"}, {"segment_text": "Of course , the public health authorities in Japan have started to prepare control measures for such events .", "label": "background"}, {"segment_text": "We report here our attempts ,", "label": "background"}, {"segment_text": "using a mathematical model , to estimate outbreak size and to examine the most effective measures ; comparing ring vaccination ( contact tracing , isolation , and vaccination among contacts ) and mass vaccination of the susceptible population in the area .", "label": "background"}, {"segment_text": "The basic framework of the mathematical model follows a model used in previous research .", "label": "method"}, {"segment_text": "The initial susceptible population is assumed to be 30 million persons .", "label": "method"}, {"segment_text": "Concerning the important parameters , such as the number of initial-exposure cases ,", "label": "method"}, {"segment_text": "R 0 ( infectious power , or natural history ) and ,", "label": "method"}, {"segment_text": "the starting day of intervention after the initial exposure ,", "label": "method"}, {"segment_text": "we checked the robustness of our conclusions by sensitivity analysis .", "label": "method"}, {"segment_text": "We found that mass vaccination is preferable to ring vaccination when the values for the initial-exposure cases and R 0 are high and when the start of intervention by public health authorities is delayed .", "label": "finding"}, {"segment_text": "In the base-case situation , the mass vaccination strategy needs almost 30 million vaccine doses .", "label": "finding"}, {"segment_text": "On the other hand , though ring vaccination needs fewer doses ,", "label": "finding"}, {"segment_text": "it needs fewer than 50 000 doses in the worst-case scenario ,", "label": "finding"}, {"segment_text": "that with larger first exposure ,", "label": "finding"}, {"segment_text": "higher R 0 , or later start of public health authority intervention .", "label": "finding"}, {"segment_text": "This mathematical model can measure the prevalence of an infectious disease and can evaluate control measures for it before an outbreak .", "label": "finding"}, {"segment_text": "Especially , it is useful for the planning of the outbreaks of emerging diseases such as severe acute respiratory syndrome ( SARS ) or for bioterrorism attacks involving such diseases as smallpox .", "label": "finding"}, {"segment_text": "In further research , we will have to take into account the population people vaccinated of for smallpox ,", "label": "finding"}, {"segment_text": "who account for about 70 % of the total population in Japan .", "label": "finding"}], "n_segments": 22}
{"paper_id": "e582bc041b65f0b488e292996f0c07d6dae95143", "title": "Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments -the importance of immunofocusing in subunit vaccine design NIH Public Access Author Manuscript", "coda_paper_id": 1205, "has_expert_labels": false, "abstract_text": "The newly emerged Middle East respiratory syndrome coronavirus ( MERS-CoV ) is currently spreading among humans , making development of effective MERS vaccines a high priority . A defined receptor-binding domain ( RBD ) in MERS-CoV spike protein can potentially serve as a subunit vaccine candidate against MERS-CoV infections . To identify an ideal vaccine candidate , we have constructed five different versions of RBD fragments , S350-588-Fc , S358-588-Fc , S367-588-Fc , S367-606-Fc , and S377-588-Fc ( their names indicate their residue range in the spike protein and their C-terminal Fc tag ) , and further investigated their receptor binding affinity , antigenicity , immunogenicity , and neutralizing potential . The results showed that S377-588-Fc is among the RBD fragments that demonstrated the highest DPP4-binding affinity and induced the highest-titer IgG antibodies in mice . In addition , S377-588-Fc elicited higher-titer neutralizing antibodies than all the other RBD fragments in mice , and also induced high-titer neutralizing antibodies in immunized rabbits . Structural analysis suggests that S377-588-Fc contains the stably folded RBD structure , the full receptor-binding site , and major neutralizing epitopes , such that additional structures to this fragment introduce non-neutralizing epitopes and may also alter the tertiary structure of the RBD . Taken together , our data suggest that the RBD fragment encompassing spike residues 377-588 is a critical neutralizing receptor-binding fragment and an ideal candidate for development of effective MERS vaccines , and that adding non-neutralizing structures to this RBD fragment diminishes its neutralizing potential . Therefore , in viral vaccine design , it is important to identify the most stable and neutralizing viral RBD fragment , while eliminating unnecessary and non-neutralizing structures , as a means of `` immunofocusing '' .", "gold_segments": [{"segment_text": "The newly emerged Middle East respiratory syndrome coronavirus ( MERS-CoV ) is currently spreading among humans ,", "label": "background"}, {"segment_text": "making development of effective MERS vaccines a high priority .", "label": "background"}, {"segment_text": "A defined receptor-binding domain ( RBD ) in MERS-CoV spike protein can potentially serve as a subunit vaccine candidate against MERS-CoV infections .", "label": "background"}, {"segment_text": "To identify an ideal vaccine candidate ,", "label": "purpose"}, {"segment_text": "we have constructed five different versions of RBD fragments ,", "label": "method"}, {"segment_text": "S350-588-Fc , S358-588-Fc , S367-588-Fc ,", "label": "method"}, {"segment_text": "S367-606-Fc , and S377-588-Fc ( their names indicate their residue range in the spike protein and their C-terminal Fc tag ) ,", "label": "method"}, {"segment_text": "and further investigated their receptor binding affinity ,", "label": "method"}, {"segment_text": "antigenicity , immunogenicity , and neutralizing potential .", "label": "method"}, {"segment_text": "The results showed that S377-588-Fc is among the RBD fragments that demonstrated the highest DPP4-binding affinity and induced the highest-titer IgG antibodies in mice .", "label": "finding"}, {"segment_text": "In addition , S377-588-Fc elicited higher-titer neutralizing antibodies than all the other RBD fragments in mice ,", "label": "finding"}, {"segment_text": "and also induced high-titer neutralizing antibodies in immunized rabbits .", "label": "finding"}, {"segment_text": "Structural analysis suggests that S377-588-Fc contains the stably folded RBD structure ,", "label": "finding"}, {"segment_text": "the full receptor-binding site , and major neutralizing epitopes ,", "label": "finding"}, {"segment_text": "such that additional structures to this fragment introduce non-neutralizing epitopes and may also alter the tertiary structure of the RBD .", "label": "finding"}, {"segment_text": "Taken together , our data suggest that the RBD fragment encompassing spike residues 377-588 is a critical neutralizing receptor-binding fragment and an ideal candidate for development of effective MERS vaccines ,", "label": "finding"}, {"segment_text": "and that adding non-neutralizing structures to this RBD fragment diminishes its neutralizing potential .", "label": "finding"}, {"segment_text": "Therefore , in viral vaccine design ,", "label": "finding"}, {"segment_text": "it is important to identify the most stable and neutralizing viral RBD fragment ,", "label": "finding"}, {"segment_text": "while eliminating unnecessary and non-neutralizing structures ,", "label": "finding"}, {"segment_text": "as a means of `` immunofocusing '' .", "label": "finding"}], "n_segments": 21}
{"paper_id": "56feb53034b99302ba30fa1c3e2042b2118fe6cb", "title": "Systematic screening for novel, serologically reactive Hepatitis E Virus epitopes", "coda_paper_id": 1811, "has_expert_labels": false, "abstract_text": "Background : The National Institutes of Health classified Hepatitis E as an emerging disease since Hepatitis E Virus ( HEV ) is the major cause of acute hepatitis in developing countries . Interestingly , an increasing number of sporadic cases of HEV infections are described in industrialized countries as zoonosis from domestic livestock . Despite the increasing relevance of this pathogen in clinical virology , commercial antibody assays are mainly based on fragments of HEV open reading frame ( ORF ) 2 and ORF3 . The largest ORF1 ( poly - ) protein , however , is not part of current testing formats . Methods : From a synthesized full length HEV genotype 1 cDNA-bank we constructed a complete HEV gene library consisting of 15 respective HEV ORF domains . After bacterial expression and purification of nine recombinant HEV proteins under denaturating conditions serum profiling experiments using 55 sera from patients with known infection status were performed in microarray format . SPSS software assessed the antigenic potential of these nine ORF domains in comparison to seven commercial HEV antigens ( genotype 1 and 3 ) by performing receiver operator characteristics , logistic regression and correlation analysis . Results : HEV antigens produced with our method for serum profiling experiments exhibit the same quality and characteristics as commercial antigens . Serum profiling experiments detected Y , V and X domains as ORF1-antigens with potentially comparable diagnostic significance as the well established epitopes of ORF2 and ORF3 . However no obvious additional increase in sensitivity or specificity was achieved in diagnostic testing as revealed by bioinformatic analysis . Additionally we found that the C-terminal domain of the potential transmembrane protein ORF3 is responsible for IgG and IgM seroreactivity . Data suggest that there might be a genotype specific seroreactivity of homologous ORF2-antigens . Conclusions : The diagnostic value of identified ORF1 epitopes might not necessarily improve sensitivity and specificity , but broaden the overall quality of existing test systems . ORF2 and ORF3-antigens are still commonly used in diagnostic assays and possibly hold the potential to serologically differentiate between genotype 1 and 3 infections . Our systematic approach is a suitable method to investigate HEV domains for their serologic antigenicity . Epitope screening of native viral domains could be a preferable tool in developing new serologic test components .", "gold_segments": [{"segment_text": "Background : The National Institutes of Health classified Hepatitis E as an emerging disease since Hepatitis E Virus ( HEV ) is the major cause of acute hepatitis in developing countries .", "label": "background"}, {"segment_text": "Interestingly , an increasing number of sporadic cases of HEV infections are described in industrialized countries as zoonosis from domestic livestock .", "label": "background"}, {"segment_text": "Despite the increasing relevance of this pathogen in clinical virology ,", "label": "background"}, {"segment_text": "commercial antibody assays are mainly based on fragments of HEV open reading frame ( ORF ) 2 and ORF3 .", "label": "background"}, {"segment_text": "The largest ORF1 ( poly - ) protein ,", "label": "background"}, {"segment_text": "however , is not part of current testing formats .", "label": "background"}, {"segment_text": "Methods : From a synthesized full length HEV genotype 1 cDNA-bank we constructed a complete HEV gene library consisting of 15 respective HEV ORF domains .", "label": "method"}, {"segment_text": "After bacterial expression and purification of nine recombinant HEV proteins under denaturating conditions serum profiling experiments using 55 sera from patients with known infection status were performed in microarray format .", "label": "method"}, {"segment_text": "SPSS software assessed the antigenic potential of these nine ORF domains in comparison to seven commercial HEV antigens ( genotype 1 and 3 ) by performing receiver operator characteristics ,", "label": "method"}, {"segment_text": "logistic regression and correlation analysis .", "label": "method"}, {"segment_text": "Results : HEV antigens produced with our method for serum profiling experiments exhibit the same quality and characteristics as commercial antigens .", "label": "finding"}, {"segment_text": "Serum profiling experiments detected Y ,", "label": "finding"}, {"segment_text": "V and X domains as ORF1-antigens with potentially comparable diagnostic significance as the well established epitopes of ORF2 and ORF3 .", "label": "finding"}, {"segment_text": "However no obvious additional increase in sensitivity or specificity was achieved in diagnostic testing as revealed by bioinformatic analysis .", "label": "finding"}, {"segment_text": "Additionally we found that the C-terminal domain of the potential transmembrane protein ORF3 is responsible for IgG and IgM seroreactivity .", "label": "finding"}, {"segment_text": "Data suggest that there might be a genotype specific seroreactivity of homologous ORF2-antigens .", "label": "finding"}, {"segment_text": "Conclusions : The diagnostic value of identified ORF1 epitopes might not necessarily improve sensitivity and specificity ,", "label": "finding"}, {"segment_text": "but broaden the overall quality of existing test systems .", "label": "finding"}, {"segment_text": "ORF2 and ORF3-antigens are still commonly used in diagnostic assays and possibly hold the potential to serologically differentiate between genotype 1 and 3 infections .", "label": "finding"}, {"segment_text": "Our systematic approach is a suitable method to investigate HEV domains for their serologic antigenicity .", "label": "finding"}, {"segment_text": "Epitope screening of native viral domains could be a preferable tool in developing new serologic test components .", "label": "finding"}], "n_segments": 21}
{"paper_id": "04af84a05b74df6500b8f04040b763b8a67eeb36", "title": "Age effects in monetary valuation of reduced mortality risks: the relevance of age-specific hazard rates", "coda_paper_id": 1330, "has_expert_labels": false, "abstract_text": "This paper highlights the relevance of agespecific hazard rates in explaining the age variation in `` value of statistical life '' ( VSL ) figures . The analysiswhich refers to a stated preference framework-contributes to the ongoing discussion of whether benefits resulting from reduced mortality risk should be valued differently depending on the age of the beneficiaries . By focussing on a life-threatening environmental phenomenon I show that the consideration of the individual 's age-specific hazard rate is important . If a particular risk affects all individuals regardless of their age so that their hazard rate is ageindependent , VSL is rather constant for people at different age ; if hazard rate varies with age , VSL estimates are sensitive to age . The results provide an explanation for the mixed outcomes in empirical studies and illustrate in which cases an adjustment to age may or may not be justified . Efficient provision of live-saving measures requires that such differences to be taken into account .", "gold_segments": [{"segment_text": "This paper highlights the relevance of agespecific hazard rates in explaining the age variation in `` value of statistical life '' ( VSL ) figures .", "label": "purpose"}, {"segment_text": "The analysiswhich refers to a stated preference framework-contributes to the ongoing discussion of whether benefits resulting from reduced mortality risk should be valued differently depending on the age of the beneficiaries .", "label": "background"}, {"segment_text": "By focussing on a life-threatening environmental phenomenon I show that the consideration of the individual 's age-specific hazard rate is important .", "label": "background"}, {"segment_text": "If a particular risk affects all individuals regardless of their age so that their hazard rate is ageindependent ,", "label": "finding"}, {"segment_text": "VSL is rather constant for people at different age ; if hazard rate varies with age ,", "label": "finding"}, {"segment_text": "VSL estimates are sensitive to age .", "label": "finding"}, {"segment_text": "The results provide an explanation for the mixed outcomes in empirical studies and illustrate in which cases an adjustment to age may or may not be justified .", "label": "finding"}, {"segment_text": "Efficient provision of live-saving measures requires that such differences to be taken into account .", "label": "finding"}], "n_segments": 8}
{"paper_id": "31b6292728805572de28133c6eb02ed1d44ef211", "title": "Bioinformatics and Biology Insights o r I g I n A L r e s e A r C h Automated Detection of conformational epitopes Using phage Display peptide sequences", "coda_paper_id": 1211, "has_expert_labels": false, "abstract_text": "Background : Precise determination of conformational epitopes of neutralizing antibodies represents a key step in the rational design of novel vaccines . A powerful experimental method to gain insights on the physical chemical nature of conformational epitopes is the selection of linear peptides that bind with high affinities to a monoclonal antibody of interest by phage display technology . However , the structural characterization of conformational epitopes from these mimotopes is not straightforward , and in the past the interpretation of peptide sequences from phage display experiments focused on linear sequence analysis to find a consensus sequence or common sequence motifs . We present a fully automated search method , EpiSearch that predicts the possible location of conformational epitopes on the surface of an antigen . The algorithm uses peptide sequences from phage display experiments as input , and ranks all surface exposed patches according to the frequency distribution of similar residues in the peptides and in the patch . We have tested the performance of the EpiSearch algorithm for six experimental data sets of phage display experiments , the human epidermal growth factor receptor-2 ( HER-2 / neu ) , the antibody mAb Bo2C11 targeting the C 2 domain of FVIII , antibodies mAb 17b and mAb b12 of the HIV envelope protein gp120 , mAb 13b5 targeting HIV-1 capsid protein and 80R of the SARS coronavirus spike protein . In all these examples the conformational epitopes as determined by the X-ray crystal structures of the antibody-antigen complexes , were found within the highest scoring patches of EpiSearch , covering in most cases more than 50 % residues of experimental observed conformational epitopes . Input options of the program include mapping of a single peptide or a set of peptides on the antigen structure , and the results of the calculation can be visualized on our interactive web server . Availability : Users can access the EpiSearch from our web server", "gold_segments": [{"segment_text": "Background : Precise determination of conformational epitopes of neutralizing antibodies represents a key step in the rational design of novel vaccines .", "label": "background"}, {"segment_text": "A powerful experimental method to gain insights on the physical chemical nature of conformational epitopes is the selection of linear peptides that bind with high affinities to a monoclonal antibody of interest by phage display technology .", "label": "background"}, {"segment_text": "However , the structural characterization of conformational epitopes from these mimotopes is not straightforward ,", "label": "background"}, {"segment_text": "and in the past the interpretation of peptide sequences from phage display experiments focused on linear sequence analysis to find a consensus sequence or common sequence motifs .", "label": "background"}, {"segment_text": "We present a fully automated search method ,", "label": "purpose"}, {"segment_text": "EpiSearch that predicts the possible location of conformational epitopes on the surface of an antigen .", "label": "method"}, {"segment_text": "The algorithm uses peptide sequences from phage display experiments as input ,", "label": "method"}, {"segment_text": "and ranks all surface exposed patches according to the frequency distribution of similar residues in the peptides and in the patch .", "label": "method"}, {"segment_text": "We have tested the performance of the EpiSearch algorithm for six experimental data sets of phage display experiments ,", "label": "method"}, {"segment_text": "the human epidermal growth factor receptor-2 ( HER-2 / neu ) ,", "label": "method"}, {"segment_text": "the antibody mAb Bo2C11 targeting the C 2 domain of FVIII ,", "label": "method"}, {"segment_text": "antibodies mAb 17b and mAb b12 of the HIV envelope protein gp120 ,", "label": "method"}, {"segment_text": "mAb 13b5 targeting HIV-1 capsid protein and 80R of the SARS coronavirus spike protein .", "label": "method"}, {"segment_text": "In all these examples the conformational epitopes as determined by the X-ray crystal structures of the antibody-antigen complexes ,", "label": "finding"}, {"segment_text": "were found within the highest scoring patches of EpiSearch ,", "label": "finding"}, {"segment_text": "covering in most cases more than 50 % residues of experimental observed conformational epitopes .", "label": "finding"}, {"segment_text": "Input options of the program include mapping of a single peptide or a set of peptides on the antigen structure ,", "label": "finding"}, {"segment_text": "and the results of the calculation can be visualized on our interactive web server .", "label": "finding"}, {"segment_text": "Availability : Users can access the EpiSearch from our web server", "label": "finding"}], "n_segments": 19}
{"paper_id": "0150622984aaf93314f67898865dd75ec543b00c", "title": "Macrophages: Their role, activation and polarization in pulmonary diseases", "coda_paper_id": 1394, "has_expert_labels": false, "abstract_text": "Macrophages , circulating in the blood or concatenated into different organs and tissues constitute the first barrier against any disease . They are foremost controllers of both innate and acquired immunity , healthy tissue homeostasis , vasculogenesis and congenital metabolism . Two hallmarks of macrophages are diversity and plasticity due to which they acquire a wobbling array of phenotypes . These phenotypes are appropriately synchronized responses to a variety of different stimuli from either the tissue microenvironment ormicrobes or their products . Based on the phenotype , macrophages are classified into classically activated / ( M1 ) and alternatively activated / ( M2 ) which are further sub-categorized into M2a , M2b , M2c and M2d based upon gene expression profiles . Macrophage phenotype metamorphosis is the regulating factor in initiation , progression , and termination of numerous inflammatory diseases . Several transcriptional factors and other factors controlling gene expression such as miRNAs contribute to the transformation of macrophages at different points in different diseases . Understanding the mechanisms of macrophage polarization and modulation of their phenotypes to adjust to the micro environmental conditions might provide us a great prospective for designing novel therapeutic strategy . In view of the above , this review summarises the activation of macrophages , the factors intricated in activation along with benefaction of macrophage polarization in response to microbial infections , pulmonary toxicity , lung injury and other inflammatory diseases such as chronic obstructive pulmonary dysplasia ( COPD ) , bronchopulmonary dysplasia ( BPD ) , asthma and sepsis , along with the existing efforts to develop therapies targeting this facet of macrophage biology .", "gold_segments": [{"segment_text": "Macrophages , circulating in the blood or concatenated into different organs and tissues constitute the first barrier against any disease .", "label": "background"}, {"segment_text": "They are foremost controllers of both innate and acquired immunity ,", "label": "background"}, {"segment_text": "healthy tissue homeostasis , vasculogenesis and congenital metabolism .", "label": "background"}, {"segment_text": "Two hallmarks of macrophages are diversity and plasticity due to which they acquire a wobbling array of phenotypes .", "label": "background"}, {"segment_text": "These phenotypes are appropriately synchronized responses to a variety of different stimuli from either the tissue microenvironment ormicrobes or their products .", "label": "background"}, {"segment_text": "Based on the phenotype , macrophages are classified into classically activated / ( M1 ) and alternatively activated / ( M2 ) which are further sub-categorized into M2a ,", "label": "background"}, {"segment_text": "M2b , M2c and M2d based upon gene expression profiles .", "label": "background"}, {"segment_text": "Macrophage phenotype metamorphosis is the regulating factor in initiation ,", "label": "background"}, {"segment_text": "progression , and termination of numerous inflammatory diseases .", "label": "background"}, {"segment_text": "Several transcriptional factors and other factors controlling gene expression such as miRNAs contribute to the transformation of macrophages at different points in different diseases .", "label": "background"}, {"segment_text": "Understanding the mechanisms of macrophage polarization and modulation of their phenotypes to adjust to the micro environmental conditions might provide us a great prospective for designing novel therapeutic strategy .", "label": "background"}, {"segment_text": "In view of the above ,", "label": "finding"}, {"segment_text": "this review summarises the activation of macrophages ,", "label": "finding"}, {"segment_text": "the factors intricated in activation along with benefaction of macrophage polarization in response to microbial infections ,", "label": "finding"}, {"segment_text": "pulmonary toxicity , lung injury and other inflammatory diseases such as chronic obstructive pulmonary dysplasia ( COPD ) ,", "label": "finding"}, {"segment_text": "bronchopulmonary dysplasia ( BPD ) ,", "label": "finding"}, {"segment_text": "asthma and sepsis , along with the existing efforts to develop therapies targeting this facet of macrophage biology .", "label": "finding"}], "n_segments": 17}
{"paper_id": "0a6d3a2d7197b1d4ac24d24f2f154b5fa583f230", "title": "Enzymatic pathways of the brain renin-angiotensin system: Unsolved problems and continuing challenges", "coda_paper_id": 1812, "has_expert_labels": false, "abstract_text": "The brain renin-angiotensin system continues to be enigmatic more than 40 years after the brain was first recognized to be a site of action of angiotensin II . This review focuses on the enzymatic pathways for the formation and degradation of the growing number of active angiotensins in the brain . A brief description and nomenclature of the peptidases involved in the processing of angiotensin peptides in the brain is given . Of primary interest is the array of enzymes that degrade radiolabeled angiotensins in receptor binding assays . This poses major challenges to studies of brain angiotensin receptors and it is debatable whether an accurate determination of brain angiotensin receptor binding kinetics has yet been made . The quandary facing the investigator of brain angiotensin receptors is the need to protect the radioligand from metabolic alteration while maintaining the characteristics of the receptors in situ . It is the tenet of this review that we have yet to fully understand the binding characteristics of brain angiotensin receptors and the extent of their distribution in the brain because of our inability to fully protect the angiotensins from metabolic alteration until equilibrium binding conditions can be attained .", "gold_segments": [{"segment_text": "The brain renin-angiotensin system continues to be enigmatic more than 40 years after the brain was first recognized to be a site of action of angiotensin II .", "label": "background"}, {"segment_text": "This review focuses on the enzymatic pathways for the formation and degradation of the growing number of active angiotensins in the brain .", "label": "purpose"}, {"segment_text": "A brief description and nomenclature of the peptidases involved in the processing of angiotensin peptides in the brain is given .", "label": "background"}, {"segment_text": "Of primary interest is the array of enzymes that degrade radiolabeled angiotensins in receptor binding assays .", "label": "background"}, {"segment_text": "This poses major challenges to studies of brain angiotensin receptors and it is debatable whether an accurate determination of brain angiotensin receptor binding kinetics has yet been made .", "label": "background"}, {"segment_text": "The quandary facing the investigator of brain angiotensin receptors is the need to protect the radioligand from metabolic alteration while maintaining the characteristics of the receptors in situ .", "label": "finding"}, {"segment_text": "It is the tenet of this review that we have yet to fully understand the binding characteristics of brain angiotensin receptors and the extent of their distribution in the brain because of our inability to fully protect the angiotensins from metabolic alteration until equilibrium binding conditions can be attained .", "label": "finding"}], "n_segments": 7}
{"paper_id": "4bc55ca2806bde632c4d929ff7da7f97009aa85f", "title": "ARTICLE Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections", "coda_paper_id": 1224, "has_expert_labels": false, "abstract_text": "The potential for avian influenza H5N1 outbreaks has increased in recent years . Thus , it is paramount to develop novel strategies to alleviate death rates . Here we show that avian influenza A H5N1-infected patients exhibit markedly increased serum levels of angiotensin II . High serum levels of angiotensin II appear to be linked to the severity and lethality of infection , at least in some patients . In experimental mouse models , infection with highly pathogenic avian influenza A H5N1 virus results in downregulation of angiotensin-converting enzyme 2 ( ACE2 ) expression in the lung and increased serum angiotensin II levels . Genetic inactivation of ACE2 causes severe lung injury in H5N1-challenged mice , confirming a role of ACE2 in H5N1-induced lung pathologies . Administration of recombinant human ACE2 ameliorates avian influenza H5N1 virus-induced lung injury in mice . Our data link H5N1 virus-induced acute lung failure to ACE2 and provide a potential treatment strategy to address future flu pandemics .", "gold_segments": [{"segment_text": "The potential for avian influenza H5N1 outbreaks has increased in recent years .", "label": "background"}, {"segment_text": "Thus , it is paramount to develop novel strategies to alleviate death rates .", "label": "background"}, {"segment_text": "Here we show that avian influenza A H5N1-infected patients exhibit markedly increased serum levels of angiotensin II .", "label": "purpose"}, {"segment_text": "High serum levels of angiotensin II appear to be linked to the severity and lethality of infection ,", "label": "background"}, {"segment_text": "at least in some patients .", "label": "background"}, {"segment_text": "In experimental mouse models , infection with highly pathogenic avian influenza A H5N1 virus results in downregulation of angiotensin-converting enzyme 2 ( ACE2 ) expression in the lung and increased serum angiotensin II levels .", "label": "finding"}, {"segment_text": "Genetic inactivation of ACE2 causes severe lung injury in H5N1-challenged mice ,", "label": "finding"}, {"segment_text": "confirming a role of ACE2 in H5N1-induced lung pathologies .", "label": "finding"}, {"segment_text": "Administration of recombinant human ACE2 ameliorates avian influenza H5N1 virus-induced lung injury in mice .", "label": "finding"}, {"segment_text": "Our data link H5N1 virus-induced acute lung failure to ACE2 and provide a potential treatment strategy to address future flu pandemics .", "label": "finding"}], "n_segments": 10}
{"paper_id": "7c05460d903238444f33dc1df904f24fd3a52222", "title": "Brief review Trends in malaria cases in Japan", "coda_paper_id": 1985, "has_expert_labels": false, "abstract_text": "Just after World War II , more than 10,000 malaria cases per year were reported in Japan , including indigenous , imported and induced malaria . Malaria has been successfully eradicated since 1961 in Japan and now only imported malaria cases are encountered . However , as the number of Japanese people who are going abroad and also the number of foreigners who are visiting Japan increases ( about 16 and 5 millions , respectively , in 2001 ) , so does the chance for Japanese doctors to see imported malaria or transfusion-transmitted malaria cases . In fact , the total number of the patients with acute malaria in Japan has been around 100-150 annually for the last 10 years . Of those , about 75 % are Japanese and 25 % are foreigners , and about 75 % are male and 25 % are female . The peak age is in the 20 s. Recently , about 45 % of patients are Plasmodium falciparum and another 45 % Plasmodium vivax infections . The former species is likely to be seen in travelers coming back from African countries and the latter is mainly from Asian countries . The important issue is that patients in Japan have not been diagnosed promptly nor treated properly because doctors in Japan are no longer familiar with tropical medicine . Therefore , some patients are dying from severe malaria as a consequence . As it is , most of the effective medicines for drug-resistant malaria or severe malaria have not been registered in Japan . There is now a need for medical practitioners to focus on travel medicine in Japan .", "gold_segments": [{"segment_text": "Just after World War II ,", "label": "background"}, {"segment_text": "more than 10,000 malaria cases per year were reported in Japan ,", "label": "background"}, {"segment_text": "including indigenous , imported and induced malaria .", "label": "background"}, {"segment_text": "Malaria has been successfully eradicated since 1961 in Japan and now only imported malaria cases are encountered .", "label": "background"}, {"segment_text": "However , as the number of Japanese people who are going abroad and also the number of foreigners who are visiting Japan increases ( about 16 and 5 millions , respectively , in 2001 ) ,", "label": "background"}, {"segment_text": "so does the chance for Japanese doctors to see imported malaria or transfusion-transmitted malaria cases .", "label": "background"}, {"segment_text": "In fact , the total number of the patients with acute malaria in Japan has been around 100-150 annually for the last 10 years .", "label": "background"}, {"segment_text": "Of those , about 75 % are Japanese and 25 % are foreigners ,", "label": "background"}, {"segment_text": "and about 75 % are male and 25 % are female .", "label": "background"}, {"segment_text": "The peak age is in the 20 s. Recently ,", "label": "background"}, {"segment_text": "about 45 % of patients are Plasmodium falciparum and another 45 % Plasmodium vivax infections .", "label": "background"}, {"segment_text": "The former species is likely to be seen in travelers coming back from African countries and the latter is mainly from Asian countries .", "label": "background"}, {"segment_text": "The important issue is that patients in Japan have not been diagnosed promptly nor treated properly because doctors in Japan are no longer familiar with tropical medicine .", "label": "background"}, {"segment_text": "Therefore , some patients are dying from severe malaria as a consequence .", "label": "background"}, {"segment_text": "As it is , most of the effective medicines for drug-resistant malaria or severe malaria have not been registered in Japan .", "label": "background"}, {"segment_text": "There is now a need for medical practitioners to focus on travel medicine in Japan .", "label": "finding"}], "n_segments": 16}
{"paper_id": "3d3b6dcb6f3a4fae4bb4242a4773d21bc222a27a", "title": "EFFECTS OF AMBIENT TEMPERATURES ON CLINICAL AND IMMUNE RESPONSES OF PIGS INFECTED WITH TRANSMISSIBLE GASTRO- ENTERITIS VIRUS", "coda_paper_id": 1672, "has_expert_labels": false, "abstract_text": "Shimizu , M. and Shimizu , Y. , 1979 . Effects of ambient temperatures on clinical and immune responses of pigs infected with transmissible gastroenteritis virus . Vet . Microbiol. , 4 : 109 -- 116 . Two-to three-months-old pigs infected with transmissible gastroenteritis ( TGE ) virus showed no clinical response when housed at 30 °C , but comparable infected pigs exposed to temperature changes from 30 °C to 4 °C following infection showed typical signs of TGE . Development of TGE-specific immune responses , as measured by blastogenic response of tissue lymphocytes , occurred at 3 days post-inoculation ( DPI ) in pigs held at 30 °C , but not until 7 DPI in infected pigs held under the adverse conditions . Immunosuppression with corticosteroids resulted in a fall in circulatory T cells , lowering of non-specific blastogenic response of circulatory lymphocytes , and clinical signs of disease when immunosuppressed pigs were infected with TGE virus and held at 30 °C . It is suggested that clinical responses to TGE virus infection may be affected by the influence of ambient temperatures on the immune responses of pigs .", "gold_segments": [{"segment_text": "Shimizu , M. and Shimizu , Y. , 1979 .", "label": "other"}, {"segment_text": "Effects of ambient temperatures on clinical and immune responses of pigs infected with transmissible gastroenteritis virus .", "label": "background"}, {"segment_text": "Vet .", "label": "other"}, {"segment_text": "Microbiol. , 4 : 109 -- 116 .", "label": "other"}, {"segment_text": "Two-to three-months-old pigs infected with transmissible gastroenteritis ( TGE ) virus showed no clinical response when housed at 30 °C ,", "label": "finding"}, {"segment_text": "but comparable infected pigs exposed to temperature changes from 30 °C to 4 °C following infection showed typical signs of TGE .", "label": "finding"}, {"segment_text": "Development of TGE-specific immune responses ,", "label": "finding"}, {"segment_text": "as measured by blastogenic response of tissue lymphocytes ,", "label": "finding"}, {"segment_text": "occurred at 3 days post-inoculation ( DPI ) in pigs held at 30 °C ,", "label": "finding"}, {"segment_text": "but not until 7 DPI in infected pigs held under the adverse conditions .", "label": "finding"}, {"segment_text": "Immunosuppression with corticosteroids resulted in a fall in circulatory T cells ,", "label": "finding"}, {"segment_text": "lowering of non-specific blastogenic response of circulatory lymphocytes ,", "label": "finding"}, {"segment_text": "and clinical signs of disease when immunosuppressed pigs were infected with TGE virus and held at 30 °C .", "label": "finding"}, {"segment_text": "It is suggested that clinical responses to TGE virus infection may be affected by the influence of ambient temperatures on the immune responses of pigs .", "label": "finding"}], "n_segments": 14}
{"paper_id": "7f3ca4133a2788e02072b7c38d2fd7dca26b7458", "title": "Recombinant vesicular stomatitis virus expressing the spike protein of genotype 2b porcine epidemic diarrhea virus: A platform for vaccine development against emerging epidemic isolates", "coda_paper_id": 1469, "has_expert_labels": false, "abstract_text": "Emerging porcine epidemic diarrhea viruses ( PEDVs ) have caused large economic losses since 2010 , and G2b is the prevalent globally epidemic genotype . Given the fastidious isolation of emerging PEDV in cell culture and difficulties in retaining the isolate infectivity upon further in vitro passage , highly attenuated recombinant vesicular stomatitis virus ( rVSV MT ) was used as a vector to express the PEDV spike ( S ) protein , aiming to develop a subunit vaccine against G2b viruses . An S protein with 19 of its cytoplasmic domain amino acids deleted could be incorporated into VSV particles , generating rVSV MT ( VSV MT - S Δ19 ) with high efficiency . Our results suggest that VSV MT - S Δ19 could effectively induce PEDV-specific immunity in pigs via intramuscular , but not intranasal , immunization . Notably , immunizations of sows with VSV MT - S Δ19 provided protective lactogenic immunity against a virulent G2b PEDV challenge in piglets . Consequently , recombinant VSV MT may be a promising platform for preparing a subunit vaccine against PEDV .", "gold_segments": [{"segment_text": "Emerging porcine epidemic diarrhea viruses ( PEDVs ) have caused large economic losses since 2010 ,", "label": "background"}, {"segment_text": "and G2b is the prevalent globally epidemic genotype .", "label": "background"}, {"segment_text": "Given the fastidious isolation of emerging PEDV in cell culture and difficulties in retaining the isolate infectivity upon further in vitro passage ,", "label": "background"}, {"segment_text": "highly attenuated recombinant vesicular stomatitis virus ( rVSV MT ) was used as a vector to express the PEDV spike ( S ) protein ,", "label": "method"}, {"segment_text": "aiming to develop a subunit vaccine against G2b viruses .", "label": "method"}, {"segment_text": "An S protein with 19 of its cytoplasmic domain amino acids deleted could be incorporated into VSV particles ,", "label": "method"}, {"segment_text": "generating rVSV MT ( VSV MT - S Δ19 ) with high efficiency .", "label": "method"}, {"segment_text": "Our results suggest that VSV MT - S Δ19 could effectively induce PEDV-specific immunity in pigs via intramuscular ,", "label": "finding"}, {"segment_text": "but not intranasal , immunization .", "label": "finding"}, {"segment_text": "Notably , immunizations of sows with VSV MT - S Δ19 provided protective lactogenic immunity against a virulent G2b PEDV challenge in piglets .", "label": "finding"}, {"segment_text": "Consequently , recombinant VSV MT may be a promising platform for preparing a subunit vaccine against PEDV .", "label": "finding"}], "n_segments": 11}
{"paper_id": "b5b9826606f22f2afe8a12ed3fc002b6e830727b", "title": "Standing your Ground to Exoribonucleases: Function of Flavivirus Long Non-coding RNAs", "coda_paper_id": 1580, "has_expert_labels": false, "abstract_text": "Members of the Flaviviridae ( e.g. Dengue virus , West Nile virus , and Hepatitis C virus ) contain a positive-sense RNA genome that encodes a large polyprotein . It is now also clear most if not all of these viruses also produce an abundant subgenomic long non-coding RNA . These non-coding RNAs , which are called subgenomicflavivirus RNAs ( sfRNAs ) or Xrn1-resistant RNAs ( xrRNAs ) , are stable decay intermediates generated from the viral genomic RNA through the stalling of the cellular exoribonuclease Xrn1 at highly structured regions . Several functions of these flavivirus long non-coding RNAs have been revealed in recent years . The generation of these sfRNAs/xrRNAs from viral transcripts results in the repression of Xrn1 and the dysregulation of cellular mRNA stability . The abundant sfRNAs also serve directly as a decoy for important cellular protein regulators of the interferon and RNA interference antiviral pathways . Thus the generation of long non-coding RNAs from flaviviruses , hepaciviruses and pestiviruses likely disrupts aspects of innate immunity and may directly contribute to viral replication , cytopathology and pathogenesis .", "gold_segments": [{"segment_text": "Members of the Flaviviridae ( e.g. Dengue virus , West Nile virus , and Hepatitis C virus ) contain a positive-sense RNA genome that encodes a large polyprotein .", "label": "background"}, {"segment_text": "It is now also clear most if not all of these viruses also produce an abundant subgenomic long non-coding RNA .", "label": "background"}, {"segment_text": "These non-coding RNAs , which are called subgenomicflavivirus RNAs ( sfRNAs ) or Xrn1-resistant RNAs ( xrRNAs ) ,", "label": "background"}, {"segment_text": "are stable decay intermediates generated from the viral genomic RNA through the stalling of the cellular exoribonuclease Xrn1 at highly structured regions .", "label": "background"}, {"segment_text": "Several functions of these flavivirus long non-coding RNAs have been revealed in recent years .", "label": "background"}, {"segment_text": "The generation of these sfRNAs/xrRNAs from viral transcripts results in the repression of Xrn1 and the dysregulation of cellular mRNA stability .", "label": "background"}, {"segment_text": "The abundant sfRNAs also serve directly as a decoy for important cellular protein regulators of the interferon and RNA interference antiviral pathways .", "label": "background"}, {"segment_text": "Thus the generation of long non-coding RNAs from flaviviruses ,", "label": "finding"}, {"segment_text": "hepaciviruses and pestiviruses likely disrupts aspects of innate immunity and may directly contribute to viral replication , cytopathology and pathogenesis .", "label": "finding"}], "n_segments": 9}
{"paper_id": "e7d8d6154bca02cc6868159cef4f7551bd9ddb89", "title": "BACULOVIRUS DISPLAY: A MULTIFUNCTIONAL TECHNOLOGY FOR GENE DELIVERY AND EUKARYOTIC LIBRARY DEVELOPMENT", "coda_paper_id": 1722, "has_expert_labels": false, "abstract_text": "For over a decade , phage display has proven to be of immense value , allowing selection of a large variety of genes with novel functions from diverse libraries . However , the folding and modification requirements of complex proteins place a severe constraint on the type of protein that can be successfully displayed using this strategy , a restriction that could be resolved by similarly engineering a eukaryotic virus for display purposes . The quite recently established eukaryotic molecular biology tool , the baculovirus display vector system ( BDVS ) , allows combination of genotype with phenotype and thereby enables presentation of eukaryotic proteins on the viral envelope or capsid . Data have shown that the baculovirus , Autographa californica multiple nucleopolyhedrovirus ( AcMNPV ) , is a versatile tool for eukaryotic virus display . Insertion of heterologous peptides and/or proteins into the viral surface by utilizing the major envelope glycoprotein gp64 , or foreign membrane-derived counterparts , allows incorporation of the sequence of interest onto the surface of infected cells and virus particles . A number of strategies are being investigated in order to further develop the display capabilities of AcMNPV and improve the complexity of a library that may be accommodated . Numerous expression vectors for various approaches of surface display have already been developed . Further improvement of both insertion and selection strategies toward development of a refined tool for 91 ADVANCES IN VIRUS RESEARCH , VOL 68 use in the creation of useful eukaryotic libraries is , however , needed . Here , the status of baculovirus display with respect to alteration of virus tropism , antigen presentation , transgene expression in mammalian cells , and development of eukaryotic libraries will be reviewed .", "gold_segments": [{"segment_text": "For over a decade , phage display has proven to be of immense value ,", "label": "background"}, {"segment_text": "allowing selection of a large variety of genes with novel functions from diverse libraries .", "label": "background"}, {"segment_text": "However , the folding and modification requirements of complex proteins place a severe constraint on the type of protein that can be successfully displayed using this strategy ,", "label": "background"}, {"segment_text": "a restriction that could be resolved by similarly engineering a eukaryotic virus for display purposes .", "label": "background"}, {"segment_text": "The quite recently established eukaryotic molecular biology tool ,", "label": "background"}, {"segment_text": "the baculovirus display vector system ( BDVS ) ,", "label": "background"}, {"segment_text": "allows combination of genotype with phenotype and thereby enables presentation of eukaryotic proteins on the viral envelope or capsid .", "label": "background"}, {"segment_text": "Data have shown that the baculovirus ,", "label": "background"}, {"segment_text": "Autographa californica multiple nucleopolyhedrovirus ( AcMNPV ) ,", "label": "background"}, {"segment_text": "is a versatile tool for eukaryotic virus display .", "label": "background"}, {"segment_text": "Insertion of heterologous peptides and/or proteins into the viral surface by utilizing the major envelope glycoprotein gp64 ,", "label": "background"}, {"segment_text": "or foreign membrane-derived counterparts , allows incorporation of the sequence of interest onto the surface of infected cells and virus particles .", "label": "background"}, {"segment_text": "A number of strategies are being investigated in order to further develop the display capabilities of AcMNPV and improve the complexity of a library that may be accommodated .", "label": "background"}, {"segment_text": "Numerous expression vectors for various approaches of surface display have already been developed .", "label": "background"}, {"segment_text": "Further improvement of both insertion and selection strategies toward development of a refined tool for 91 ADVANCES IN VIRUS RESEARCH ,", "label": "background"}, {"segment_text": "VOL 68 use in the creation of useful eukaryotic libraries is , however , needed .", "label": "background"}, {"segment_text": "Here , the status of baculovirus display with respect to alteration of virus tropism ,", "label": "finding"}, {"segment_text": "antigen presentation , transgene expression in mammalian cells ,", "label": "finding"}, {"segment_text": "and development of eukaryotic libraries will be reviewed .", "label": "finding"}], "n_segments": 19}
{"paper_id": "151b29e4b482ad11ee11e83cec4f3faebb8124c5", "title": "Oligomerized Transferrin Receptors Are Selectively Retained by a Lumenal Sorting Signal in a Long-lived Endocytic Recycling Compartment", "coda_paper_id": 1875, "has_expert_labels": false, "abstract_text": "Cross-linking of surface receptors results in 1 . Abbreviations used in this paper : 2-IT , 2-iminothiolane ; ct2-M , a2-macroglobulin ; I3-VLDL , 13-very low density lipoprotein ; Au-F-Tfl0 , fluorescein-labeled-multivalent transferrin-colloidal gold conjugate ; Cy3-Tf , Cy3-1abeled-transferrin ; DAB , diaminobenzadine ; DiI-LDL , 1,1 ' - dioctadecyl-3,3,3 ' ,3 ' - tetramethylindocarbocyanine-labeled-low density lipoprotein ; F-Tfl0 , fluorescein-labeled-multivalent transferrin ; LDL , low density lipoprotein ; sulfo-MBS , m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester ; Tf , transferrin ; TfR , transferrin receptor ; Tfl0 , multivalent transferrin .", "gold_segments": [{"segment_text": "Cross-linking of surface receptors results in 1 .", "label": "background"}, {"segment_text": "Abbreviations used in this paper : 2-IT ,", "label": "background"}, {"segment_text": "2-iminothiolane ; ct2-M , a2-macroglobulin ; I3-VLDL ,", "label": "background"}, {"segment_text": "13-very low density lipoprotein ; Au-F-Tfl0 ,", "label": "background"}, {"segment_text": "fluorescein-labeled-multivalent transferrin-colloidal gold conjugate ; Cy3-Tf ,", "label": "background"}, {"segment_text": "Cy3-1abeled-transferrin ; DAB , diaminobenzadine ; DiI-LDL ,", "label": "background"}, {"segment_text": "1,1 ' - dioctadecyl-3,3,3 ' ,3 ' - tetramethylindocarbocyanine-labeled-low density lipoprotein ; F-Tfl0 ,", "label": "background"}, {"segment_text": "fluorescein-labeled-multivalent transferrin ; LDL , low density lipoprotein ; sulfo-MBS ,", "label": "background"}, {"segment_text": "m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester ; Tf , transferrin ; TfR ,", "label": "background"}, {"segment_text": "transferrin receptor ; Tfl0 , multivalent transferrin .", "label": "background"}], "n_segments": 10}
{"paper_id": "eb65ef8d3ff24ddb51c4f091a46394f513a9d4d9", "title": "Intracranial Inoculation Is More Potent Than Intranasal Inoculation for Inducing Optic Neuritis in the Mouse Hepatitis Virus-Induced Model of Multiple Sclerosis", "coda_paper_id": 1676, "has_expert_labels": false, "abstract_text": "Neurotropic strains of mouse hepatitis virus ( MHV ) induce acute inflammation and chronic demyelination in the spinal cord and optic nerves mediated by axonal spread following intracranial inoculation in mice , with pathologic features similar to the human demyelinating disease multiple sclerosis . Spinal cord demyelination is also induced following intranasal inoculation with neurotropic MHV strains , however much higher viral doses are required as compared to intracranial inoculation . Recently , it was shown that intranasal administration of low concentrations of proteins leads to significant , rapid accumulation of protein in the optic nerve and in the eye , with only low levels reaching spinal cord and other brain regions . Thus , we examined whether intranasal inoculation with MHV at doses equivalent to those given intracranially could induce optic neuritis-inflammation , demyelination and loss of retinal ganglion cells ( RGCs ) in the optic nerve with or without inducing spinal cord demyelination . Four week old male C57BL/6J mice were inoculated intracranially with the recombinant demyelinating strain RSA59 , or intranasally with RSA59 or the non-demyelinating strain RSMHV2 as control . One month post-inoculation , mice inoculated intracranially with RSA59 had significant myelin loss in both spinal cord and optic nerves , with significant loss of RGCs as well , consistent with prior studies . As expected , intranasal inoculation with RSA59 failed to induce demyelination in spinal cord ; however , it also did not induce optic nerve demyelination . No acute inflammation was found , and no viral antigen was detected , in the optic nerve or retina 1 day after inoculation . Results confirm the neurotropic effects of RSA59 following intracranial inoculation , and suggest that direct infection with axonal transport of virus from brain to spinal cord and optic nerve is required to induce demyelinating disease . These studies suggest that MHV does not selectively concentrate in optic nerve and retina to sufficient levels to induce demyelination following intranasal inoculation . Intracranial inoculation should continue to be considered a preferred method for studies of MHV-induced optic neuritis and central nervous system ( CNS ) demyelinating disease .", "gold_segments": [{"segment_text": "Neurotropic strains of mouse hepatitis virus ( MHV ) induce acute inflammation and chronic demyelination in the spinal cord and optic nerves mediated by axonal spread following intracranial inoculation in mice ,", "label": "background"}, {"segment_text": "with pathologic features similar to the human demyelinating disease multiple sclerosis .", "label": "background"}, {"segment_text": "Spinal cord demyelination is also induced following intranasal inoculation with neurotropic MHV strains ,", "label": "background"}, {"segment_text": "however much higher viral doses are required as compared to intracranial inoculation .", "label": "background"}, {"segment_text": "Recently , it was shown that intranasal administration of low concentrations of proteins leads to significant ,", "label": "background"}, {"segment_text": "rapid accumulation of protein in the optic nerve and in the eye ,", "label": "background"}, {"segment_text": "with only low levels reaching spinal cord and other brain regions .", "label": "background"}, {"segment_text": "Thus , we examined whether intranasal inoculation with MHV at doses equivalent to those given intracranially could induce optic neuritis-inflammation ,", "label": "purpose"}, {"segment_text": "demyelination and loss of retinal ganglion cells ( RGCs ) in the optic nerve with or without inducing spinal cord demyelination .", "label": "purpose"}, {"segment_text": "Four week old male C57BL/6J mice were inoculated intracranially with the recombinant demyelinating strain RSA59 ,", "label": "method"}, {"segment_text": "or intranasally with RSA59 or the non-demyelinating strain RSMHV2 as control .", "label": "method"}, {"segment_text": "One month post-inoculation , mice inoculated intracranially with RSA59 had significant myelin loss in both spinal cord and optic nerves ,", "label": "finding"}, {"segment_text": "with significant loss of RGCs as well , consistent with prior studies .", "label": "finding"}, {"segment_text": "As expected , intranasal inoculation with RSA59 failed to induce demyelination in spinal cord ; however ,", "label": "finding"}, {"segment_text": "it also did not induce optic nerve demyelination .", "label": "finding"}, {"segment_text": "No acute inflammation was found ,", "label": "finding"}, {"segment_text": "and no viral antigen was detected ,", "label": "finding"}, {"segment_text": "in the optic nerve or retina 1 day after inoculation .", "label": "finding"}, {"segment_text": "Results confirm the neurotropic effects of RSA59 following intracranial inoculation ,", "label": "finding"}, {"segment_text": "and suggest that direct infection with axonal transport of virus from brain to spinal cord and optic nerve is required to induce demyelinating disease .", "label": "finding"}, {"segment_text": "These studies suggest that MHV does not selectively concentrate in optic nerve and retina to sufficient levels to induce demyelination following intranasal inoculation .", "label": "finding"}, {"segment_text": "Intracranial inoculation should continue to be considered a preferred method for studies of MHV-induced optic neuritis and central nervous system ( CNS ) demyelinating disease .", "label": "finding"}], "n_segments": 22}
{"paper_id": "cf3c22d1c9c1a4487c7e1356c7b1bbb1b5296117", "title": "Phage display technique identifies the interaction of severe acute respiratory syndrome coronavirus open reading frame 6 protein with nuclear pore complex interacting protein NPIPB3 in modulating Type I interferon antagonism", "coda_paper_id": 1004, "has_expert_labels": false, "abstract_text": "Background/Purpose : Severe acute respiratory syndrome coronavirus ( SARS-CoV ) proteins including ORF6 inhibit Type I interferon ( IFN ) signaling . Methods : This study identified SARS-CoV ORF6-interacting proteins using the phage displayed human lung cDNA libraries , and examined the association of ORF6ehost factor interaction with Type I IFN antagonism . After the fifth round of biopanning with Escherichia coli-synthesized ORF6-His tagged protein , the relative binding affinity of phage clones to ORF6 was determined using direct enzyme-linked immunosorbent assay . Results : The highest affinity clone to ORF6 displayed the C-terminal domain of NPIPB3 ( nuclear pore complex interacting protein family , member B3 ; also named as phosphatidylinositol-3kinase-related kinase SMG-1 isoform 1 homolog ) . The coimmunoprecipitation assay demonstrated the direct binding of ORF6 to the C-terminal domain of NPIPB3 in vitro . Confocal Journal of Microbiology , Immunology and Infection ( 2017 ) 50 , 277e285 imaging revealed a close colocalization of SARS-CoV ORF6 protein with NPIPB3 in human promonocytes . The dual luciferase reporter assay showed that the C-terminal domain of NPIPB3 attenuated the antagonistic activity of SARS-CoV ORF6 on IFN-b-induced ISRE ( IFN stimulated response element ) - responsive firefly luciferase activity . In addition , confocal imaging and Western blotting assays revealed that the increases in STAT-1 nuclear translocation and phosphorylation occurred in the transfected cells expressing both genes of ORF6 and NPIPB3 , but not in the ORF6-expressing cells in response to IFN-b . Conclusion : The overexpression of NPIPB3 restored the IFN-b responses in SARS-CoV ORF6 expressing cells , indicating that the interaction of SARS CoV ORF6 and NPIPB3 reduced Type I IFN antagonism by SARS-CoV ORF6 .", "gold_segments": [{"segment_text": "Background/Purpose : Severe acute respiratory syndrome coronavirus ( SARS-CoV ) proteins including ORF6 inhibit Type I interferon ( IFN ) signaling .", "label": "background"}, {"segment_text": "Methods : This study identified SARS-CoV ORF6-interacting proteins using the phage displayed human lung cDNA libraries ,", "label": "method"}, {"segment_text": "and examined the association of ORF6ehost factor interaction with Type I IFN antagonism .", "label": "method"}, {"segment_text": "After the fifth round of biopanning with Escherichia coli-synthesized ORF6-His tagged protein ,", "label": "method"}, {"segment_text": "the relative binding affinity of phage clones to ORF6 was determined using direct enzyme-linked immunosorbent assay .", "label": "method"}, {"segment_text": "Results : The highest affinity clone to ORF6 displayed the C-terminal domain of NPIPB3 ( nuclear pore complex interacting protein family , member B3 ; also named as phosphatidylinositol-3kinase-related kinase SMG-1 isoform 1 homolog ) .", "label": "finding"}, {"segment_text": "The coimmunoprecipitation assay demonstrated the direct binding of ORF6 to the C-terminal domain of NPIPB3 in vitro .", "label": "finding"}, {"segment_text": "Confocal Journal of Microbiology , Immunology and Infection ( 2017 ) 50 ,", "label": "finding"}, {"segment_text": "277e285 imaging revealed a close colocalization of SARS-CoV ORF6 protein with NPIPB3 in human promonocytes .", "label": "finding"}, {"segment_text": "The dual luciferase reporter assay showed that the C-terminal domain of NPIPB3 attenuated the antagonistic activity of SARS-CoV ORF6 on IFN-b-induced ISRE ( IFN stimulated response element ) - responsive firefly luciferase activity .", "label": "finding"}, {"segment_text": "In addition , confocal imaging and Western blotting assays revealed that the increases in STAT-1 nuclear translocation and phosphorylation occurred in the transfected cells expressing both genes of ORF6 and NPIPB3 ,", "label": "finding"}, {"segment_text": "but not in the ORF6-expressing cells in response to IFN-b .", "label": "finding"}, {"segment_text": "Conclusion : The overexpression of NPIPB3 restored the IFN-b responses in SARS-CoV ORF6 expressing cells ,", "label": "finding"}, {"segment_text": "indicating that the interaction of SARS CoV ORF6 and NPIPB3 reduced Type I IFN antagonism by SARS-CoV ORF6 .", "label": "finding"}], "n_segments": 14}
{"paper_id": "7f911fcc63f431561d8dc09ed831ce558ca2d773", "title": "Identification of a conserved linear B-cell epitope in the M protein of porcine epidemic diarrhea virus", "coda_paper_id": 1489, "has_expert_labels": false, "abstract_text": "Background : The major structural protein of coronaviruses , the membrane ( M ) protein , can elicit the formation of protective antibodies , but little information is available about the M protein of porcine epidemic diarrhea virus ( PEDV ) . Identification of epitopes on the PEDV M protein will be helpful in the elucidation of the antigenic properties of this protein . Results : One hybridoma cell line secreting anti-M protein monoclonal antibody ( McAb ) was generated and designated 4D4 . To map the epitopes on the PEDV M protein , a total of 17 partially overlapping fragments covering the C-terminus of M protein were expressed as fusion proteins with a 6 × His tag or a GST tag . A linear motif , 193 TGWAFYVR 200 , was identified by enzyme-linked immunosorbent assay ( ELISA ) and western blot ( WB ) analysis using McAb 4D4 . The motif 195 WAFYVR 200 was the minimal requirement for reactivity , as demonstrated by removing amino acids individually from both ends of the motif 193 TGWAFYVR 200 . The result of WB analysis showed that the 4D4-defined epitope could be recognized by PEDV-positive serum , but not transmissible gastroenteritis virus ( TGEV ) - positive serum . Furthermore , this epitope was highly conserved among different PEDV strains , as shown by alignment and comparison of sequences .", "gold_segments": [{"segment_text": "Background : The major structural protein of coronaviruses ,", "label": "background"}, {"segment_text": "the membrane ( M ) protein ,", "label": "background"}, {"segment_text": "can elicit the formation of protective antibodies ,", "label": "background"}, {"segment_text": "but little information is available about the M protein of porcine epidemic diarrhea virus ( PEDV ) .", "label": "background"}, {"segment_text": "Identification of epitopes on the PEDV M protein will be helpful in the elucidation of the antigenic properties of this protein .", "label": "background"}, {"segment_text": "Results : One hybridoma cell line secreting anti-M protein monoclonal antibody ( McAb ) was generated and designated 4D4 .", "label": "finding"}, {"segment_text": "To map the epitopes on the PEDV M protein ,", "label": "finding"}, {"segment_text": "a total of 17 partially overlapping fragments covering the C-terminus of M protein were expressed as fusion proteins with a 6 × His tag or a GST tag .", "label": "finding"}, {"segment_text": "A linear motif , 193 TGWAFYVR 200 ,", "label": "finding"}, {"segment_text": "was identified by enzyme-linked immunosorbent assay ( ELISA ) and western blot ( WB ) analysis using McAb 4D4 .", "label": "finding"}, {"segment_text": "The motif 195 WAFYVR 200 was the minimal requirement for reactivity ,", "label": "finding"}, {"segment_text": "as demonstrated by removing amino acids individually from both ends of the motif 193 TGWAFYVR 200 .", "label": "finding"}, {"segment_text": "The result of WB analysis showed that the 4D4-defined epitope could be recognized by PEDV-positive serum ,", "label": "finding"}, {"segment_text": "but not transmissible gastroenteritis virus ( TGEV ) - positive serum .", "label": "finding"}, {"segment_text": "Furthermore , this epitope was highly conserved among different PEDV strains ,", "label": "finding"}, {"segment_text": "as shown by alignment and comparison of sequences .", "label": "finding"}], "n_segments": 16}
{"paper_id": "2cd9b37d110968368ce6f837e002788ac6158af8", "title": "Under-reporting of TB cases and associated factors: a case study in China", "coda_paper_id": 1214, "has_expert_labels": false, "abstract_text": "Background : Tuberculosis is a leading cause of death worldwide and has become a high global health priority . Accurate country level surveillance is critical to ending the pandemic . Effective routine reporting systems which track the course of the epidemic are vital in addressing TB . China , which has the third largest TB epidemic in the world and has developed a reporting system to help with the control and prevention of TB , this study examined its effectiveness in Eastern China . Methods : The number of TB cases reported internally in two hospitals in Eastern China were compared to the number TB cases reported by these same hospitals in the national reporting systems in order to assess the accuracy of reporting . Qualitative data from interviews with key health officials and researcher experience using the TB reporting systems were used to identify factors affecting the accuracy of TB cases being reported in the national systems . Results : This study found that over a quarter of TB cases recorded in the internal hospital records were not entered into the national TB reporting systems , leading to an under representation of national TB cases . Factors associated with underreporting included unqualified and overworked health personnel , poor supervision and accountability at local and national levels , and a complicated incohesive health information management system . Conclusions : This study demonstrates that TB in Eastern China is being underreported . Given that Eastern China is a developed province , one could assume similar problems may be found in other parts of China with fewer resources as well as many low-and middle-income countries . Having an accurate account of the number of national TB cases is essential to understanding the national and global burden of the disease and in managing TB prevention and control efforts . As such , factors associated with underreporting need to be addressed in order to reduce underreporting .", "gold_segments": [{"segment_text": "Background : Tuberculosis is a leading cause of death worldwide and has become a high global health priority .", "label": "background"}, {"segment_text": "Accurate country level surveillance is critical to ending the pandemic .", "label": "background"}, {"segment_text": "Effective routine reporting systems which track the course of the epidemic are vital in addressing TB .", "label": "background"}, {"segment_text": "China , which has the third largest TB epidemic in the world and has developed a reporting system to help with the control and prevention of TB ,", "label": "background"}, {"segment_text": "this study examined its effectiveness in Eastern China .", "label": "background"}, {"segment_text": "Methods : The number of TB cases reported internally in two hospitals in Eastern China were compared to the number TB cases reported by these same hospitals in the national reporting systems in order to assess the accuracy of reporting .", "label": "method"}, {"segment_text": "Qualitative data from interviews with key health officials and researcher experience using the TB reporting systems were used to identify factors affecting the accuracy of TB cases being reported in the national systems .", "label": "method"}, {"segment_text": "Results : This study found that over a quarter of TB cases recorded in the internal hospital records were not entered into the national TB reporting systems ,", "label": "finding"}, {"segment_text": "leading to an under representation of national TB cases .", "label": "finding"}, {"segment_text": "Factors associated with underreporting included unqualified and overworked health personnel ,", "label": "finding"}, {"segment_text": "poor supervision and accountability at local and national levels ,", "label": "finding"}, {"segment_text": "and a complicated incohesive health information management system .", "label": "finding"}, {"segment_text": "Conclusions : This study demonstrates that TB in Eastern China is being underreported .", "label": "finding"}, {"segment_text": "Given that Eastern China is a developed province ,", "label": "finding"}, {"segment_text": "one could assume similar problems may be found in other parts of China with fewer resources as well as many low-and middle-income countries .", "label": "finding"}, {"segment_text": "Having an accurate account of the number of national TB cases is essential to understanding the national and global burden of the disease and in managing TB prevention and control efforts .", "label": "finding"}, {"segment_text": "As such , factors associated with underreporting need to be addressed in order to reduce underreporting .", "label": "finding"}], "n_segments": 17}
{"paper_id": "db9a1efb58ae0ed12ff657b5cc78fcc2615f0c73", "title": "Clinical Infectious Diseases Comprehensive Molecular Testing for Respiratory Pathogens in Community-Acquired Pneumonia", "coda_paper_id": 1209, "has_expert_labels": false, "abstract_text": "See the Editorial Commentaries by Musher on pages 824-5 and Jain and Pavia on pages 826-8 . ) Background . The frequent lack of a microbiological diagnosis in community-acquired pneumonia ( CAP ) impairs pathogendirected antimicrobial therapy . This study assessed the use of comprehensive multibacterial , multiviral molecular testing , including quantification , in adults hospitalized with CAP . Methods . Clinical and laboratory data were collected for 323 adults with radiologically-confirmed CAP admitted to 2 UK tertiary care hospitals . Sputum ( 96 % ) or endotracheal aspirate ( 4 % ) specimens were cultured as per routine practice and also tested with fast multiplex real-time polymerase-chain reaction ( PCR ) assays for 26 respiratory bacteria and viruses . Bacterial loads were also calculated for 8 bacterial pathogens . Appropriate pathogen-directed therapy was retrospectively assessed using national guidelines adapted for local antimicrobial susceptibility patterns . Results . Comprehensive molecular testing of single lower respiratory tract ( LRT ) specimens achieved pathogen detection in 87 % of CAP patients compared with 39 % with culture-based methods . Haemophilus influenzae and Streptococcus pneumoniae were the main agents detected , along with a wide variety of typical and atypical pathogens . Viruses were present in 30 % of cases ; 82 % of these were codetections with bacteria . Most ( 85 % ) patients had received antimicrobials in the 72 hours before admission . Of these , 78 % had a bacterial pathogen detected by PCR but only 32 % were culture-positive ( P < .0001 ) . Molecular testing had the potential to enable de-escalation in number and/or spectrum of antimicrobials in 77 % of patients . Conclusions . Comprehensive molecular testing significantly improves pathogen detection in CAP , particularly in antimicrobialexposed patients , and requires only a single LRT specimen . It also has the potential to enable early de-escalation from broadspectrum empirical antimicrobials to pathogen-directed therapy .", "gold_segments": [{"segment_text": "See the Editorial Commentaries by Musher on pages 824-5 and Jain and Pavia on pages 826-8 . )", "label": "other"}, {"segment_text": "Background .", "label": "background"}, {"segment_text": "The frequent lack of a microbiological diagnosis in community-acquired pneumonia ( CAP ) impairs pathogendirected antimicrobial therapy .", "label": "background"}, {"segment_text": "This study assessed the use of comprehensive multibacterial ,", "label": "purpose"}, {"segment_text": "multiviral molecular testing , including quantification ,", "label": "purpose"}, {"segment_text": "in adults hospitalized with CAP .", "label": "purpose"}, {"segment_text": "Methods .", "label": "method"}, {"segment_text": "Clinical and laboratory data were collected for 323 adults with radiologically-confirmed CAP admitted to 2 UK tertiary care hospitals .", "label": "method"}, {"segment_text": "Sputum ( 96 % ) or endotracheal aspirate ( 4 % ) specimens were cultured as per routine practice and also tested with fast multiplex real-time polymerase-chain reaction ( PCR ) assays for 26 respiratory bacteria and viruses .", "label": "method"}, {"segment_text": "Bacterial loads were also calculated for 8 bacterial pathogens .", "label": "method"}, {"segment_text": "Appropriate pathogen-directed therapy was retrospectively assessed using national guidelines adapted for local antimicrobial susceptibility patterns .", "label": "method"}, {"segment_text": "Results .", "label": "finding"}, {"segment_text": "Comprehensive molecular testing of single lower respiratory tract ( LRT ) specimens achieved pathogen detection in 87 % of CAP patients compared with 39 % with culture-based methods .", "label": "finding"}, {"segment_text": "Haemophilus influenzae and Streptococcus pneumoniae were the main agents detected ,", "label": "finding"}, {"segment_text": "along with a wide variety of typical and atypical pathogens .", "label": "finding"}, {"segment_text": "Viruses were present in 30 % of cases ; 82 % of these were codetections with bacteria .", "label": "finding"}, {"segment_text": "Most ( 85 % ) patients had received antimicrobials in the 72 hours before admission .", "label": "finding"}, {"segment_text": "Of these , 78 % had a bacterial pathogen detected by PCR but only 32 % were culture-positive ( P < .0001 ) .", "label": "finding"}, {"segment_text": "Molecular testing had the potential to enable de-escalation in number and/or spectrum of antimicrobials in 77 % of patients .", "label": "finding"}, {"segment_text": "Conclusions .", "label": "finding"}, {"segment_text": "Comprehensive molecular testing significantly improves pathogen detection in CAP ,", "label": "finding"}, {"segment_text": "particularly in antimicrobialexposed patients , and requires only a single LRT specimen .", "label": "finding"}, {"segment_text": "It also has the potential to enable early de-escalation from broadspectrum empirical antimicrobials to pathogen-directed therapy .", "label": "finding"}], "n_segments": 23}
{"paper_id": "3185dfda3a47db56f43d7927c47f19cbaa6841f6", "title": "Comparison of genomic and amino acid sequences of eight Japanese encephalitis virus isolates from bats", "coda_paper_id": 1126, "has_expert_labels": false, "abstract_text": "We compared nucleotide and deduced amino acid sequences of eight Japanese encephalitis virus ( JEV ) isolates derived from bats in China . We also compared the bat JEV isolates with other JEV isolates available from GenBank to determine their genetic similarity . We found a high genetic homogeneity among the bat JEVs isolated in different geographical areas from various bat species at different time periods . All eight bat JEV isolates belonged to genotype III . The mean evolutionary rate of bat JEV isolates was lower than those of isolates of other origin , but this difference was not statistically significant . Based on these results , we presume that the bat JEV isolates might be evolutionarily conserved . The eight bat JEV isolates were phylogenetically similar to mosquito BN19 and human Liyujie isolates of JEV . These results indicate that bats might be involved in natural cycle of JEV .", "gold_segments": [{"segment_text": "We compared nucleotide and deduced amino acid sequences of eight Japanese encephalitis virus ( JEV ) isolates derived from bats in China .", "label": "method"}, {"segment_text": "We also compared the bat JEV isolates with other JEV isolates available from GenBank to determine their genetic similarity .", "label": "method"}, {"segment_text": "We found a high genetic homogeneity among the bat JEVs isolated in different geographical areas from various bat species at different time periods .", "label": "finding"}, {"segment_text": "All eight bat JEV isolates belonged to genotype III .", "label": "finding"}, {"segment_text": "The mean evolutionary rate of bat JEV isolates was lower than those of isolates of other origin ,", "label": "finding"}, {"segment_text": "but this difference was not statistically significant .", "label": "finding"}, {"segment_text": "Based on these results , we presume that the bat JEV isolates might be evolutionarily conserved .", "label": "finding"}, {"segment_text": "The eight bat JEV isolates were phylogenetically similar to mosquito BN19 and human Liyujie isolates of JEV .", "label": "finding"}, {"segment_text": "These results indicate that bats might be involved in natural cycle of JEV .", "label": "finding"}], "n_segments": 9}
{"paper_id": "eb1b9685e0eaa51bef8c8a20729643d888e0a324", "title": "Pros and Cons of Antigen-Presenting Cell Targeted Tumor Vaccines", "coda_paper_id": 1395, "has_expert_labels": false, "abstract_text": "In therapeutic antitumor vaccination , dendritic cells play the leading role since they decide if , how , when , and where a potent antitumor immune response will take place . Since the disentanglement of the complexity and merit of different antigen-presenting cell subtypes , antitumor immunotherapeutic research started to investigate the potential benefit of targeting these subtypes in situ . This review will discuss which antigen-presenting cell subtypes are at play and how they have been targeted and finally question the true meaning of targeting antitumor-based vaccines .", "gold_segments": [{"segment_text": "In therapeutic antitumor vaccination , dendritic cells play the leading role since they decide if ,", "label": "background"}, {"segment_text": "how , when , and where a potent antitumor immune response will take place .", "label": "background"}, {"segment_text": "Since the disentanglement of the complexity and merit of different antigen-presenting cell subtypes ,", "label": "background"}, {"segment_text": "antitumor immunotherapeutic research started to investigate the potential benefit of targeting these subtypes in situ .", "label": "background"}, {"segment_text": "This review will discuss which antigen-presenting cell subtypes are at play and how they have been targeted and finally question the true meaning of targeting antitumor-based vaccines .", "label": "purpose"}], "n_segments": 5}
{"paper_id": "4c0c45505f453a59c60314c682e0f3d7c9fd9adc", "title": "Integrity of mating behaviors and seasonal reproduction in coyotes (Canis latrans) following treatment with estradiol benzoate", "coda_paper_id": 1512, "has_expert_labels": false, "abstract_text": "Coyotes ( Canis latrans ) are seasonally monestrous and form perennial pair-bonds . Breeding is dominated by each pack 's alpha male and female , and both sexes share responsibility for territory defense and pup-rearing . They are also opportunistic predators on domestic livestock and pets . But while dominant adults have been implicated as primary killers , depredation is reduced when coyotes are without pups . Contraception , therefore , may represent a non-lethal solution for conflicts between coyotes and humans . Steroid hormones successfully control fertility in some species , but have been considered contraindicated in wildlife and canids in particular ; specific concerns include possible induction of aberrant behavior , or uterine and hematopoietic pathologies . Herein we describe a study examining the physiological effectiveness , health safety , and behavioral consequences following treatment of estrous coyotes with exogenous estrogen . We treated captive adult female coyotes in estrus with 0.01 mg/kg estradiol benzoate ( EB ) , either before ( n = 5 ) or immediately after ovulation ( n = 6 ) , then documented reproductive outcome , physiological variables and behavioral responses , during and after treatment . Pregnancy was averted in six females treated after ovulation , suggesting that appropriate timing of treatment proved crucial . A transient suppression of sexual behavior was observed , and in some cases , estrus appeared slightly lengthened . However , neither ovulation nor mating behavior was fully suppressed . Importantly , non-pregnant females ( and their mates ) displayed diestrous socio-sexual behavior similar to pregnant coyotes ( behavioral pseudopregnancy ) . Furthermore , nonpregnant coyotes did not mate again until the next native breeding season , and we observed no deleterious physiological effects during diestrus or subsequent ovarian cycles .", "gold_segments": [{"segment_text": "Coyotes ( Canis latrans ) are seasonally monestrous and form perennial pair-bonds .", "label": "background"}, {"segment_text": "Breeding is dominated by each pack 's alpha male and female ,", "label": "background"}, {"segment_text": "and both sexes share responsibility for territory defense and pup-rearing .", "label": "background"}, {"segment_text": "They are also opportunistic predators on domestic livestock and pets .", "label": "background"}, {"segment_text": "But while dominant adults have been implicated as primary killers ,", "label": "background"}, {"segment_text": "depredation is reduced when coyotes are without pups .", "label": "background"}, {"segment_text": "Contraception , therefore , may represent a non-lethal solution for conflicts between coyotes and humans .", "label": "background"}, {"segment_text": "Steroid hormones successfully control fertility in some species ,", "label": "background"}, {"segment_text": "but have been considered contraindicated in wildlife and canids in particular ; specific concerns include possible induction of aberrant behavior ,", "label": "background"}, {"segment_text": "or uterine and hematopoietic pathologies .", "label": "background"}, {"segment_text": "Herein we describe a study examining the physiological effectiveness ,", "label": "purpose"}, {"segment_text": "health safety , and behavioral consequences following treatment of estrous coyotes with exogenous estrogen .", "label": "purpose"}, {"segment_text": "We treated captive adult female coyotes in estrus with 0.01 mg/kg estradiol benzoate ( EB ) ,", "label": "method"}, {"segment_text": "either before ( n = 5 ) or immediately after ovulation ( n = 6 ) ,", "label": "method"}, {"segment_text": "then documented reproductive outcome , physiological variables and behavioral responses , during and after treatment .", "label": "method"}, {"segment_text": "Pregnancy was averted in six females treated after ovulation ,", "label": "finding"}, {"segment_text": "suggesting that appropriate timing of treatment proved crucial .", "label": "finding"}, {"segment_text": "A transient suppression of sexual behavior was observed ,", "label": "finding"}, {"segment_text": "and in some cases , estrus appeared slightly lengthened .", "label": "finding"}, {"segment_text": "However , neither ovulation nor mating behavior was fully suppressed .", "label": "finding"}, {"segment_text": "Importantly , non-pregnant females ( and their mates ) displayed diestrous socio-sexual behavior similar to pregnant coyotes ( behavioral pseudopregnancy ) .", "label": "finding"}, {"segment_text": "Furthermore , nonpregnant coyotes did not mate again until the next native breeding season ,", "label": "finding"}, {"segment_text": "and we observed no deleterious physiological effects during diestrus or subsequent ovarian cycles .", "label": "finding"}], "n_segments": 23}
{"paper_id": "8856e1f2644acc2d51c57d3ead6dd14a929a014b", "title": "Interferon Lambda: A New Sword in Cancer Immunotherapy", "coda_paper_id": 1684, "has_expert_labels": false, "abstract_text": "The discovery of the interferon-lambda ( IFN-λ ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer . IFN-λ proteins belong to the new type III IFN group . Type III IFN is structurally similar to type II IFN ( IFN-γ ) but functionally identical to type I IFN ( IFN-α/β ) . However , in contrast to type I or type II IFNs , the response to type III IFN is highly cell-type specific . Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ . This particular pattern of response is controlled by the differential expression of the IFN-λ receptor , which , in contrast to IFN-α , should result in limited side effects in patients . Recently , we and other groups have shown in several animal models a potent antitumor role of IFN-λ that will open a new challenging era for the current IFN therapy . Biological Properties of IFN-λ Although type I and type III induced similar cell signaling ,", "gold_segments": [{"segment_text": "The discovery of the interferon-lambda ( IFN-λ ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer .", "label": "background"}, {"segment_text": "IFN-λ proteins belong to the new type III IFN group .", "label": "background"}, {"segment_text": "Type III IFN is structurally similar to type II IFN ( IFN-γ ) but functionally identical to type I IFN ( IFN-α/β ) .", "label": "background"}, {"segment_text": "However , in contrast to type I or type II IFNs ,", "label": "background"}, {"segment_text": "the response to type III IFN is highly cell-type specific .", "label": "background"}, {"segment_text": "Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ .", "label": "background"}, {"segment_text": "This particular pattern of response is controlled by the differential expression of the IFN-λ receptor ,", "label": "background"}, {"segment_text": "which , in contrast to IFN-α ,", "label": "background"}, {"segment_text": "should result in limited side effects in patients .", "label": "background"}, {"segment_text": "Recently , we and other groups have shown in several animal models a potent antitumor role of IFN-λ that will open a new challenging era for the current IFN therapy .", "label": "finding"}, {"segment_text": "Biological Properties of IFN-λ", "label": "finding"}, {"segment_text": "Although type I and type III induced similar cell signaling ,", "label": "finding"}], "n_segments": 12}
{"paper_id": "072ad3450fc4330b8fd7d17f8a3ce50e4089f366", "title": "Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection", "coda_paper_id": 1447, "has_expert_labels": false, "abstract_text": "Severe acute respiratory syndrome ( SARS ) is a highly contagious infectious disease which first emerged in late 2002 , caused by a then novel human coronavirus , SARS coronavirus ( SARS-CoV ) . The virus is believed to have originated from bats and transmitted to human through intermediate animals such as civet cats . The re-emergence of SARS-CoV remains a valid concern due to the continual persistence of zoonotic SARS-CoVs and SARS-like CoVs ( SL-CoVs ) in bat reservoirs . In this study , the screening for the presence of SARS-specific T cells in a cohort of three SARS-recovered individuals at 9 and 11 years post-infection was carried out , and all memory T cell responses detected target the SARS-CoV structural proteins . Two CD8 + T cell responses targeting the SARS-CoV membrane ( M ) and nucleocapsid ( N ) proteins were characterized by determining their HLA restriction and minimal T cell epitope regions . Furthermore , these responses were found to persist up to 11 years post-infection . An absence of cross-reactivity of these CD8 + T cell responses against the newly-emerged Middle East respiratory syndrome coronavirus ( MERS-CoV ) was also demonstrated . The knowledge of the persistence of SARS-specific celullar immunity targeting the viral structural proteins in SARS-recovered individuals is important in the design and development of SARS vaccines , which are currently unavailable .", "gold_segments": [{"segment_text": "Severe acute respiratory syndrome ( SARS ) is a highly contagious infectious disease which first emerged in late 2002 ,", "label": "background"}, {"segment_text": "caused by a then novel human coronavirus ,", "label": "background"}, {"segment_text": "SARS coronavirus ( SARS-CoV ) .", "label": "background"}, {"segment_text": "The virus is believed to have originated from bats and transmitted to human through intermediate animals such as civet cats .", "label": "background"}, {"segment_text": "The re-emergence of SARS-CoV remains a valid concern due to the continual persistence of zoonotic SARS-CoVs and SARS-like CoVs ( SL-CoVs ) in bat reservoirs .", "label": "background"}, {"segment_text": "In this study , the screening for the presence of SARS-specific T cells in a cohort of three SARS-recovered individuals at 9 and 11 years post-infection was carried out ,", "label": "finding"}, {"segment_text": "and all memory T cell responses detected target the SARS-CoV structural proteins .", "label": "finding"}, {"segment_text": "Two CD8 + T cell responses targeting the SARS-CoV membrane ( M ) and nucleocapsid ( N ) proteins were characterized by determining their HLA restriction and minimal T cell epitope regions .", "label": "finding"}, {"segment_text": "Furthermore , these responses were found to persist up to 11 years post-infection .", "label": "finding"}, {"segment_text": "An absence of cross-reactivity of these CD8 + T cell responses against the newly-emerged Middle East respiratory syndrome coronavirus ( MERS-CoV ) was also demonstrated .", "label": "finding"}, {"segment_text": "The knowledge of the persistence of SARS-specific celullar immunity targeting the viral structural proteins in SARS-recovered individuals is important in the design and development of SARS vaccines , which are currently unavailable .", "label": "finding"}], "n_segments": 11}
{"paper_id": "b1be7d31c3101fa5b0c803ee2d354eb7d3943526", "title": "Gemcitabine, a broad-spectrum antiviral drug, suppresses enterovirus infections through innate immunity induced by the inhibition of pyrimidine biosynthesis and nucleotide depletion", "coda_paper_id": 1086, "has_expert_labels": false, "abstract_text": "Copyright : Lee et al. . This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 ( CC BY 3.0 ) , which permits unrestricted use , distribution , and reproduction in any medium , provided the original author and source are credited . Gemcitabine , an anti-cancer chemotherapy drug , has additionally shown the antiviral activity against a broad range of viruses and we also have previously reported its synergistic antiviral activity with ribavirin against enteroviruses . As a cytidine analog , gemcitabine has been reported to have an inhibitory activity on the pyrimidine biosynthesis . In addition , a few inhibitors of the pyrimidine biosynthesis have shown to induce the innate immunity in a yet-to-be-determined manner and inhibit the virus infection . Thus , we also investigated whether the anti-enteroviral activity of gemcitabine is mediated by innate immunity , induction of which is related with the inhibition of the pyrimidine synthesis . In this study , we found that the addition of exogenous cytidine , uridine and uridine mono-phosphate ( UMP ) effectively reversed the antiviral activity of gemcitabine in enterovirus-infected as well as enteroviral replicon-harboring cells , demonstrating gemcitabine 's targeting of the salvage pathway . Moreover , the expression of several interferon ( IFN ) - stimulated genes ( ISGs ) was significantly induced by the treatment of gemcitabine , which was also suppressed by the co-treatment with cytidine . These results suggest that the antiviral activity of gemcitabine involves ISGs induced by the inhibition of the pyrimidine biosynthesis .", "gold_segments": [{"segment_text": "Copyright : Lee et al. .", "label": "other"}, {"segment_text": "This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 ( CC BY 3.0 ) ,", "label": "background"}, {"segment_text": "which permits unrestricted use , distribution ,", "label": "background"}, {"segment_text": "and reproduction in any medium ,", "label": "background"}, {"segment_text": "provided the original author and source are credited .", "label": "background"}, {"segment_text": "Gemcitabine , an anti-cancer chemotherapy drug ,", "label": "background"}, {"segment_text": "has additionally shown the antiviral activity against a broad range of viruses and we also have previously reported its synergistic antiviral activity with ribavirin against enteroviruses .", "label": "background"}, {"segment_text": "As a cytidine analog , gemcitabine has been reported to have an inhibitory activity on the pyrimidine biosynthesis .", "label": "background"}, {"segment_text": "In addition , a few inhibitors of the pyrimidine biosynthesis have shown to induce the innate immunity in a yet-to-be-determined manner and inhibit the virus infection .", "label": "background"}, {"segment_text": "Thus , we also investigated whether the anti-enteroviral activity of gemcitabine is mediated by innate immunity ,", "label": "purpose"}, {"segment_text": "induction of which is related with the inhibition of the pyrimidine synthesis .", "label": "purpose"}, {"segment_text": "In this study , we found that the addition of exogenous cytidine ,", "label": "finding"}, {"segment_text": "uridine and uridine mono-phosphate ( UMP ) effectively reversed the antiviral activity of gemcitabine in enterovirus-infected as well as enteroviral replicon-harboring cells ,", "label": "finding"}, {"segment_text": "demonstrating gemcitabine 's targeting of the salvage pathway .", "label": "finding"}, {"segment_text": "Moreover , the expression of several interferon ( IFN ) - stimulated genes ( ISGs ) was significantly induced by the treatment of gemcitabine ,", "label": "finding"}, {"segment_text": "which was also suppressed by the co-treatment with cytidine .", "label": "finding"}, {"segment_text": "These results suggest that the antiviral activity of gemcitabine involves ISGs induced by the inhibition of the pyrimidine biosynthesis .", "label": "finding"}], "n_segments": 17}
{"paper_id": "323ece9056ef7a1d81faf3422e98def1efd38f70", "title": "Immune pathways and defence mechanisms in honey bees Apis mellifera", "coda_paper_id": 1061, "has_expert_labels": false, "abstract_text": "Here we focus on individual defences , by presenting a genome-wide analysis of immunity in a social insect , the honey bee Apis mellifera . We present honey bee models for each of four signalling pathways associated with immunity , identifying plausible orthologues for nearly all predicted pathway members . When compared to the sequenced Drosophila and Anopheles genomes , honey bees possess roughly one-third as many genes in 17 gene families implicated in insect immunity . We suggest that an implied reduction in immune flexibility in bees reflects either the strength of social barriers to disease , or a tendency for bees to be attacked by a limited set of highly coevolved pathogens .", "gold_segments": [{"segment_text": "Here we focus on individual defences ,", "label": "background"}, {"segment_text": "by presenting a genome-wide analysis of immunity in a social insect ,", "label": "background"}, {"segment_text": "the honey bee Apis mellifera .", "label": "background"}, {"segment_text": "We present honey bee models for each of four signalling pathways associated with immunity ,", "label": "method"}, {"segment_text": "identifying plausible orthologues for nearly all predicted pathway members .", "label": "method"}, {"segment_text": "When compared to the sequenced Drosophila and Anopheles genomes ,", "label": "finding"}, {"segment_text": "honey bees possess roughly one-third as many genes in 17 gene families implicated in insect immunity .", "label": "finding"}, {"segment_text": "We suggest that an implied reduction in immune flexibility in bees reflects either the strength of social barriers to disease ,", "label": "finding"}, {"segment_text": "or a tendency for bees to be attacked by a limited set of highly coevolved pathogens .", "label": "finding"}], "n_segments": 9}
{"paper_id": "6c7341f17bfd790cdc05b6d1010c63f4f8eb5890", "title": "Antivirals for influenza-like illness? Protocol for a randomized controlled trial of clinical and cost effectiveness in primary care (ALIC 4 E) Antivirals for influenza-Like Illness? A randomized Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC4E): The ALIC4E Protocol Antivirals for influenza-Like Illness? A randomized Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC 4 E): The ALIC 4 E Protocol Antivirals for influenza-Like Illness? A randomized Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC4E): The ALIC4E Protocol Antivirals for influenza-Like Illness? A randomized Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC 4 E): The ALIC 4 E Protocol", "coda_paper_id": 1023, "has_expert_labels": false, "abstract_text": "Effective management of seasonal and pandemic influenza is a high priority internationally . Guidelines in many countries recommend antiviral treatment for older people and individuals with co-morbidity at increased risk of complications . However , antivirals are not often prescribed in primary care in Europe , because its clinical benefit has been insufficiently demonstrated by non-industry funded and pragmatic studies . ALIC 4 E is a European multi-national , multi-centre , phase IV , open-labelled , non-industry funded , pragmatic , adaptive-platform , randomised controlled trial ( RCT ) . Initial trial arms will be best usual primary care , and best usual primary care plus treatment with oseltamivir for five days . We aim to recruit at least 2500 participants ≥ 1 year old presenting with influenza-like illness ( ILI ) , with symptom duration ≤ 72 hours in primary care over three consecutive periods of confirmed high influenza incidence . Participant outcomes will be followed-up to 28 days by diary and telephone . The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever , head-and muscle-ache reduced to minor severity or less . Secondary objectives include determining cost-effectiveness , benefits in subgroups of participants according to age ( < 12 , 12-64 , > 64 years ) , severity of symptoms ( low , medium , high ) , comorbidity ( yes/no ) , and duration of symptoms ( ≤ 48hours / > 48-72 hours ) , decrease in For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open", "gold_segments": [{"segment_text": "Effective management of seasonal and pandemic influenza is a high priority internationally .", "label": "background"}, {"segment_text": "Guidelines in many countries recommend antiviral treatment for older people and individuals with co-morbidity at increased risk of complications .", "label": "background"}, {"segment_text": "However , antivirals are not often prescribed in primary care in Europe ,", "label": "background"}, {"segment_text": "because its clinical benefit has been insufficiently demonstrated by non-industry funded and pragmatic studies .", "label": "background"}, {"segment_text": "ALIC 4 E is a European multi-national ,", "label": "background"}, {"segment_text": "multi-centre , phase IV , open-labelled ,", "label": "background"}, {"segment_text": "non-industry funded , pragmatic , adaptive-platform ,", "label": "background"}, {"segment_text": "randomised controlled trial ( RCT ) .", "label": "background"}, {"segment_text": "Initial trial arms will be best usual primary care ,", "label": "background"}, {"segment_text": "and best usual primary care plus treatment with oseltamivir for five days .", "label": "background"}, {"segment_text": "We aim to recruit at least 2500 participants ≥ 1 year old presenting with influenza-like illness ( ILI ) ,", "label": "purpose"}, {"segment_text": "with symptom duration ≤ 72 hours in primary care over three consecutive periods of confirmed high influenza incidence .", "label": "purpose"}, {"segment_text": "Participant outcomes will be followed-up to 28 days by diary and telephone .", "label": "method"}, {"segment_text": "The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever ,", "label": "purpose"}, {"segment_text": "head-and muscle-ache reduced to minor severity or less .", "label": "purpose"}, {"segment_text": "Secondary objectives include determining cost-effectiveness ,", "label": "purpose"}, {"segment_text": "benefits in subgroups of participants according to age ( < 12 , 12-64 , > 64 years ) ,", "label": "purpose"}, {"segment_text": "severity of symptoms ( low , medium , high ) ,", "label": "purpose"}, {"segment_text": "comorbidity ( yes/no ) , and duration of symptoms ( ≤ 48hours / > 48-72 hours ) , decrease in", "label": "purpose"}, {"segment_text": "For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open", "label": "other"}], "n_segments": 20}
{"paper_id": "08d822c186460651ee5f3a44d365b0701aff56e3", "title": "Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases", "coda_paper_id": 1434, "has_expert_labels": false, "abstract_text": "During lytic Kaposi 's sarcoma-associated herpesvirus ( KSHV ) infection , the viral endonuclease SOX promotes widespread degradation of cytoplasmic messenger RNA ( mRNA ) . However , select mRNAs , including the transcript encoding interleukin-6 ( IL-6 ) , escape SOX-induced cleavage . IL-6 escape is mediated through a 3 ' UTR RNA regulatory element that overrides the SOX targeting mechanism . Here , we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases . However , it does not impede cleavage by cellular endonucleases . The IL-6 protective sequence may be representative of a larger class of nuclease escape elements , as we identified a similar protective element in the GADD45B mRNA . The IL-6 and GADD45B-derived elements display similarities in their sequence , putative structure , and several associated RNA binding proteins . However , the overall composition of their ribonucleoprotein complexes appears distinct , leading to differences in the breadth of nucleases restricted . These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation .", "gold_segments": [{"segment_text": "During lytic Kaposi 's sarcoma-associated herpesvirus ( KSHV ) infection ,", "label": "background"}, {"segment_text": "the viral endonuclease SOX promotes widespread degradation of cytoplasmic messenger RNA ( mRNA ) .", "label": "background"}, {"segment_text": "However , select mRNAs , including the transcript encoding interleukin-6 ( IL-6 ) , escape SOX-induced cleavage .", "label": "background"}, {"segment_text": "IL-6 escape is mediated through a 3 ' UTR RNA regulatory element that overrides the SOX targeting mechanism .", "label": "background"}, {"segment_text": "Here , we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases .", "label": "purpose"}, {"segment_text": "However , it does not impede cleavage by cellular endonucleases .", "label": "finding"}, {"segment_text": "The IL-6 protective sequence may be representative of a larger class of nuclease escape elements ,", "label": "finding"}, {"segment_text": "as we identified a similar protective element in the GADD45B mRNA .", "label": "finding"}, {"segment_text": "The IL-6 and GADD45B-derived elements display similarities in their sequence ,", "label": "finding"}, {"segment_text": "putative structure , and several associated RNA binding proteins .", "label": "finding"}, {"segment_text": "However , the overall composition of their ribonucleoprotein complexes appears distinct ,", "label": "finding"}, {"segment_text": "leading to differences in the breadth of nucleases restricted .", "label": "finding"}, {"segment_text": "These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation .", "label": "finding"}], "n_segments": 13}
{"paper_id": "f0d935a0e0f1360bf4166b9db8e4cddf67aa9cd7", "title": "Activation of the Antiviral Kinase PKR and Viral Countermeasures", "coda_paper_id": 1768, "has_expert_labels": false, "abstract_text": "The interferon-induced double-stranded ( ds ) RNA-dependent protein kinase ( PKR ) limits viral replication by an eIF2 - mediated block of translation . Although many negative-strand RNA viruses activate PKR , the responsible RNAs have long remained elusive , as dsRNA , the canonical activator of PKR , has not been detected in cells infected with such viruses . In this review we focus on the activating RNA molecules of different virus families , in particular the negative-strand RNA viruses . We discuss the recently identified non-canonical activators 5 ' - triphosphate RNA and the vRNP of influenza virus and give an update on strategies of selected RNA and DNA viruses to prevent activation of PKR .", "gold_segments": [{"segment_text": "The interferon-induced double-stranded ( ds ) RNA-dependent protein kinase ( PKR ) limits viral replication by an eIF2 - mediated block of translation .", "label": "background"}, {"segment_text": "Although many negative-strand RNA viruses activate PKR ,", "label": "background"}, {"segment_text": "the responsible RNAs have long remained elusive ,", "label": "background"}, {"segment_text": "as dsRNA , the canonical activator of PKR ,", "label": "background"}, {"segment_text": "has not been detected in cells infected with such viruses .", "label": "background"}, {"segment_text": "In this review we focus on the activating RNA molecules of different virus families ,", "label": "purpose"}, {"segment_text": "in particular the negative-strand RNA viruses .", "label": "purpose"}, {"segment_text": "We discuss the recently identified non-canonical activators 5 ' - triphosphate RNA and the vRNP of influenza virus and give an update on strategies of selected RNA and DNA viruses to prevent activation of PKR .", "label": "purpose"}], "n_segments": 8}
{"paper_id": "654bd8540af8e404debb6f7712df44efb39c58f6", "title": "A retrospective clinical and epidemiological study on feline coronavirus (FCoV) in cats in Istanbul, Turkey", "coda_paper_id": 1641, "has_expert_labels": false, "abstract_text": "The presence of antibodies to feline coronavirus ( FCoV ) and feline immunodeficiency virus ( FIV ) , together with feline leukemia virus ( FeLV ) antigen was investigated in 169 ill household and stray cats attending a veterinary surgery in Istanbul in 2009-14 . The estimated FCoV and FIV seroprevalence ( 95 % confidence intervals ) were 37 % ( 30-45 % ) and 11 % ( 6-16 % ) , respectively and FeLV prevalence was 1 % ( 0-3 % ) . FCoV seroprevalence increased until 2 years of age , was highest in 2014 and among household cats living with other cats and with outdoor access , and was lower in FIV seropositive compared to seronegative cats . Symptoms typically associated with wet feline infectious peritonitis ( FIP ) including ascites , abdominal distention or pleural effusion , coupled in many cases with non-antibiotic responsive fever , were observed in 19 % ( 32/169 ) of cats , and 75 % ( 24/32 ) of these cats were FCoV seropositive . FCoV seropositivity was also associated with a high white blood cell count , high plasma globulin , low plasma albumin and low blood urea nitrogen . The percentage of FCoV seropositive and seronegative cats that died in spite of supportive veterinary treatment was 33 % ( 21/63 ) and 12 % ( 13/106 ) , respectively . These results indicate that FCoV is widespread and has a severe clinical impact in cats from Istanbul . Moreover , the incidence of FCoV infections could be rising , and in the absence of effective vaccination cat owners need to be made aware of ways to minimize the spread of this virus .", "gold_segments": [{"segment_text": "The presence of antibodies to feline coronavirus ( FCoV ) and feline immunodeficiency virus ( FIV ) ,", "label": "background"}, {"segment_text": "together with feline leukemia virus ( FeLV ) antigen was investigated in 169 ill household and stray cats attending a veterinary surgery in Istanbul in 2009-14 .", "label": "background"}, {"segment_text": "The estimated FCoV and FIV seroprevalence ( 95 % confidence intervals ) were 37 % ( 30-45 % ) and 11 % ( 6-16 % ) ,", "label": "finding"}, {"segment_text": "respectively and FeLV prevalence was 1 % ( 0-3 % ) .", "label": "finding"}, {"segment_text": "FCoV seroprevalence increased until 2 years of age ,", "label": "finding"}, {"segment_text": "was highest in 2014 and among household cats living with other cats and with outdoor access ,", "label": "finding"}, {"segment_text": "and was lower in FIV seropositive compared to seronegative cats .", "label": "finding"}, {"segment_text": "Symptoms typically associated with wet feline infectious peritonitis ( FIP ) including ascites ,", "label": "finding"}, {"segment_text": "abdominal distention or pleural effusion ,", "label": "finding"}, {"segment_text": "coupled in many cases with non-antibiotic responsive fever ,", "label": "finding"}, {"segment_text": "were observed in 19 % ( 32/169 ) of cats ,", "label": "finding"}, {"segment_text": "and 75 % ( 24/32 ) of these cats were FCoV seropositive .", "label": "finding"}, {"segment_text": "FCoV seropositivity was also associated with a high white blood cell count ,", "label": "finding"}, {"segment_text": "high plasma globulin , low plasma albumin and low blood urea nitrogen .", "label": "finding"}, {"segment_text": "The percentage of FCoV seropositive and seronegative cats that died in spite of supportive veterinary treatment was 33 % ( 21/63 ) and 12 % ( 13/106 ) , respectively .", "label": "finding"}, {"segment_text": "These results indicate that FCoV is widespread and has a severe clinical impact in cats from Istanbul .", "label": "finding"}, {"segment_text": "Moreover , the incidence of FCoV infections could be rising ,", "label": "finding"}, {"segment_text": "and in the absence of effective vaccination cat owners need to be made aware of ways to minimize the spread of this virus .", "label": "finding"}], "n_segments": 18}
{"paper_id": "4caeac77d9c3f4fb7c6ed5d62c56a2a24660267a", "title": "", "coda_paper_id": 1796, "has_expert_labels": false, "abstract_text": "In the present study , the regulatory effect of cytokine-induced neutrophil chemoattractant ( CINC ) and epithelial neutrophil-activating peptide 78 ( ENA-78 ) on pulmonary neutrophil ( PMN ) accumulation in lipopolysaccharide ( LPS ) - induced acute respiratory distress syndrome ( ARDS ) mice , and the therapeutic effect of pyrrolidine dithiocarbamate ( PDTC ) , was investigated . BALB/c mice were divided into control , LPS and PDTC + LPS groups using a random number table . The phosphorylation of nuclear factor-κB ( NF-κB ) was detected using a western blot , and the mRNA expression levels of CINC were evaluated using reverse transcription-quantitative polymerase chain reaction . The expression of NF-κB , CINC and ENA-78 was detected using immunohistochemistry . The production of interleukin ( IL ) -8 and IL-10 in serum and broncho-alveolar lavage fluid ( BALF ) was analyzed using an enzyme-linked immunosorbent assay . The total number of leukocytes and proportion of PMNs in BALF was also determined . Following injection with LPS ( 20 mg/kg ) , the expression levels of p-NF-κB , CINC and ENA-78 were increased in lung tissue , and the expression levels of IL-8 , IL-10 and the number of PMNs increased in serum and BALF . However , in comparison with the LPS group , the degree of lung injury was reduced in ARDS mice that were treated with PDTC . In addition , the expression level of p-NF-κB and the production of chemokines in lung tissue decreased in ARDS mice that were treated with PDTC , and the number of PMNs in BALF also decreased . In conclusion , the results of the present study suggest that the LPS-induced phosphorylation of NF-κB may result in the synthesis and release of CINC and ENA-78 , which induce the accumulation of PMNs in the lung . Therefore , PDTC may be used to reduce the production of chemokines and cytokines , thereby decreasing the activation of PMNs in lung tissue and reducing the damage of lung tissue in ARDS .", "gold_segments": [{"segment_text": "In the present study , the regulatory effect of cytokine-induced neutrophil chemoattractant ( CINC ) and epithelial neutrophil-activating peptide 78 ( ENA-78 ) on pulmonary neutrophil ( PMN ) accumulation in lipopolysaccharide ( LPS ) - induced acute respiratory distress syndrome ( ARDS ) mice ,", "label": "background"}, {"segment_text": "and the therapeutic effect of pyrrolidine dithiocarbamate ( PDTC ) , was investigated .", "label": "background"}, {"segment_text": "BALB/c mice were divided into control ,", "label": "method"}, {"segment_text": "LPS and PDTC + LPS groups using a random number table .", "label": "method"}, {"segment_text": "The phosphorylation of nuclear factor-κB ( NF-κB ) was detected using a western blot ,", "label": "method"}, {"segment_text": "and the mRNA expression levels of CINC were evaluated using reverse transcription-quantitative polymerase chain reaction .", "label": "method"}, {"segment_text": "The expression of NF-κB , CINC and ENA-78 was detected using immunohistochemistry .", "label": "method"}, {"segment_text": "The production of interleukin ( IL ) -8 and IL-10 in serum and broncho-alveolar lavage fluid ( BALF ) was analyzed using an enzyme-linked immunosorbent assay .", "label": "method"}, {"segment_text": "The total number of leukocytes and proportion of PMNs in BALF was also determined .", "label": "method"}, {"segment_text": "Following injection with LPS ( 20 mg/kg ) ,", "label": "method"}, {"segment_text": "the expression levels of p-NF-κB ,", "label": "method"}, {"segment_text": "CINC and ENA-78 were increased in lung tissue ,", "label": "finding"}, {"segment_text": "and the expression levels of IL-8 ,", "label": "finding"}, {"segment_text": "IL-10 and the number of PMNs increased in serum and BALF .", "label": "finding"}, {"segment_text": "However , in comparison with the LPS group ,", "label": "finding"}, {"segment_text": "the degree of lung injury was reduced in ARDS mice that were treated with PDTC .", "label": "finding"}, {"segment_text": "In addition , the expression level of p-NF-κB and the production of chemokines in lung tissue decreased in ARDS mice that were treated with PDTC ,", "label": "finding"}, {"segment_text": "and the number of PMNs in BALF also decreased .", "label": "finding"}, {"segment_text": "In conclusion , the results of the present study suggest that the LPS-induced phosphorylation of NF-κB may result in the synthesis and release of CINC and ENA-78 ,", "label": "finding"}, {"segment_text": "which induce the accumulation of PMNs in the lung .", "label": "finding"}, {"segment_text": "Therefore , PDTC may be used to reduce the production of chemokines and cytokines ,", "label": "finding"}, {"segment_text": "thereby decreasing the activation of PMNs in lung tissue and reducing the damage of lung tissue in ARDS .", "label": "finding"}], "n_segments": 22}
{"paper_id": "ddd0fb0cae99bad6466775c11b4d5a0c30be9219", "title": "Different Types of Door-Opening Motions as Contributing Factors to Containment Failures in Hospital Isolation Rooms", "coda_paper_id": 1080, "has_expert_labels": false, "abstract_text": "Hospital isolation rooms are vital for the containment ( when under negative pressure ) of patients with , or the protection ( when under positive pressure ) of patients , from airborne infectious agents . Such facilities were essential for the management of highly contagious patients during the 2003 severe acute respiratory syndrome ( SARS ) outbreaks and the more recent 2009 A/H1N1 influenza pandemic . Many different types of door designs are used in the construction of such isolation rooms , which may be related to the space available and affordability . Using colored food dye as a tracer , the qualitative effects of door-opening motions on the dissemination of potentially contaminated air into and out of a single isolation room were visualized and filmed using Reynolds-number-equivalent , small-scale , water-tank models fitted with programmable door-opening and moving human figure motions . Careful scaling considerations involved in the design and construction of these water-tank models enabled these results to be accurately extrapolated to the full-scale situation . Four simple types of door design were tested : variable speed single and double , sliding and hinged doors , in combination with the moving human figure . The resulting video footage was edited , synchronized and presented in a series of split-screen formats . From these experiments , it is clear that double-hinged doors pose the greatest risk of leakage into or out of the room , followed by ( in order of decreasing risk ) single-hinged , double-sliding and single-sliding doors . The relative effect of the moving human figure on spreading any potential contamination was greatest with the sliding doors , as the bulk airflows induced were large relative to those resulting from these door-opening motions . However , with the hinged doors , the airflows induced by these door-opening motions were significantly greater . Further experiments involving a simulated ventilated environment are required , but from these findings alone , it appears that sliding-doors are far more effective for hospital isolation room containment .", "gold_segments": [{"segment_text": "Hospital isolation rooms are vital for the containment ( when under negative pressure ) of patients with ,", "label": "background"}, {"segment_text": "or the protection ( when under positive pressure ) of patients , from airborne infectious agents .", "label": "background"}, {"segment_text": "Such facilities were essential for the management of highly contagious patients during the 2003 severe acute respiratory syndrome ( SARS ) outbreaks and the more recent 2009 A/H1N1 influenza pandemic .", "label": "background"}, {"segment_text": "Many different types of door designs are used in the construction of such isolation rooms ,", "label": "background"}, {"segment_text": "which may be related to the space available and affordability .", "label": "background"}, {"segment_text": "Using colored food dye as a tracer ,", "label": "method"}, {"segment_text": "the qualitative effects of door-opening motions on the dissemination of potentially contaminated air into and out of a single isolation room were visualized and filmed using Reynolds-number-equivalent ,", "label": "method"}, {"segment_text": "small-scale , water-tank models fitted with programmable door-opening and moving human figure motions .", "label": "method"}, {"segment_text": "Careful scaling considerations involved in the design and construction of these water-tank models enabled these results to be accurately extrapolated to the full-scale situation .", "label": "method"}, {"segment_text": "Four simple types of door design were tested : variable speed single and double ,", "label": "method"}, {"segment_text": "sliding and hinged doors , in combination with the moving human figure .", "label": "method"}, {"segment_text": "The resulting video footage was edited ,", "label": "method"}, {"segment_text": "synchronized and presented in a series of split-screen formats .", "label": "method"}, {"segment_text": "From these experiments , it is clear that double-hinged doors pose the greatest risk of leakage into or out of the room ,", "label": "finding"}, {"segment_text": "followed by ( in order of decreasing risk ) single-hinged , double-sliding and single-sliding doors .", "label": "finding"}, {"segment_text": "The relative effect of the moving human figure on spreading any potential contamination was greatest with the sliding doors ,", "label": "finding"}, {"segment_text": "as the bulk airflows induced were large relative to those resulting from these door-opening motions .", "label": "finding"}, {"segment_text": "However , with the hinged doors ,", "label": "finding"}, {"segment_text": "the airflows induced by these door-opening motions were significantly greater .", "label": "finding"}, {"segment_text": "Further experiments involving a simulated ventilated environment are required ,", "label": "finding"}, {"segment_text": "but from these findings alone ,", "label": "finding"}, {"segment_text": "it appears that sliding-doors are far more effective for hospital isolation room containment .", "label": "finding"}], "n_segments": 22}
{"paper_id": "a8a03b14c70211bd944a5f49bcf9147045492c77", "title": "Hyposialylated a1-acid glycoprotein inhibits phagocytosis of feline neutrophils", "coda_paper_id": 1572, "has_expert_labels": false, "abstract_text": "a-1-Acid glycoprotein Flow cytometry Feline infectious peritonitis a b s t r a c t Feline a1-acid glycoprotein ( fAGP ) modifies both its serum concentration and its glycan moiety during diseases . fAGP is hyposialylated in cats with feline infectious peritonitis ( FIP ) , but not in clinically healthy cats or in cats with other diseases . This study was aimed to determine whether hyposialylated fAGP influences phagocytosis . A flow cytometric method based on ingestion of fluoresceinated bacteria and adapted to feline blood was used to assess phagocytosis of leukocytes incubated with ` non-pathological ' fAGP ( purified from sera with normal concentrations of AGP ) and ` pathological ' fAGP ( purified from sera with > 1.5 mg/mL hyposialylated AGP ) . The flow cytometric method provided repeatable results for neutrophils ( coefficients of variations , CVs < 15 % ) but not for monocytes ( CVs > 20 % ) which had also a high individual variability . Compared with saline solution and with non-pathological fAGP , pathological fAGP significantly decreased phagocytosis in neutrophils and monocytes . This study demonstrated that hyposialylated fAGP down-regulates the phagocytic activity of feline neutrophils .", "gold_segments": [{"segment_text": "a-1-Acid glycoprotein Flow cytometry Feline infectious peritonitis a b s t r a c t Feline a1-acid glycoprotein ( fAGP ) modifies both its serum concentration and its glycan moiety during diseases .", "label": "background"}, {"segment_text": "fAGP is hyposialylated in cats with feline infectious peritonitis ( FIP ) ,", "label": "background"}, {"segment_text": "but not in clinically healthy cats or in cats with other diseases .", "label": "background"}, {"segment_text": "This study was aimed to determine whether hyposialylated fAGP influences phagocytosis .", "label": "purpose"}, {"segment_text": "A flow cytometric method based on ingestion of fluoresceinated bacteria and adapted to feline blood was used to assess phagocytosis of leukocytes incubated with ` non-pathological ' fAGP ( purified from sera with normal concentrations of AGP ) and ` pathological ' fAGP ( purified from sera with > 1.5 mg/mL hyposialylated AGP ) .", "label": "method"}, {"segment_text": "The flow cytometric method provided repeatable results for neutrophils ( coefficients of variations , CVs < 15 % ) but not for monocytes ( CVs > 20 % ) which had also a high individual variability .", "label": "finding"}, {"segment_text": "Compared with saline solution and with non-pathological fAGP ,", "label": "finding"}, {"segment_text": "pathological fAGP significantly decreased phagocytosis in neutrophils and monocytes .", "label": "finding"}, {"segment_text": "This study demonstrated that hyposialylated fAGP down-regulates the phagocytic activity of feline neutrophils .", "label": "finding"}], "n_segments": 9}
{"paper_id": "48aab88de4df103519c31d5533d561053b07bbb4", "title": "Rapid identification viruses from nasal pharyngeal aspirates in acute viral respiratory infections by RT-PCR and electrospray ionization mass spectrometry ଝ,ଝଝ", "coda_paper_id": 1645, "has_expert_labels": false, "abstract_text": "Diagnosis of the etiologic agent of respiratory viral infection relies traditionally on culture or antigen detection . This pilot evaluation compared performance characteristics of the RT-PCR and electrospray ionization mass spectrometry ( RT-PCR/ESI-MS ) platform to conventional virologic methods for identifying multiple clinically relevant respiratory viruses in nasopharyngeal aspirates . The RT-PCR/ESI-MS respiratory virus surveillance kit was designed to detect respiratory syncytial virus , influenza A and B , parainfluenza types 1-4 , adenoviridae types A-F , coronaviridae , human bocavirus , and human metapneumovirus . Patients ( N = 192 ) attending an emergency department during the 2007-2008 respiratory season consented , and `` excess '' frozen archived nasopharyngeal aspirates were analysed ; 46 were positive by conventional virology and 69 by RT-PCR/ESI-MS , among which there were six samples with multiple viral pathogens detected . The sensitivity and specificity of the assay were 89.1 % and 80.3 % , respectively . Additional viruses that were not identified by conventional virology assays were detected ( 4 human bocaviruses and 7 coronaviruses ) . Samples in which the RT-PCR/ESI-MS results disagreed with conventional virology were sent for analysis by a third method using a commercial RT-PCR-based assay , which can identify viruses not detectable by conventional virologic procedures . Time to first result of RT-PCR/ESI-MS was 8 h. RT-PCR/ESI-MS demonstrated capacity to detect respiratory viruses identifiable and unidentifiable by conventional methods rapidly .", "gold_segments": [{"segment_text": "Diagnosis of the etiologic agent of respiratory viral infection relies traditionally on culture or antigen detection .", "label": "background"}, {"segment_text": "This pilot evaluation compared performance characteristics of the RT-PCR and electrospray ionization mass spectrometry ( RT-PCR/ESI-MS ) platform to conventional virologic methods for identifying multiple clinically relevant respiratory viruses in nasopharyngeal aspirates .", "label": "purpose"}, {"segment_text": "The RT-PCR/ESI-MS respiratory virus surveillance kit was designed to detect respiratory syncytial virus ,", "label": "method"}, {"segment_text": "influenza A and B , parainfluenza types 1-4 ,", "label": "method"}, {"segment_text": "adenoviridae types A-F , coronaviridae ,", "label": "method"}, {"segment_text": "human bocavirus , and human metapneumovirus .", "label": "method"}, {"segment_text": "Patients ( N = 192 ) attending an emergency department during the 2007-2008 respiratory season consented ,", "label": "method"}, {"segment_text": "and `` excess '' frozen archived nasopharyngeal aspirates were analysed ; 46 were positive by conventional virology and 69 by RT-PCR/ESI-MS ,", "label": "method"}, {"segment_text": "among which there were six samples with multiple viral pathogens detected .", "label": "finding"}, {"segment_text": "The sensitivity and specificity of the assay were 89.1 % and 80.3 % , respectively .", "label": "finding"}, {"segment_text": "Additional viruses that were not identified by conventional virology assays were detected ( 4 human bocaviruses and 7 coronaviruses ) .", "label": "finding"}, {"segment_text": "Samples in which the RT-PCR/ESI-MS results disagreed with conventional virology were sent for analysis by a third method using a commercial RT-PCR-based assay ,", "label": "finding"}, {"segment_text": "which can identify viruses not detectable by conventional virologic procedures .", "label": "finding"}, {"segment_text": "Time to first result of RT-PCR/ESI-MS was 8 h. RT-PCR/ESI-MS demonstrated capacity to detect respiratory viruses identifiable and unidentifiable by conventional methods rapidly .", "label": "finding"}], "n_segments": 14}
{"paper_id": "f2813a7e7a7f0a9dbce57e42585ffc35d2da4a8c", "title": "Minireview New agents modulating the renin-angiotensin-aldosterone system-Will there be a new therapeutic option?", "coda_paper_id": 1675, "has_expert_labels": false, "abstract_text": "The renin-angiotensin-aldosterone system ( RAAS ) is more complex than it was originally regarded . According to the current subject knowledge , there are two main axes of the RAAS : ( 1 ) angiotensin-converting enzyme ( ACE ) - angiotensin II-AT 1 receptor axis and ( 2 ) ACE2-angiotensin - ( 1-7 ) - Mas receptor axis . The activation of the first axis leads to deleterious effects , including vasoconstriction , endothelial dysfunction , thrombosis , inflammation , and fibrosis ; therefore , blocking the components of this axis is a highly rational and commonly used therapeutic procedure . The ACE2-Ang - ( 1-7 ) - Mas receptor axis has a different role , since it often opposes the effects induced by the classical ACE-Ang II-AT 1 axis . Once the positive effects of the ACE2-Ang - ( 1-7 ) - Mas axis were discovered , the alternative ways of pharmacotherapy activating this axis of RAAS appeared . This article briefly describes new molecules affecting the RAAS , namely : recombinant human ACE2 , ACE2 activators , angiotensin - ( 1-7 ) peptide and non-peptide analogs , aldosterone synthase inhibitors , and the third and fourth generation of mineralocorticoid receptor antagonists . The results of the experimental and clinical studies are encouraging , which leads us to believe that these new molecules can support the treatment of cardiovascular diseases as well as cardiometabolic disorders .", "gold_segments": [{"segment_text": "The renin-angiotensin-aldosterone system ( RAAS ) is more complex than it was originally regarded .", "label": "background"}, {"segment_text": "According to the current subject knowledge ,", "label": "background"}, {"segment_text": "there are two main axes of the RAAS : ( 1 ) angiotensin-converting enzyme ( ACE ) - angiotensin II-AT 1 receptor axis and ( 2 ) ACE2-angiotensin - ( 1-7 ) - Mas receptor axis .", "label": "background"}, {"segment_text": "The activation of the first axis leads to deleterious effects ,", "label": "background"}, {"segment_text": "including vasoconstriction , endothelial dysfunction ,", "label": "background"}, {"segment_text": "thrombosis , inflammation , and fibrosis ; therefore ,", "label": "background"}, {"segment_text": "blocking the components of this axis is a highly rational and commonly used therapeutic procedure .", "label": "background"}, {"segment_text": "The ACE2-Ang - ( 1-7 ) - Mas receptor axis has a different role ,", "label": "background"}, {"segment_text": "since it often opposes the effects induced by the classical ACE-Ang II-AT 1 axis .", "label": "background"}, {"segment_text": "Once the positive effects of the ACE2-Ang - ( 1-7 ) - Mas axis were discovered ,", "label": "background"}, {"segment_text": "the alternative ways of pharmacotherapy activating this axis of RAAS appeared .", "label": "background"}, {"segment_text": "This article briefly describes new molecules affecting the RAAS ,", "label": "purpose"}, {"segment_text": "namely : recombinant human ACE2 ,", "label": "purpose"}, {"segment_text": "ACE2 activators , angiotensin - ( 1-7 ) peptide and non-peptide analogs ,", "label": "purpose"}, {"segment_text": "aldosterone synthase inhibitors , and the third and fourth generation of mineralocorticoid receptor antagonists .", "label": "purpose"}, {"segment_text": "The results of the experimental and clinical studies are encouraging ,", "label": "finding"}, {"segment_text": "which leads us to believe that these new molecules can support the treatment of cardiovascular diseases as well as cardiometabolic disorders .", "label": "finding"}], "n_segments": 17}
{"paper_id": "f3a5b128f4800dbbb0f49ee409acb2c0216e24dc", "title": "Estimating Sensitivity of Laboratory Testing for Influenza in Canada through Modelling", "coda_paper_id": 1099, "has_expert_labels": false, "abstract_text": "Background : The weekly proportion of laboratory tests that are positive for influenza is used in public health surveillance systems to identify periods of influenza activity . We aimed to estimate the sensitivity of influenza testing in Canada based on results of a national respiratory virus surveillance system . The weekly number of influenza-negative tests from 1999 to 2006 was modelled as a function of laboratory-confirmed positive tests for influenza , respiratory syncytial virus ( RSV ) , adenovirus and parainfluenza viruses , seasonality , and trend using Poisson regression . Sensitivity was calculated as the number of influenza positive tests divided by the number of influenza positive tests plus the model-estimated number of false negative tests . The sensitivity of influenza testing was estimated to be 33 % ( 95 % CI 32-34 % ) , varying from 30-40 % depending on the season and region . The estimated sensitivity of influenza tests reported to this national laboratory surveillance system is considerably less than reported test characteristics for most laboratory tests . A number of factors may explain this difference , including sample quality and specimen procurement issues as well as test characteristics . Improved diagnosis would permit better estimation of the burden of influenza .", "gold_segments": [{"segment_text": "Background : The weekly proportion of laboratory tests that are positive for influenza is used in public health surveillance systems to identify periods of influenza activity .", "label": "background"}, {"segment_text": "We aimed to estimate the sensitivity of influenza testing in Canada based on results of a national respiratory virus surveillance system .", "label": "purpose"}, {"segment_text": "The weekly number of influenza-negative tests from 1999 to 2006 was modelled as a function of laboratory-confirmed positive tests for influenza ,", "label": "method"}, {"segment_text": "respiratory syncytial virus ( RSV ) ,", "label": "method"}, {"segment_text": "adenovirus and parainfluenza viruses , seasonality ,", "label": "method"}, {"segment_text": "and trend using Poisson regression .", "label": "method"}, {"segment_text": "Sensitivity was calculated as the number of influenza positive tests divided by the number of influenza positive tests plus the model-estimated number of false negative tests .", "label": "method"}, {"segment_text": "The sensitivity of influenza testing was estimated to be 33 % ( 95 % CI 32-34 % ) ,", "label": "finding"}, {"segment_text": "varying from 30-40 % depending on the season and region .", "label": "finding"}, {"segment_text": "The estimated sensitivity of influenza tests reported to this national laboratory surveillance system is considerably less than reported test characteristics for most laboratory tests .", "label": "finding"}, {"segment_text": "A number of factors may explain this difference ,", "label": "finding"}, {"segment_text": "including sample quality and specimen procurement issues as well as test characteristics .", "label": "finding"}, {"segment_text": "Improved diagnosis would permit better estimation of the burden of influenza .", "label": "finding"}], "n_segments": 13}
{"paper_id": "98b4d77a72da361c2c9a4d914fb354e4c4cfb717", "title": "Tracking and predicting growth areas in science", "coda_paper_id": 1881, "has_expert_labels": false, "abstract_text": "We explore the possibility of using co-citation clusters over three time periods to track the emergence and growth of research areas , and predict their near term change . Data sets are from three overlapping six-year periods : . The methodologies of co-citation clustering , mapping , and string formation are reviewed , and a measure of cluster currency is defined as the average age of highly cited papers relative to the year span of the data set . An association is found between the currency variable in a prior period and the percentage change in cluster size and citation frequency in the following period . The conflating factor of `` single-issue clusters '' is discussed and dealt with using a new metric called in-group citation .", "gold_segments": [{"segment_text": "We explore the possibility of using co-citation clusters over three time periods to track the emergence and growth of research areas ,", "label": "purpose"}, {"segment_text": "and predict their near term change .", "label": "purpose"}, {"segment_text": "Data sets are from three overlapping six-year periods : .", "label": "method"}, {"segment_text": "The methodologies of co-citation clustering ,", "label": "method"}, {"segment_text": "mapping , and string formation are reviewed ,", "label": "method"}, {"segment_text": "and a measure of cluster currency is defined as the average age of highly cited papers relative to the year span of the data set .", "label": "method"}, {"segment_text": "An association is found between the currency variable in a prior period and the percentage change in cluster size and citation frequency in the following period .", "label": "finding"}, {"segment_text": "The conflating factor of `` single-issue clusters '' is discussed and dealt with using a new metric called in-group citation .", "label": "finding"}], "n_segments": 8}
{"paper_id": "f8741a6a2f6c5af7585ba60b367c7a550cea4a1d", "title": "Selection for 3 0 end triplets for polymerase chain reaction primers", "coda_paper_id": 1556, "has_expert_labels": false, "abstract_text": "The 3 0 end of a primer is a key component of PCR primer design . Many recommendations for the composition and sequence of the 3 0 end have been suggested based on theoretical considerations , but have not been verified experimentally . We analyzed 3 0 end triplets of PCR primer sequences obtained from refereed journal articles , to test those recommendations and to make empirical recommendations for primer design . The frequencies of the 64 possible 3 0 end triplets among 2137 PCR primers from the VirOligo database were not uniformly distributed . From the analysis , we found that unfavored and preferred 3 0 end triplets existed , and that the apparent preferences were not due to base compositions in viral genome sequences . Comparison of the sequences preferred by practitioners to those recommended , suggested that no single recommendation is entirely satisfactory . We suggest that recommendations be replaced with a scoring system incorporating empirical frequencies such as those reported here . q", "gold_segments": [{"segment_text": "The 3 0 end of a primer is a key component of PCR primer design .", "label": "background"}, {"segment_text": "Many recommendations for the composition and sequence of the 3 0 end have been suggested based on theoretical considerations ,", "label": "background"}, {"segment_text": "but have not been verified experimentally .", "label": "background"}, {"segment_text": "We analyzed 3 0 end triplets of PCR primer sequences obtained from refereed journal articles ,", "label": "method"}, {"segment_text": "to test those recommendations and to make empirical recommendations for primer design .", "label": "method"}, {"segment_text": "The frequencies of the 64 possible 3 0 end triplets among 2137 PCR primers from the VirOligo database were not uniformly distributed .", "label": "method"}, {"segment_text": "From the analysis , we found that unfavored and preferred 3 0 end triplets existed ,", "label": "finding"}, {"segment_text": "and that the apparent preferences were not due to base compositions in viral genome sequences .", "label": "finding"}, {"segment_text": "Comparison of the sequences preferred by practitioners to those recommended ,", "label": "finding"}, {"segment_text": "suggested that no single recommendation is entirely satisfactory .", "label": "finding"}, {"segment_text": "We suggest that recommendations be replaced with a scoring system incorporating empirical frequencies such as those reported here .", "label": "finding"}, {"segment_text": "q", "label": "other"}], "n_segments": 12}
{"paper_id": "f16c920736841eabbd63861480e12d70a832f7d8", "title": "Detection and Isolation of Exotic Newcastle Disease Virus from Field-Collected Flies", "coda_paper_id": 1046, "has_expert_labels": false, "abstract_text": "Flies were collected by sweep net from the vicinity of two small groups of `` backyard '' poultry ( 10 Ð20 chickens per group ) that had been identiÞed as infected with exotic Newcastle disease virus ( family Paramyxoviridae , genus avulavirus , ENDV ) in Los Angeles County , CA , during the 2002Ð2003 END outbreak . Collected ßies were subdivided into pools and homogenized in brain-heart infusion broth with antibiotics . The separated supernatant was tested for the presence of ENDV by inoculation into embryonated chicken eggs . Exotic Newcastle disease virus was isolated from pools of Phaenicia cuprina ( Wiedemann ) , Fannia canicularis ( L. ) , and Musca domestica L. , and it was identiÞed by hemagglutination inhibition with Newcastle disease virus antiserum . Viral concentration in positive pools was low ( Ͻ1 egg infectious dose 50 per ßy ) . Isolated virus demonstrated identical monoclonal antibody binding proÞles as well as 99 % sequence homology in the 635-bp fusion gene sequence compared with ENDV recovered from infected commercial egg layer poultry during the 2002 outbreak .", "gold_segments": [{"segment_text": "Flies were collected by sweep net from the vicinity of two small groups of `` backyard '' poultry ( 10 Ð20 chickens per group ) that had been identiÞed as infected with exotic Newcastle disease virus ( family Paramyxoviridae , genus avulavirus , ENDV ) in Los Angeles County ,", "label": "method"}, {"segment_text": "CA , during the 2002Ð2003 END outbreak .", "label": "background"}, {"segment_text": "Collected ßies were subdivided into pools and homogenized in brain-heart infusion broth with antibiotics .", "label": "method"}, {"segment_text": "The separated supernatant was tested for the presence of ENDV by inoculation into embryonated chicken eggs .", "label": "method"}, {"segment_text": "Exotic Newcastle disease virus was isolated from pools of Phaenicia cuprina ( Wiedemann ) ,", "label": "method"}, {"segment_text": "Fannia canicularis ( L. ) ,", "label": "method"}, {"segment_text": "and Musca domestica L. , and it was identiÞed by hemagglutination inhibition with Newcastle disease virus antiserum .", "label": "method"}, {"segment_text": "Viral concentration in positive pools was low ( Ͻ1 egg infectious dose 50 per ßy ) .", "label": "finding"}, {"segment_text": "Isolated virus demonstrated identical monoclonal antibody binding proÞles as well as 99 % sequence homology in the 635-bp fusion gene sequence compared with ENDV recovered from infected commercial egg layer poultry during the 2002 outbreak .", "label": "finding"}], "n_segments": 9}
{"paper_id": "bb99b6dde050807939930f078e0eed8a4693a710", "title": "A comprehensive in silico analysis for identification of therapeutic epitopes in HPV16, 18, 31 and 45 oncoproteins", "coda_paper_id": 1636, "has_expert_labels": false, "abstract_text": "Human papillomaviruses ( HPVs ) are a group of circular double-stranded DNA viruses , showing severe tropism to mucosal tissues . A subset of HPVs , especially HPV16 and 18 , are the primary etiological cause for several epithelial cell malignancies , causing about 5.2 % of all cancers worldwide . Due to the high prevalence and mortality , HPV-associated cancers have remained as a significant health problem in human society , making an urgent need to develop an effective therapeutic vaccine against them . Achieving this goal is primarily dependent on the identification of efficient tumor-associated epitopes , inducing a robust cell-mediated immune response . Previous information has shown that E5 , E6 , and E7 early proteins are responsible for the induction and maintenance of HPV-associated cancers . Therefore , the prediction of major histocompatibility complex ( MHC ) class I T cell epitopes of HPV16 , 18 , 31 and 45 oncoproteins was targeted in this study . For this purpose , a twostep plan was designed to identify the most probable CD8 + T cell epitopes . In the first step , MHC-I and II binding , MHC-I processing , MHC-I population coverage and MHC-I immunogenicity prediction analyses , and in the second step , MHC-I and II protein-peptide docking , epitope conservation , and cross-reactivity with host antigens ' analyses were carried out successively by different tools . Finally , we introduced five probable CD8 + T cell epitopes for each oncoprotein of the HPV genotypes ( 60 epitopes in total ) , which obtained better scores by an integrated approach . These predicted epitopes are valuable candidates for in vitro or in vivo therapeutic vaccine studies against the HPV-associated cancers . Additionally , this two-step plan that each step includes several analyses to find appropriate epitopes provides a rational basis for DNA-or peptide-based vaccine development .", "gold_segments": [{"segment_text": "Human papillomaviruses ( HPVs ) are a group of circular double-stranded DNA viruses ,", "label": "background"}, {"segment_text": "showing severe tropism to mucosal tissues .", "label": "background"}, {"segment_text": "A subset of HPVs , especially HPV16 and 18 ,", "label": "background"}, {"segment_text": "are the primary etiological cause for several epithelial cell malignancies ,", "label": "background"}, {"segment_text": "causing about 5.2 % of all cancers worldwide .", "label": "background"}, {"segment_text": "Due to the high prevalence and mortality ,", "label": "background"}, {"segment_text": "HPV-associated cancers have remained as a significant health problem in human society ,", "label": "background"}, {"segment_text": "making an urgent need to develop an effective therapeutic vaccine against them .", "label": "background"}, {"segment_text": "Achieving this goal is primarily dependent on the identification of efficient tumor-associated epitopes ,", "label": "background"}, {"segment_text": "inducing a robust cell-mediated immune response .", "label": "background"}, {"segment_text": "Previous information has shown that E5 ,", "label": "background"}, {"segment_text": "E6 , and E7 early proteins are responsible for the induction and maintenance of HPV-associated cancers .", "label": "background"}, {"segment_text": "Therefore , the prediction of major histocompatibility complex ( MHC ) class I T cell epitopes of HPV16 ,", "label": "purpose"}, {"segment_text": "18 , 31 and 45 oncoproteins was targeted in this study .", "label": "purpose"}, {"segment_text": "For this purpose , a twostep plan was designed to identify the most probable CD8 + T cell epitopes .", "label": "method"}, {"segment_text": "In the first step , MHC-I and II binding ,", "label": "finding"}, {"segment_text": "MHC-I processing , MHC-I population coverage and MHC-I immunogenicity prediction analyses ,", "label": "finding"}, {"segment_text": "and in the second step ,", "label": "finding"}, {"segment_text": "MHC-I and II protein-peptide docking ,", "label": "finding"}, {"segment_text": "epitope conservation , and cross-reactivity with host antigens ' analyses were carried out successively by different tools .", "label": "finding"}, {"segment_text": "Finally , we introduced five probable CD8 + T cell epitopes for each oncoprotein of the HPV genotypes ( 60 epitopes in total ) ,", "label": "method"}, {"segment_text": "which obtained better scores by an integrated approach .", "label": "finding"}, {"segment_text": "These predicted epitopes are valuable candidates for in vitro or in vivo therapeutic vaccine studies against the HPV-associated cancers .", "label": "finding"}, {"segment_text": "Additionally , this two-step plan that each step includes several analyses to find appropriate epitopes provides a rational basis for DNA-or peptide-based vaccine development .", "label": "finding"}], "n_segments": 24}
{"paper_id": "4b2ef217cb3fedccaffa0ecdd43344810630987b", "title": "Identification of human leukemia antigen A*0201-restricted epitopes derived from epidermal growth factor pathway substrate number 8", "coda_paper_id": 1442, "has_expert_labels": false, "abstract_text": "T-cell-mediated immunotherapy of hematological malignancies requires selection of targeted tumor-associated antigens and T-cell epitopes contained in these tumor proteins . Epidermal growth factor receptor pathway substrate 8 ( EPS8 ) , whose function is pivotal for tumor proliferation , progression and metastasis , has been found to be overexpressed in most human tumor types , while its expression in normal tissue is low . The aim of the present study was to identify human leukemia antigen ( HLA ) - A * 0201-restricted epitopes of EPS8 by using a reverse immunology approach . To achieve this , computer algorithms were used to predict HLA-A * 0201 molecular binding , proteasome cleavage patterns as well as translocation of transporters associated with antigen processing . Candidate peptides were experimentally validated by T2 binding affinity assay and brefeldin-A decay assay . The functional avidity of peptide-specific cytotoxic T lymphocytes ( CTLs ) induced from peripheral blood mononuclear cells of healthy volunteers were evaluated by using an enzyme-linked immunosorbent spot assay and a cytotoxicity assay . Four peptides , designated as P455 , P92 , P276 and P360 , had high affinity and stability of binding towards the HLA-A * 0201 molecule , and specific CTLs induced by them significantly responded to the corresponding peptides and secreted IFN-γ . At the same time , the CTLs were able to specifically lyse EPS8-expressing cell lines in an HLA-A * 0201-restricted manner . The present study demonstrated that P455 , P92 , P276 and P360 were CTL epitopes of EPS8 , and were able to be used for epitope-defined adoptive T-cell transfer and multi-epitope-based vaccine design .", "gold_segments": [{"segment_text": "T-cell-mediated immunotherapy of hematological malignancies requires selection of targeted tumor-associated antigens and T-cell epitopes contained in these tumor proteins .", "label": "background"}, {"segment_text": "Epidermal growth factor receptor pathway substrate 8 ( EPS8 ) ,", "label": "background"}, {"segment_text": "whose function is pivotal for tumor proliferation ,", "label": "background"}, {"segment_text": "progression and metastasis , has been found to be overexpressed in most human tumor types ,", "label": "background"}, {"segment_text": "while its expression in normal tissue is low .", "label": "background"}, {"segment_text": "The aim of the present study was to identify human leukemia antigen ( HLA ) - A * 0201-restricted epitopes of EPS8 by using a reverse immunology approach .", "label": "purpose"}, {"segment_text": "To achieve this , computer algorithms were used to predict HLA-A * 0201 molecular binding ,", "label": "method"}, {"segment_text": "proteasome cleavage patterns as well as translocation of transporters associated with antigen processing .", "label": "method"}, {"segment_text": "Candidate peptides were experimentally validated by T2 binding affinity assay and brefeldin-A decay assay .", "label": "method"}, {"segment_text": "The functional avidity of peptide-specific cytotoxic T lymphocytes ( CTLs ) induced from peripheral blood mononuclear cells of healthy volunteers were evaluated by using an enzyme-linked immunosorbent spot assay and a cytotoxicity assay .", "label": "method"}, {"segment_text": "Four peptides , designated as P455 ,", "label": "finding"}, {"segment_text": "P92 , P276 and P360 ,", "label": "finding"}, {"segment_text": "had high affinity and stability of binding towards the HLA-A * 0201 molecule ,", "label": "finding"}, {"segment_text": "and specific CTLs induced by them significantly responded to the corresponding peptides and secreted IFN-γ .", "label": "finding"}, {"segment_text": "At the same time , the CTLs were able to specifically lyse EPS8-expressing cell lines in an HLA-A * 0201-restricted manner .", "label": "finding"}, {"segment_text": "The present study demonstrated that P455 ,", "label": "finding"}, {"segment_text": "P92 , P276 and P360 were CTL epitopes of EPS8 ,", "label": "finding"}, {"segment_text": "and were able to be used for epitope-defined adoptive T-cell transfer and multi-epitope-based vaccine design .", "label": "finding"}], "n_segments": 18}
{"paper_id": "85410eee6126af27739d721539e7eb7d29a7f08c", "title": "Genetic host specificity of hepatitis E virus", "coda_paper_id": 1956, "has_expert_labels": false, "abstract_text": "Hepatitis E virus ( HEV ) causes epidemic and sporadic cases of hepatitis worldwide . HEV genotypes 3 ( HEV3 ) and 4 ( HEV4 ) infect humans and animals , with swine being the primary reservoir . The relevance of HEV genetic diversity to host adaptation is poorly understood . We employed a Bayesian network ( BN ) analysis of HEV3 and HEV4 to detect epistatic connectivity among protein sites and its association with the host specificity in each genotype . The data imply coevolution among $ 70 % of polymorphic sites from all HEV proteins and association of numerous coevolving sites with adaptation to swine or humans . BN models for individual proteins and domains of the nonstructural polyprotein detected the host origin of HEV strains with accuracy of 74-93 % and 63-87 % , respectively . These findings , taken together with lack of phylogenetic association to host , suggest that the HEV host specificity is a heritable and convergent phenotypic trait achievable through variety of genetic pathways ( abundance ) , and explain a broad host range for HEV3 and HEV4 . Published by Elsevier B.V.", "gold_segments": [{"segment_text": "Hepatitis E virus ( HEV ) causes epidemic and sporadic cases of hepatitis worldwide .", "label": "background"}, {"segment_text": "HEV genotypes 3 ( HEV3 ) and 4 ( HEV4 ) infect humans and animals ,", "label": "background"}, {"segment_text": "with swine being the primary reservoir .", "label": "background"}, {"segment_text": "The relevance of HEV genetic diversity to host adaptation is poorly understood .", "label": "background"}, {"segment_text": "We employed a Bayesian network ( BN ) analysis of HEV3 and HEV4 to detect epistatic connectivity among protein sites and its association with the host specificity in each genotype .", "label": "method"}, {"segment_text": "The data imply coevolution among $ 70 % of polymorphic sites from all HEV proteins and association of numerous coevolving sites with adaptation to swine or humans .", "label": "finding"}, {"segment_text": "BN models for individual proteins and domains of the nonstructural polyprotein detected the host origin of HEV strains with accuracy of 74-93 % and 63-87 % , respectively .", "label": "finding"}, {"segment_text": "These findings , taken together with lack of phylogenetic association to host ,", "label": "finding"}, {"segment_text": "suggest that the HEV host specificity is a heritable and convergent phenotypic trait achievable through variety of genetic pathways ( abundance ) ,", "label": "finding"}, {"segment_text": "and explain a broad host range for HEV3 and HEV4 .", "label": "finding"}, {"segment_text": "Published by Elsevier B.V.", "label": "other"}], "n_segments": 11}
{"paper_id": "d2625ad44759486a98925121112bcfa525d82542", "title": "CHEMICAL COMPOSITION, ANTIOXIDANT AND ANTIMICROBIAL ACTIVITIES OF SANGUISORBA OFFICINALIS L. EXTRACTS", "coda_paper_id": 1028, "has_expert_labels": false, "abstract_text": "Sanquisorba officinalis has been used internally for the treatment of intestinal infections and duodenal ulcers , as well as hemorrhoids , phlebitis and varicose veins and female disorders , and topically to heal wounds , burns , and ulcers . In our study , the antioxidant and antimicrobial activities , as well as quantitative analysis of polyphenols ( phenolic acids , flavonoids and total polyphenols ) in methanol and aqueous extracts from S. officinalis herbs are presented . A correlation between the antioxidant activity and composition of tested extracts indicates that flavonoids are the major compounds causing scavenging of free radicals . Higher content of flavonoids was found in the methanol extract , while the content of total phenolics was higher in the aqueous extract . Both extracts from S. officinalis herbs showed antioxidant activity and high antimicrobial activity in a wide spectrum of test strains .", "gold_segments": [{"segment_text": "Sanquisorba officinalis has been used internally for the treatment of intestinal infections and duodenal ulcers ,", "label": "background"}, {"segment_text": "as well as hemorrhoids , phlebitis and varicose veins and female disorders ,", "label": "background"}, {"segment_text": "and topically to heal wounds , burns , and ulcers .", "label": "background"}, {"segment_text": "In our study , the antioxidant and antimicrobial activities ,", "label": "purpose"}, {"segment_text": "as well as quantitative analysis of polyphenols ( phenolic acids , flavonoids and total polyphenols ) in methanol and aqueous extracts from S. officinalis herbs are presented .", "label": "purpose"}, {"segment_text": "A correlation between the antioxidant activity and composition of tested extracts indicates that flavonoids are the major compounds causing scavenging of free radicals .", "label": "finding"}, {"segment_text": "Higher content of flavonoids was found in the methanol extract ,", "label": "finding"}, {"segment_text": "while the content of total phenolics was higher in the aqueous extract .", "label": "finding"}, {"segment_text": "Both extracts from S. officinalis herbs showed antioxidant activity and high antimicrobial activity in a wide spectrum of test strains .", "label": "finding"}], "n_segments": 9}
{"paper_id": "35e8dceea633286d25a75c27f429088ea46e623a", "title": "Modeling triple-diffusions of infectious diseases, information, and preventive behaviors through a metropolitan social networkdAn agent-based simulation", "coda_paper_id": 1058, "has_expert_labels": false, "abstract_text": "A typical epidemic often involves the transmission of a disease , the flow of information regarding the disease , and the spread of human preventive behaviors against the disease . These three processes diffuse simultaneously through human social networks , and interact with one another , forming negative and positive feedback loops in the complex human-disease systems . Few studies , however , have been devoted to coupling all the three diffusions together and representing their interactions . To fill the knowledge gap , this article proposes a spatially explicit agent-based model to simulate a triple-diffusion process in a metropolitan area of 1 million people . The individual-based approach , network model , behavioral theories , and stochastic processes are used to formulate the three diffusions and integrate them together . Compared to the observed facts , the model results reasonably replicate the trends of influenza spread and information propagation . The model thus could be a valid and effective tool to evaluate information/behavior-based intervention strategies . Besides its implications to the public health , the research findings also contribute to network modeling , systems science , and medical geography .", "gold_segments": [{"segment_text": "A typical epidemic often involves the transmission of a disease ,", "label": "background"}, {"segment_text": "the flow of information regarding the disease ,", "label": "background"}, {"segment_text": "and the spread of human preventive behaviors against the disease .", "label": "background"}, {"segment_text": "These three processes diffuse simultaneously through human social networks ,", "label": "background"}, {"segment_text": "and interact with one another ,", "label": "background"}, {"segment_text": "forming negative and positive feedback loops in the complex human-disease systems .", "label": "background"}, {"segment_text": "Few studies , however , have been devoted to coupling all the three diffusions together and representing their interactions .", "label": "background"}, {"segment_text": "To fill the knowledge gap ,", "label": "purpose"}, {"segment_text": "this article proposes a spatially explicit agent-based model to simulate a triple-diffusion process in a metropolitan area of 1 million people .", "label": "purpose"}, {"segment_text": "The individual-based approach , network model ,", "label": "method"}, {"segment_text": "behavioral theories , and stochastic processes are used to formulate the three diffusions and integrate them together .", "label": "method"}, {"segment_text": "Compared to the observed facts ,", "label": "finding"}, {"segment_text": "the model results reasonably replicate the trends of influenza spread and information propagation .", "label": "finding"}, {"segment_text": "The model thus could be a valid and effective tool to evaluate information/behavior-based intervention strategies .", "label": "finding"}, {"segment_text": "Besides its implications to the public health ,", "label": "finding"}, {"segment_text": "the research findings also contribute to network modeling ,", "label": "finding"}, {"segment_text": "systems science , and medical geography .", "label": "finding"}], "n_segments": 17}
{"paper_id": "6f6a250f3aff31bb8315d124050ec9d064d2cd50", "title": "Neonatal vaccine effectiveness and the role of adjuvants", "coda_paper_id": 1738, "has_expert_labels": false, "abstract_text": "Introduction : Neonates are less responsive to vaccines than adults , making it harder to protect newborns against infection . Neonatal differences in antigen-presenting cell , B and T cell function , all likely contribute . A key question is whether novel adjuvants might be able to make neonatal vaccines more effective . Areas covered : This review addresses the issues of how to improve neonatal vaccines , which we have defined as vaccines given in the first 4 weeks of life in a human infant or the first week of life in a mouse . A search was performed using keywords including ` neonatal immunity ' , ` neonatal immunisation ' , ` vaccine ' and ` adjuvant ' of PubMed articles published between 1960 and 2018 . Expert opinion : Sugar-like structures have recently been shown to prime the infant adaptive immune system to respond to vaccines , being potentially more effective than traditional adjuvants . Sugar-based compounds with beneficial adjuvant effects in neonatal vaccine models include delta inulin ( Advax ) , curdlan , and trehalose 6,6ʹ-dibehenate . Such compounds make interesting neonatal adjuvant candidates , either used alone or in combination with traditional innate immune adjuvants . ARTICLE HISTORY", "gold_segments": [{"segment_text": "Introduction : Neonates are less responsive to vaccines than adults ,", "label": "background"}, {"segment_text": "making it harder to protect newborns against infection .", "label": "background"}, {"segment_text": "Neonatal differences in antigen-presenting cell ,", "label": "background"}, {"segment_text": "B and T cell function , all likely contribute .", "label": "background"}, {"segment_text": "A key question is whether novel adjuvants might be able to make neonatal vaccines more effective .", "label": "purpose"}, {"segment_text": "Areas covered : This review addresses the issues of how to improve neonatal vaccines ,", "label": "purpose"}, {"segment_text": "which we have defined as vaccines given in the first 4 weeks of life in a human infant or the first week of life in a mouse .", "label": "purpose"}, {"segment_text": "A search was performed using keywords including ` neonatal immunity ' ,", "label": "method"}, {"segment_text": "` neonatal immunisation ' , ` vaccine ' and ` adjuvant ' of PubMed articles published between 1960 and 2018 .", "label": "method"}, {"segment_text": "Expert opinion : Sugar-like structures have recently been shown to prime the infant adaptive immune system to respond to vaccines ,", "label": "finding"}, {"segment_text": "being potentially more effective than traditional adjuvants .", "label": "finding"}, {"segment_text": "Sugar-based compounds with beneficial adjuvant effects in neonatal vaccine models include delta inulin ( Advax ) ,", "label": "finding"}, {"segment_text": "curdlan , and trehalose 6,6ʹ-dibehenate .", "label": "finding"}, {"segment_text": "Such compounds make interesting neonatal adjuvant candidates ,", "label": "finding"}, {"segment_text": "either used alone or in combination with traditional innate immune adjuvants .", "label": "finding"}, {"segment_text": "ARTICLE HISTORY", "label": "other"}], "n_segments": 16}
{"paper_id": "079d111701795855b92f705afd54262d4e853edc", "title": "SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology", "coda_paper_id": 1557, "has_expert_labels": false, "abstract_text": "Highlights d SARS-CoV small viral RNAs ( svRNA ) were identified in infected lungs and cell culture d SARS-CoV svRNAs biogenesis was RNase III , cell type , and species independent d svRNA-N repressed the expression of mRNAs with 3 0 UTR specific target sequences d svRNA-N inhibition in vivo reduced lung pathology and proinflammatory cytokines SUMMARY Severe acute respiratory syndrome coronavirus ( SARS-CoV ) causes lethal disease in humans , which is characterized by exacerbated inflammatory response and extensive lung pathology . To address the relevance of small non-coding RNAs in SARS-CoV pathology , we deep sequenced RNAs from the lungs of infected mice and discovered three 18-22 nt small viral RNAs ( svRNAs ) . The three svRNAs were derived from the nsp3 ( svRNA-nsp3.1 and - nsp3 .2 ) and N ( svRNA-N ) genomic regions of SARS-CoV . Biogenesis of CoV svRNAs was RNase III , cell type , and host species independent , but it was dependent on the extent of viral replication . Antagomir-mediated inhibition of svRNA-N significantly reduced in vivo lung pathology and pro-inflammatory cytokine expression . Taken together , these data indicate that svRNAs contribute to SARS-CoV pathogenesis and highlight the potential of svRNA-N antagomirs as antivirals . Zú ñ iga , S. , Cruz , J.L. , Sola , I. , Mateos-Gó mez , P.A. , Palacio , L. , and Enjuanes , L. ( 2010 ) . Coronavirus nucleocapsid protein facilitates template switching and is required for efficient transcription .", "gold_segments": [{"segment_text": "Highlights d SARS-CoV small viral RNAs ( svRNA ) were identified in infected lungs and cell culture d SARS-CoV svRNAs biogenesis was RNase III ,", "label": "background"}, {"segment_text": "cell type , and species independent d svRNA-N repressed the expression of mRNAs with 3 0 UTR specific target sequences d svRNA-N inhibition in vivo reduced lung pathology and proinflammatory cytokines SUMMARY Severe acute respiratory syndrome coronavirus ( SARS-CoV ) causes lethal disease in humans ,", "label": "background"}, {"segment_text": "which is characterized by exacerbated inflammatory response and extensive lung pathology .", "label": "background"}, {"segment_text": "To address the relevance of small non-coding RNAs in SARS-CoV pathology ,", "label": "purpose"}, {"segment_text": "we deep sequenced RNAs from the lungs of infected mice and discovered three 18-22 nt small viral RNAs ( svRNAs ) .", "label": "method"}, {"segment_text": "The three svRNAs were derived from the nsp3 ( svRNA-nsp3.1 and - nsp3 .2 ) and N ( svRNA-N ) genomic regions of SARS-CoV .", "label": "method"}, {"segment_text": "Biogenesis of CoV svRNAs was RNase III ,", "label": "method"}, {"segment_text": "cell type , and host species independent ,", "label": "method"}, {"segment_text": "but it was dependent on the extent of viral replication .", "label": "method"}, {"segment_text": "Antagomir-mediated inhibition of svRNA-N significantly reduced in vivo lung pathology and pro-inflammatory cytokine expression .", "label": "finding"}, {"segment_text": "Taken together , these data indicate that svRNAs contribute to SARS-CoV pathogenesis and highlight the potential of svRNA-N antagomirs as antivirals .", "label": "finding"}, {"segment_text": "Zú ñ iga , S. ,", "label": "other"}, {"segment_text": "Cruz , J.L. , Sola ,", "label": "other"}, {"segment_text": "I. , Mateos-Gó mez , P.A. ,", "label": "other"}, {"segment_text": "Palacio , L. , and Enjuanes , L. ( 2010 ) .", "label": "other"}, {"segment_text": "Coronavirus nucleocapsid protein facilitates template switching and is required for efficient transcription .", "label": "finding"}], "n_segments": 16}
{"paper_id": "5e9785e2c514967a87ee220c0e6a1a542eb6d1ef", "title": "Carbohydrates as Recognition Receptors in Biosensing Applications", "coda_paper_id": 1683, "has_expert_labels": false, "abstract_text": "Carbohydrates are involved in crucial physiological and pathological events . One can take advantage of carbohydrate-based interaction for drug discovery , diagnosis , antibiotics , vaccine , etc. . This chapter deals with biosensors and microarrays that take advantage of carbohydrates-based interactions with a special interest in devices that are designed for medical applications . A large overview of glycochemistry , followed by the biological role of carbohydrates , is given . Carbohydrate-based biosensors are then described with special emphasis on surface chemistry and signal transduction . Finally , medically relevant applications illustrate the use of carbohydrates as recognition receptors in biosensing .", "gold_segments": [{"segment_text": "Carbohydrates are involved in crucial physiological and pathological events .", "label": "background"}, {"segment_text": "One can take advantage of carbohydrate-based interaction for drug discovery ,", "label": "background"}, {"segment_text": "diagnosis , antibiotics , vaccine , etc. .", "label": "background"}, {"segment_text": "This chapter deals with biosensors and microarrays that take advantage of carbohydrates-based interactions with a special interest in devices that are designed for medical applications .", "label": "purpose"}, {"segment_text": "A large overview of glycochemistry ,", "label": "method"}, {"segment_text": "followed by the biological role of carbohydrates , is given .", "label": "method"}, {"segment_text": "Carbohydrate-based biosensors are then described with special emphasis on surface chemistry and signal transduction .", "label": "method"}, {"segment_text": "Finally , medically relevant applications illustrate the use of carbohydrates as recognition receptors in biosensing .", "label": "finding"}], "n_segments": 8}
{"paper_id": "d5772ae858256cb8d44805aff6e26800c6868eb4", "title": "", "coda_paper_id": 1186, "has_expert_labels": false, "abstract_text": "The complement system was defined over a century ago based on its ability to `` complement '' the antibodymediated and cell-mediated immune responses against pathogens . Today our understanding of this ancient part of innate immunity has changed substantially and we know now that complement plays an undisputed pivotal role in the regulation of both innate and adaptive immunity . The complement system consists of over 50 bloodcirculating , cell-surface expressed and intracellular proteins . It is key in the recognition and elimination of invading pathogens , also in the removal of self-derived danger such as apoptotic cells , and it supports innate immune responses and the initiation of the general inflammatory reactions . The long prevailing classic view of complement was that of a serum-operative danger sensor and first line of defence system , however , recent experimental and clinical evidences have demonstrated that `` local '' tissue and surprisingly intracellular complement ( the complosome ) activation impacts on normal cell physiology . This review will focus on novel aspects of intracellular complement activation and its unexpected roles in basic cell processes such as metabolism . We also discuss what the existence of the complosome potentially means for how the host handles intracellular pathogens such as viruses .", "gold_segments": [{"segment_text": "The complement system was defined over a century ago based on its ability to `` complement '' the antibodymediated and cell-mediated immune responses against pathogens .", "label": "background"}, {"segment_text": "Today our understanding of this ancient part of innate immunity has changed substantially and we know now that complement plays an undisputed pivotal role in the regulation of both innate and adaptive immunity .", "label": "background"}, {"segment_text": "The complement system consists of over 50 bloodcirculating ,", "label": "background"}, {"segment_text": "cell-surface expressed and intracellular proteins .", "label": "background"}, {"segment_text": "It is key in the recognition and elimination of invading pathogens ,", "label": "background"}, {"segment_text": "also in the removal of self-derived danger such as apoptotic cells ,", "label": "background"}, {"segment_text": "and it supports innate immune responses and the initiation of the general inflammatory reactions .", "label": "background"}, {"segment_text": "The long prevailing classic view of complement was that of a serum-operative danger sensor and first line of defence system ,", "label": "background"}, {"segment_text": "however , recent experimental and clinical evidences have demonstrated that `` local '' tissue and surprisingly intracellular complement ( the complosome ) activation impacts on normal cell physiology .", "label": "background"}, {"segment_text": "This review will focus on novel aspects of intracellular complement activation and its unexpected roles in basic cell processes such as metabolism .", "label": "purpose"}, {"segment_text": "We also discuss what the existence of the complosome potentially means for how the host handles intracellular pathogens such as viruses .", "label": "purpose"}], "n_segments": 11}
{"paper_id": "8eb42a48e41d9008951de5a8fc7bfd24df6fc588", "title": "molecules Amyloidogenic Peptides in Human Neuro-Degenerative Diseases and in Microorganisms: A Sorrow Shared Is a Sorrow Halved?", "coda_paper_id": 1581, "has_expert_labels": false, "abstract_text": "The term `` amyloid '' refers to proteinaceous deposits of peptides that might be generated from larger precursor proteins e.g. , by proteolysis . Common to these peptides is a stable cross-β dominated secondary structure which allows self-assembly , leading to insoluble oligomers and lastly to fibrils . These highly ordered protein aggregates have been , for a long time , mainly associated with human neurodegenerative diseases such as Alzheimer 's disease ( Amyloid-β peptides ) . However , they also exert physiological functions such as in release of deposited hormones in human beings . In the light of the rediscovery of our microbial commensals as important companions in health and disease , the fact that microbes also possess amyloidogenic peptides is intriguing . Transmission of amyloids by iatrogenic means or by consumption of contaminated meat from diseased animals is a well-known fact . What if also our microbial commensals might drive human amyloidosis or suffer from our aggregated amyloids ? Moreover , as the microbial amyloids are evolutionarily older , we might learn from these organisms how to cope with the sword of Damocles forged of endogenous , potentially toxic peptides . This review summarizes knowledge about the interplay between human amyloids involved in neurodegenerative diseases and microbial amyloids . Molecules 2020 , 25 , 925 2 of 14 decades ago ( see Table 1 ) . For AD , APP gives rise-via subsequent proteolytic processing-to the amyloid-β peptide ( Figure 1A ) while in PD α-synuclein represents the amyloidogenic compound . For familial cases of both and other protein-deposit-based diseases , heredity of mutated variants of the amyloid-encoding genes or genes encoding respective processing enzymes are key to pathogenesis . The vast majority of cases still though is designated sporadic , indicating that the underlying mechanism has not been identified yet .", "gold_segments": [{"segment_text": "The term `` amyloid '' refers to proteinaceous deposits of peptides that might be generated from larger precursor proteins e.g. , by proteolysis .", "label": "background"}, {"segment_text": "Common to these peptides is a stable cross-β dominated secondary structure which allows self-assembly ,", "label": "background"}, {"segment_text": "leading to insoluble oligomers and lastly to fibrils .", "label": "background"}, {"segment_text": "These highly ordered protein aggregates have been ,", "label": "background"}, {"segment_text": "for a long time , mainly associated with human neurodegenerative diseases such as Alzheimer 's disease ( Amyloid-β peptides ) .", "label": "background"}, {"segment_text": "However , they also exert physiological functions such as in release of deposited hormones in human beings .", "label": "background"}, {"segment_text": "In the light of the rediscovery of our microbial commensals as important companions in health and disease ,", "label": "background"}, {"segment_text": "the fact that microbes also possess amyloidogenic peptides is intriguing .", "label": "background"}, {"segment_text": "Transmission of amyloids by iatrogenic means or by consumption of contaminated meat from diseased animals is a well-known fact .", "label": "background"}, {"segment_text": "What if also our microbial commensals might drive human amyloidosis or suffer from our aggregated amyloids ?", "label": "background"}, {"segment_text": "Moreover , as the microbial amyloids are evolutionarily older ,", "label": "background"}, {"segment_text": "we might learn from these organisms how to cope with the sword of Damocles forged of endogenous , potentially toxic peptides .", "label": "background"}, {"segment_text": "This review summarizes knowledge about the interplay between human amyloids involved in neurodegenerative diseases and microbial amyloids .", "label": "purpose"}, {"segment_text": "Molecules 2020 , 25 , 925 2 of 14 decades ago ( see Table 1 ) .", "label": "finding"}, {"segment_text": "For AD , APP gives rise-via subsequent proteolytic processing-to the amyloid-β peptide ( Figure 1A ) while in PD α-synuclein represents the amyloidogenic compound .", "label": "finding"}, {"segment_text": "For familial cases of both and other protein-deposit-based diseases ,", "label": "finding"}, {"segment_text": "heredity of mutated variants of the amyloid-encoding genes or genes encoding respective processing enzymes are key to pathogenesis .", "label": "finding"}, {"segment_text": "The vast majority of cases still though is designated sporadic ,", "label": "finding"}, {"segment_text": "indicating that the underlying mechanism has not been identified yet .", "label": "finding"}], "n_segments": 19}
{"paper_id": "2598b577511eeb7e5c296b82030fe365a61723c4", "title": "Comparison of the photosynthetic characteristics of four Lycoris species with leaf appearing in autumn under field conditions", "coda_paper_id": 1510, "has_expert_labels": false, "abstract_text": "The diurnal trends of gas exchange and chlorophyll fluorescence parameters in four Lycoris species ( L. houdyshelii , L. aurea , L. radiata var . pumila and L. albiflora ) were determined and compared with a portable photosynthesis analysis system . Our study revealed that L. houdyshelii had the lowest light compensation point ( LCP ) , while the other three species had higher LCP ( 12.37-14.99 μmol m -2 s -1 ) ; L. aurea had the highest light saturation point ( LSP ) ( 1,189 μmol m -2 s -1 ) , and L. houdyshelii and L. albiflora had lower LSP with the values being 322 and 345 μmol m -2 s -1 , respectively , and L. radiata var . pumila showed the intermediate LSP . Both the species L. houdyshelii and L. albiflora exhibited a typical and obvious decline in net photosynthetic rate ( P N ) during midday , which was not observed in L. aurea . This indicated a possible photoinhibition in L. houdyshelii and L. albiflora as the ratio of variable to maximum fluorescence ( F v / F m ) values were higher in these two species . The minimal fluorescence ( F 0 ) values were lower in L. aurea and L. radiata var . pumila . The diurnal changes of transpiration rate ( E ) in all four species presented only one peak , appearing between 11:00 h or 13:00 h. By using simple correlation analyses , it was observed that the environmental factors affecting P N were different among four species and the main factors were photosynthetic photon flux density ( PPFD ) and relative humidity especially for L. aurea and L. radiata . The results of studying indicated that the four species could be divided into two groups . The species L. radiata var . pumila and L. aurea were more adapted to a relatively high irradiance , and L. houdyshelii and L. albiflora could be grown in moderate-shade environment in order to scale up their growth and productivity . Abbreviations : AQY - apparent quantum yield ; C i - intercellular CO 2 concentration ; Chl - chlorophyll ; E - transpiration rate ; F 0 - minimal fluorescence of dark adapted state ; F v / F m - ratio of variable to maximum fluorescence ; g s - stomatal conductance for CO 2 ; LCP - light compensation point ; LSP - light saturation point ; P max - photon-saturated photosynthetic rate ; P N - net photosynthetic rate ; PPFD - photosynthetic photon flux density ; T air - air temperature .", "gold_segments": [{"segment_text": "The diurnal trends of gas exchange and chlorophyll fluorescence parameters in four Lycoris species ( L. houdyshelii , L. aurea , L. radiata var .", "label": "background"}, {"segment_text": "pumila and L. albiflora ) were determined and compared with a portable photosynthesis analysis system .", "label": "background"}, {"segment_text": "Our study revealed that L. houdyshelii had the lowest light compensation point ( LCP ) ,", "label": "finding"}, {"segment_text": "while the other three species had higher LCP ( 12.37-14.99 μmol m -2 s -1 ) ; L. aurea had the highest light saturation point ( LSP ) ( 1,189 μmol m -2 s -1 ) ,", "label": "finding"}, {"segment_text": "and L. houdyshelii and L. albiflora had lower LSP with the values being 322 and 345 μmol m -2 s -1 ,", "label": "finding"}, {"segment_text": "respectively , and L. radiata var .", "label": "finding"}, {"segment_text": "pumila showed the intermediate LSP .", "label": "finding"}, {"segment_text": "Both the species L. houdyshelii and L. albiflora exhibited a typical and obvious decline in net photosynthetic rate ( P N ) during midday ,", "label": "finding"}, {"segment_text": "which was not observed in L. aurea .", "label": "finding"}, {"segment_text": "This indicated a possible photoinhibition in L. houdyshelii and L. albiflora as the ratio of variable to maximum fluorescence ( F v / F m ) values were higher in these two species .", "label": "finding"}, {"segment_text": "The minimal fluorescence ( F 0 ) values were lower in L. aurea and L. radiata var .", "label": "finding"}, {"segment_text": "pumila .", "label": "finding"}, {"segment_text": "The diurnal changes of transpiration rate ( E ) in all four species presented only one peak ,", "label": "finding"}, {"segment_text": "appearing between 11:00 h or 13:00 h. By using simple correlation analyses ,", "label": "finding"}, {"segment_text": "it was observed that the environmental factors affecting P N were different among four species and the main factors were photosynthetic photon flux density ( PPFD ) and relative humidity especially for L. aurea and L. radiata .", "label": "finding"}, {"segment_text": "The results of studying indicated that the four species could be divided into two groups .", "label": "finding"}, {"segment_text": "The species L. radiata var .", "label": "finding"}, {"segment_text": "pumila and L. aurea were more adapted to a relatively high irradiance ,", "label": "finding"}, {"segment_text": "and L. houdyshelii and L. albiflora could be grown in moderate-shade environment in order to scale up their growth and productivity .", "label": "finding"}, {"segment_text": "Abbreviations : AQY - apparent quantum yield ; C i - intercellular CO 2 concentration ; Chl - chlorophyll ; E - transpiration rate ; F 0 - minimal fluorescence of dark adapted state ; F v / F m - ratio of variable to maximum fluorescence ; g s - stomatal conductance for CO 2 ; LCP - light compensation point ; LSP - light saturation point ; P max - photon-saturated photosynthetic rate ; P N - net photosynthetic rate ; PPFD - photosynthetic photon flux density ; T air - air temperature .", "label": "finding"}], "n_segments": 20}
{"paper_id": "8198fbb4175a2f90bcb43dafc0a365677c916d77", "title": "Using a Pan-Viral Microarray Assay (Virochip) to Screen Clinical Samples for Viral Pathogens", "coda_paper_id": 1775, "has_expert_labels": false, "abstract_text": "The diagnosis of viral causes of many infectious diseases is difficult due to the inherent sequence diversity of viruses as well as the ongoing emergence of novel viral pathogens , such as SARS coronavirus and 2009 pandemic H1N1 influenza virus , that are not detectable by traditional methods . To address these challenges , we have previously developed and validated a pan-viral microarray platform called the Virochip with the capacity to detect all known viruses as well as novel variants on the basis of conserved sequence homology", "gold_segments": [{"segment_text": "The diagnosis of viral causes of many infectious diseases is difficult due to the inherent sequence diversity of viruses as well as the ongoing emergence of novel viral pathogens ,", "label": "background"}, {"segment_text": "such as SARS coronavirus and 2009 pandemic H1N1 influenza virus ,", "label": "background"}, {"segment_text": "that are not detectable by traditional methods .", "label": "background"}, {"segment_text": "To address these challenges , we have previously developed and validated a pan-viral microarray platform called the Virochip with the capacity to detect all known viruses as well as novel variants on the basis of conserved sequence homology", "label": "finding"}], "n_segments": 4}
{"paper_id": "6a7736a56100d92a60d3916b68296fc5f43fb1fa", "title": "VIRUSOLOGY Structural Organization of the Genome of SARS-Associated Coronavirus (Strain SoD) Isolated on the Territory of the Russian Federation", "coda_paper_id": 1547, "has_expert_labels": false, "abstract_text": "Complete nucleotide cDNA sequence ( 29715 nucleotides ) of SARS-associated coronavirus ( strain SoD ) isolated for the first time in the territory of the Russian Federation was determined . Phylogenetic analysis revealed maximum similarity between strain SoD genome and Frankfurt 1 strain genome . Three nucleotide substitutions determining two amino acid substitutions were detected .", "gold_segments": [{"segment_text": "Complete nucleotide cDNA sequence ( 29715 nucleotides ) of SARS-associated coronavirus ( strain SoD ) isolated for the first time in the territory of the Russian Federation was determined .", "label": "purpose"}, {"segment_text": "Phylogenetic analysis revealed maximum similarity between strain SoD genome and Frankfurt 1 strain genome .", "label": "finding"}, {"segment_text": "Three nucleotide substitutions determining two amino acid substitutions were detected .", "label": "finding"}], "n_segments": 3}
{"paper_id": "a6d23f73678d80d9b2079c6a169819b18e5f1aab", "title": "Expanding roles for CD4 + T cells in immunity to viruses", "coda_paper_id": 1075, "has_expert_labels": false, "abstract_text": "| Viral pathogens often induce strong effector CD4 + T cell responses that are best known for their ability to help B cell and CD8 + T cell responses . However , recent studies have uncovered additional roles for CD4 + T cells , some of which are independent of other lymphocytes , and have described previously unappreciated functions for memory CD4 + T cells in immunity to viruses . Here , we review the full range of antiviral functions of CD4 + T cells , discussing the activities of these cells in helping other lymphocytes and in inducing innate immune responses , as well as their direct antiviral roles . We suggest that all of these functions of CD4 + T cells are integrated to provide highly effective immune protection against viral pathogens . www.nature.com/reviews / immunol", "gold_segments": [{"segment_text": "| Viral pathogens often induce strong effector CD4 + T cell responses that are best known for their ability to help B cell and CD8 + T cell responses .", "label": "background"}, {"segment_text": "However , recent studies have uncovered additional roles for CD4 + T cells ,", "label": "background"}, {"segment_text": "some of which are independent of other lymphocytes ,", "label": "background"}, {"segment_text": "and have described previously unappreciated functions for memory CD4 + T cells in immunity to viruses .", "label": "background"}, {"segment_text": "Here , we review the full range of antiviral functions of CD4 + T cells ,", "label": "method"}, {"segment_text": "discussing the activities of these cells in helping other lymphocytes and in inducing innate immune responses ,", "label": "method"}, {"segment_text": "as well as their direct antiviral roles .", "label": "method"}, {"segment_text": "We suggest that all of these functions of CD4 + T cells are integrated to provide highly effective immune protection against viral pathogens .", "label": "finding"}, {"segment_text": "www.nature.com/reviews / immunol", "label": "other"}], "n_segments": 9}
{"paper_id": "3143b59926711602587ac69d5814964a9caa27ae", "title": "Sockeye: A 3D Environment for Comparative Genomics", "coda_paper_id": 1499, "has_expert_labels": false, "abstract_text": "Comparative genomics techniques are used in bioinformatics analyses to identify the structural and functional properties of DNA sequences . As the amount of available sequence data steadily increases , the ability to perform large-scale comparative analyses has become increasingly relevant . In addition , the growing complexity of genomic feature annotation means that new approaches to genomic visualization need to be explored . We have developed a Java-based application called Sockeye that uses three-dimensional ( 3D ) graphics technology to facilitate the visualization of annotation and conservation across multiple sequences . This software uses the Ensembl database project to import sequence and annotation information from several eukaryotic species . A user can additionally import their own custom sequence and annotation data . Individual annotation objects are displayed in Sockeye by using custom 3D models . Ensembl-derived and imported sequences can be analyzed by using a suite of multiple and pair-wise alignment algorithms . The results of these comparative analyses are also displayed in the 3D environment of Sockeye . By using the Java3D API to visualize genomic data in a 3D environment , we are able to compactly display cross-sequence comparisons . This provides the user with a novel platform for visualizing and comparing genomic feature organization . ( Supplemental material is available online at www.genome.org . ) 3 Corresponding author . E-MAIL sjones@bcgsc.bc.ca ; FAX -LRB-604-RRB- 877-6085 . Article and publication are at", "gold_segments": [{"segment_text": "Comparative genomics techniques are used in bioinformatics analyses to identify the structural and functional properties of DNA sequences .", "label": "background"}, {"segment_text": "As the amount of available sequence data steadily increases ,", "label": "background"}, {"segment_text": "the ability to perform large-scale comparative analyses has become increasingly relevant .", "label": "background"}, {"segment_text": "In addition , the growing complexity of genomic feature annotation means that new approaches to genomic visualization need to be explored .", "label": "background"}, {"segment_text": "We have developed a Java-based application called Sockeye that uses three-dimensional ( 3D ) graphics technology to facilitate the visualization of annotation and conservation across multiple sequences .", "label": "method"}, {"segment_text": "This software uses the Ensembl database project to import sequence and annotation information from several eukaryotic species .", "label": "method"}, {"segment_text": "A user can additionally import their own custom sequence and annotation data .", "label": "method"}, {"segment_text": "Individual annotation objects are displayed in Sockeye by using custom 3D models .", "label": "method"}, {"segment_text": "Ensembl-derived and imported sequences can be analyzed by using a suite of multiple and pair-wise alignment algorithms .", "label": "method"}, {"segment_text": "The results of these comparative analyses are also displayed in the 3D environment of Sockeye .", "label": "finding"}, {"segment_text": "By using the Java3D API to visualize genomic data in a 3D environment ,", "label": "finding"}, {"segment_text": "we are able to compactly display cross-sequence comparisons .", "label": "finding"}, {"segment_text": "This provides the user with a novel platform for visualizing and comparing genomic feature organization .", "label": "finding"}, {"segment_text": "( Supplemental material is available online at www.genome.org . )", "label": "other"}, {"segment_text": "3 Corresponding author .", "label": "other"}, {"segment_text": "E-MAIL sjones@bcgsc.bc.ca ; FAX -LRB-604-RRB- 877-6085 .", "label": "other"}, {"segment_text": "Article and publication are at", "label": "other"}], "n_segments": 17}
{"paper_id": "9369b15083026f2929d6eb01a67999d1800e2ec0", "title": "NOTE Reliability of clinical diagnosis and laboratory testing techniques currently used for identification of canine parvovirus enteritis in clinical settings", "coda_paper_id": 1454, "has_expert_labels": false, "abstract_text": "Canine parvovirus type 2 ( CPV-2 ) is the main etiological agent of viral enteritis in dogs . Actually in literature , CPV-2 has been reported with clinical signs that vary from the classical disease , and immunochromatography test and PCR technique have been introduced to veterinary hospitals to confirm CPV-2 diagnosis and other infections . However , the reliability of these techniques has been poorly analyzed . In this study , we evaluated the sensitivity and specificity of veterinary clinical diagnosis , immunochromatography test and PCR technique . Our data indicate that variations in the clinical signs of CPV-2 complicate the gathering of an appropriate diagnosis ; and immunochromatography test and PCR technique do not have adequate sensitivity to diagnose positive cases .", "gold_segments": [{"segment_text": "Canine parvovirus type 2 ( CPV-2 ) is the main etiological agent of viral enteritis in dogs .", "label": "background"}, {"segment_text": "Actually in literature , CPV-2 has been reported with clinical signs that vary from the classical disease ,", "label": "background"}, {"segment_text": "and immunochromatography test and PCR technique have been introduced to veterinary hospitals to confirm CPV-2 diagnosis and other infections .", "label": "background"}, {"segment_text": "However , the reliability of these techniques has been poorly analyzed .", "label": "background"}, {"segment_text": "In this study , we evaluated the sensitivity and specificity of veterinary clinical diagnosis ,", "label": "purpose"}, {"segment_text": "immunochromatography test and PCR technique .", "label": "purpose"}, {"segment_text": "Our data indicate that variations in the clinical signs of CPV-2 complicate the gathering of an appropriate diagnosis ; and immunochromatography test and PCR technique do not have adequate sensitivity to diagnose positive cases .", "label": "finding"}], "n_segments": 7}
{"paper_id": "5479a0b2eb8bb566074e933d9e398fbb7db09ab1", "title": "Metagenomic Approach to Characterizing Disease Epidemiology in a Disease-Endemic Environment in Northern Thailand", "coda_paper_id": 1437, "has_expert_labels": false, "abstract_text": "In this study , we used a metagenomic approach to analyze bacterial communities from diverse populations ( humans , animals , and vectors ) to investigate the role of these microorganisms as causative agents of disease in human and animal populations . Wild rodents and ectoparasites were collected from 2014 to 2018 in Nan province , Thailand where scrub typhus is highly endemic . Samples from undifferentiated febrile illness ( UFI ) patients were obtained from a local hospital . A total of 200 UFI patient samples were obtained and 309 rodents and 420 pools of ectoparasites were collected from rodents ( n = 285 ) and domestic animals ( n = 135 ) . The bacterial 16S rRNA gene was amplified and sequenced with the Illumina . Real-time PCR and Sanger sequencing were used to confirm the next-generation sequencing ( NGS ) results and to characterize pathogen species . Several pathogens were detected by NGS in all populations studied and the most common pathogens identified included Bartonella spp. , Rickettsia spp. , Leptospira spp. , and Orientia tsutsugamushi . Interestingly , Anaplasma spp. was detected in patient , rodent and tick populations , although they were not previously known to cause human disease from this region . Candidatus Neoehrlichia , Neorickettsia spp. , Borrelia spp. , and Ehrlichia spp. were detected in rodents and their associated ectoparasites . The same O. tsutsugamushi genotypes were shared among UFI patients , rodents , and chiggers in a single district indicating that the chiggers found on rodents were also likely responsible for transmitting to people . Serological testing using immunofluorescence assays in UFI samples showed high prevalence ( IgM/IgG ) of Rickettsia and Orientia pathogens , most notably among samples collected during September-November . Additionally , a higher number of seropositive samples belonged to patients in the working age population ( 20-60 years old ) . The results presented in this study demonstrate that the increased risk of human infection or exposure to chiggers and their associated pathogen ( O. tsutsugamushi ) resulted in part from two important factors ; working age group and seasons for rice cultivation and harvesting . Evidence of pathogen exposure was shown Frontiers in Microbiology | www.frontiersin.org 1 February 2019 | Volume 10 | Article 319 Takhampunya et al. . Metagenomics for Disease Epidemiology to occur as there was seropositivity ( IgG ) in UFI patients for bartonellosis as well as for anaplasmosis . Using a metagenomic approach , this study demonstrated the circulation and transmission of several pathogens in the environment , some of which are known causative agents of illness in human populations .", "gold_segments": [{"segment_text": "In this study , we used a metagenomic approach to analyze bacterial communities from diverse populations ( humans , animals , and vectors ) to investigate the role of these microorganisms as causative agents of disease in human and animal populations .", "label": "method"}, {"segment_text": "Wild rodents and ectoparasites were collected from 2014 to 2018 in Nan province ,", "label": "method"}, {"segment_text": "Thailand where scrub typhus is highly endemic .", "label": "method"}, {"segment_text": "Samples from undifferentiated febrile illness ( UFI ) patients were obtained from a local hospital .", "label": "method"}, {"segment_text": "A total of 200 UFI patient samples were obtained and 309 rodents and 420 pools of ectoparasites were collected from rodents ( n = 285 ) and domestic animals ( n = 135 ) .", "label": "method"}, {"segment_text": "The bacterial 16S rRNA gene was amplified and sequenced with the Illumina .", "label": "method"}, {"segment_text": "Real-time PCR and Sanger sequencing were used to confirm the next-generation sequencing ( NGS ) results and to characterize pathogen species .", "label": "method"}, {"segment_text": "Several pathogens were detected by NGS in all populations studied and the most common pathogens identified included Bartonella spp. ,", "label": "finding"}, {"segment_text": "Rickettsia spp. , Leptospira spp. , and Orientia tsutsugamushi .", "label": "finding"}, {"segment_text": "Interestingly , Anaplasma spp. was detected in patient ,", "label": "finding"}, {"segment_text": "rodent and tick populations , although they were not previously known to cause human disease from this region .", "label": "finding"}, {"segment_text": "Candidatus Neoehrlichia , Neorickettsia spp. ,", "label": "finding"}, {"segment_text": "Borrelia spp. , and Ehrlichia spp. were detected in rodents and their associated ectoparasites .", "label": "finding"}, {"segment_text": "The same O. tsutsugamushi genotypes were shared among UFI patients ,", "label": "finding"}, {"segment_text": "rodents , and chiggers in a single district indicating that the chiggers found on rodents were also likely responsible for transmitting to people .", "label": "finding"}, {"segment_text": "Serological testing using immunofluorescence assays in UFI samples showed high prevalence ( IgM/IgG ) of Rickettsia and Orientia pathogens ,", "label": "finding"}, {"segment_text": "most notably among samples collected during September-November .", "label": "finding"}, {"segment_text": "Additionally , a higher number of seropositive samples belonged to patients in the working age population ( 20-60 years old ) .", "label": "finding"}, {"segment_text": "The results presented in this study demonstrate that the increased risk of human infection or exposure to chiggers and their associated pathogen ( O. tsutsugamushi ) resulted in part from two important factors ; working age group and seasons for rice cultivation and harvesting .", "label": "finding"}, {"segment_text": "Evidence of pathogen exposure was shown Frontiers in Microbiology | www.frontiersin.org 1 February 2019 | Volume 10 | Article 319 Takhampunya et al. .", "label": "finding"}, {"segment_text": "Metagenomics for Disease Epidemiology", "label": "finding"}, {"segment_text": "to occur as there was seropositivity ( IgG ) in UFI patients for bartonellosis as well as for anaplasmosis .", "label": "finding"}, {"segment_text": "Using a metagenomic approach , this study demonstrated the circulation and transmission of several pathogens in the environment ,", "label": "finding"}, {"segment_text": "some of which are known causative agents of illness in human populations .", "label": "finding"}], "n_segments": 24}
{"paper_id": "d65ef4b00759d797d28454625b4de2814675bb56", "title": "Interferon-induced HERC5 is evolving under positive selection and inhibits HIV-1 particle production by a novel mechanism targeting Rev/RRE-dependent RNA nuclear export Interferon-induced HERC5 is evolving under positive selection and inhibits HIV-1 particle production by a novel mechanism targeting Rev/RRE-dependent RNA nuclear export", "coda_paper_id": 1096, "has_expert_labels": false, "abstract_text": "Background : Type I interferon ( IFN ) inhibits virus replication by activating multiple antiviral mechanisms and pathways . It has long been recognized that type I IFNs can potently block HIV-1 replication in vitro ; as such , HIV-1 has been used as a system to identify and characterize IFN-induced antiviral proteins responsible for this block . IFN-induced HERC5 contains an amino-terminal Regulator of Chromosome Condensation 1 ( RCC1 ) - like domain and a carboxyl-terminal Homologous to the E6-AP Carboxyl Terminus ( HECT ) domain . HERC5 is the main cellular E3 ligase that conjugates the IFN-induced protein ISG15 to proteins . This E3 ligase activity was previously shown to inhibit the replication of evolutionarily diverse viruses , including HIV-1 . The contribution of the RCC1-like domain to the antiviral activity of HERC5 was previously unknown . Results : In this study , we showed that HERC5 inhibits HIV-1 particle production by a second distinct mechanism that targets the nuclear export of Rev/RRE-dependent RNA . Unexpectedly , the E3 ligase activity of HERC5 was not required for this inhibition . Instead , this activity required the amino-terminal RCC1-like domain of HERC5 . Inhibition correlated with a reduction in intracellular RanGTP protein levels and/or the ability of RanGTP to interact with RanBP1 . Inhibition also correlated with altered subcellular localization of HIV-1 Rev. In addition , we demonstrated that positive evolutionary selection is operating on HERC5 . We identified a region in the RCC1-like domain that exhibits an exceptionally high probability of having evolved under positive selection and showed that this region is required for HERC5-mediated inhibition of nuclear export . Conclusions : We have identified a second distinct mechanism by which HERC5 inhibits HIV-1 replication and demonstrate that HERC5 is evolving under strong positive selection . Together , our findings contribute to a growing body of evidence suggesting that HERC5 is a novel host restriction factor .", "gold_segments": [{"segment_text": "Background : Type I interferon ( IFN ) inhibits virus replication by activating multiple antiviral mechanisms and pathways .", "label": "background"}, {"segment_text": "It has long been recognized that type I IFNs can potently block HIV-1 replication in vitro ; as such ,", "label": "background"}, {"segment_text": "HIV-1 has been used as a system to identify and characterize IFN-induced antiviral proteins responsible for this block .", "label": "background"}, {"segment_text": "IFN-induced HERC5 contains an amino-terminal Regulator of Chromosome Condensation 1 ( RCC1 ) - like domain and a carboxyl-terminal Homologous to the E6-AP Carboxyl Terminus ( HECT ) domain .", "label": "background"}, {"segment_text": "HERC5 is the main cellular E3 ligase that conjugates the IFN-induced protein ISG15 to proteins .", "label": "background"}, {"segment_text": "This E3 ligase activity was previously shown to inhibit the replication of evolutionarily diverse viruses , including HIV-1 .", "label": "background"}, {"segment_text": "The contribution of the RCC1-like domain to the antiviral activity of HERC5 was previously unknown .", "label": "background"}, {"segment_text": "Results : In this study ,", "label": "finding"}, {"segment_text": "we showed that HERC5 inhibits HIV-1 particle production by a second distinct mechanism that targets the nuclear export of Rev/RRE-dependent RNA .", "label": "finding"}, {"segment_text": "Unexpectedly , the E3 ligase activity of HERC5 was not required for this inhibition .", "label": "finding"}, {"segment_text": "Instead , this activity required the amino-terminal RCC1-like domain of HERC5 .", "label": "finding"}, {"segment_text": "Inhibition correlated with a reduction in intracellular RanGTP protein levels and/or the ability of RanGTP to interact with RanBP1 .", "label": "finding"}, {"segment_text": "Inhibition also correlated with altered subcellular localization of HIV-1 Rev. In addition ,", "label": "finding"}, {"segment_text": "we demonstrated that positive evolutionary selection is operating on HERC5 .", "label": "finding"}, {"segment_text": "We identified a region in the RCC1-like domain that exhibits an exceptionally high probability of having evolved under positive selection and showed that this region is required for HERC5-mediated inhibition of nuclear export .", "label": "finding"}, {"segment_text": "Conclusions : We have identified a second distinct mechanism by which HERC5 inhibits HIV-1 replication and demonstrate that HERC5 is evolving under strong positive selection .", "label": "finding"}, {"segment_text": "Together , our findings contribute to a growing body of evidence suggesting that HERC5 is a novel host restriction factor .", "label": "finding"}], "n_segments": 17}
{"paper_id": "b376aa9443596f299e7ddaaa123b4c811ea89c77", "title": "The role of seabirds of the Iles Eparses as reservoirs and disseminators of parasites and pathogens", "coda_paper_id": 1419, "has_expert_labels": false, "abstract_text": "The role of birds as reservoirs and disseminators of parasites and pathogens has received much attention over the past several years due to their high vagility . Seabirds are particularly interesting hosts in this respect . In addition to incredible long-distance movements during migration , foraging and prospecting , these birds are long-lived , site faithful and breed in dense aggregations in specific colony locations . These different characteristics can favor both the local maintenance and large-scale dissemination of parasites and pathogens . The Iles Eparses provide breeding and feeding grounds for more than 3 million breeding pairs of seabirds including at least 13 species . Breeding colonies on these islands are relatively undisturbed by human activities and represent natural metapopulations in which seabird population dynamics , movement and dispersal can be studied in relation to that of circulating parasites and pathogens . In this review , we summarize previous knowledge and recently-acquired data on the parasites and pathogens found in association with seabirds of the Iles Eparses . These studies have revealed the presence of a rich diversity of infectious agents ( viruses , bacteria and parasites ) carried by the birds and / or their local ectoparasites ( ticks and louse flies ) . Many of these agents are widespread and found in other ecosystems confirming a role for seabirds in their large scale dissemination and maintenance . The heterogeneous distribution of parasites and infectious agents among islands and seabird species suggests that relatively independent metacommunities of interacting species may exist within the western Indian Ocean . In this context , we discuss how the patterns and determinants of seabird movements may alter parasite and pathogen circulation . We conclude by outlining key aspects for future research given the baseline data now available and current concerns in eco-epidemiology and biodiversity conservation .", "gold_segments": [{"segment_text": "The role of birds as reservoirs and disseminators of parasites and pathogens has received much attention over the past several years due to their high vagility .", "label": "background"}, {"segment_text": "Seabirds are particularly interesting hosts in this respect .", "label": "background"}, {"segment_text": "In addition to incredible long-distance movements during migration ,", "label": "background"}, {"segment_text": "foraging and prospecting , these birds are long-lived ,", "label": "background"}, {"segment_text": "site faithful and breed in dense aggregations in specific colony locations .", "label": "background"}, {"segment_text": "These different characteristics can favor both the local maintenance and large-scale dissemination of parasites and pathogens .", "label": "background"}, {"segment_text": "The Iles Eparses provide breeding and feeding grounds for more than 3 million breeding pairs of seabirds including at least 13 species .", "label": "background"}, {"segment_text": "Breeding colonies on these islands are relatively undisturbed by human activities and represent natural metapopulations in which seabird population dynamics ,", "label": "background"}, {"segment_text": "movement and dispersal can be studied in relation to that of circulating parasites and pathogens .", "label": "background"}, {"segment_text": "In this review , we summarize previous knowledge and recently-acquired data on the parasites and pathogens found in association with seabirds of the Iles Eparses .", "label": "method"}, {"segment_text": "These studies have revealed the presence of a rich diversity of infectious agents ( viruses , bacteria and parasites ) carried by the birds and / or their local ectoparasites ( ticks and louse flies ) .", "label": "finding"}, {"segment_text": "Many of these agents are widespread and found in other ecosystems confirming a role for seabirds in their large scale dissemination and maintenance .", "label": "finding"}, {"segment_text": "The heterogeneous distribution of parasites and infectious agents among islands and seabird species suggests that relatively independent metacommunities of interacting species may exist within the western Indian Ocean .", "label": "finding"}, {"segment_text": "In this context , we discuss how the patterns and determinants of seabird movements may alter parasite and pathogen circulation .", "label": "finding"}, {"segment_text": "We conclude by outlining key aspects for future research given the baseline data now available and current concerns in eco-epidemiology and biodiversity conservation .", "label": "finding"}], "n_segments": 15}
{"paper_id": "f57ea3af8be491ddf35cfc5af7178997e12e928a", "title": "Novel hantavirus identified in European bat species Nyctalus noctula", "coda_paper_id": 1737, "has_expert_labels": false, "abstract_text": "Hantaviruses are emerging RNA viruses that cause human diseases predominantly in Asia , Europe , and the Americas . Besides rodents , insectivores and bats serve as hantavirus reservoirs . We report the detection and genome characterization of a novel bat-borne hantavirus isolated from insectivorous common noctule bat . The newfound virus was tentatively named as Brno virus .", "gold_segments": [{"segment_text": "Hantaviruses are emerging RNA viruses that cause human diseases predominantly in Asia ,", "label": "background"}, {"segment_text": "Europe , and the Americas .", "label": "background"}, {"segment_text": "Besides rodents , insectivores and bats serve as hantavirus reservoirs .", "label": "background"}, {"segment_text": "We report the detection and genome characterization of a novel bat-borne hantavirus isolated from insectivorous common noctule bat .", "label": "finding"}, {"segment_text": "The newfound virus was tentatively named as Brno virus .", "label": "finding"}], "n_segments": 5}
{"paper_id": "818b42cf815357fc1ee73a17caa5dfef24c55027", "title": "Stress, Nutrition, and Intestinal Immune Responses in Pigs -A Review", "coda_paper_id": 1089, "has_expert_labels": false, "abstract_text": "Modern livestock production became highly intensive and large scaled to increase production efficiency . This production environment could add stressors affecting the health and growth of animals . Major stressors can include environment ( air quality and temperature ) , nutrition , and infection . These stressors can reduce growth performance and alter immune systems at systemic and local levels including the gastrointestinal tract . Heat stress increases the permeability , oxidative stress , and inflammatory responses in the gut . Nutritional stress from fasting , antinutritional compounds , and toxins induces the leakage and destruction of the tight junction proteins in the gut . Fasting is shown to suppress pro-inflammatory cytokines , whereas deoxynivalenol increases the recruitment of intestinal pro-inflammatory cytokines and the level of lymphocytes in the gut . Pathogenic and viral infections such as Enterotoxigenic E. coli ( ETEC ) and porcine epidemic diarrhea virus can lead to loosening the intestinal epithelial barrier . On the other hand , supplementation of Lactobacillus or Saccharaomyces reduced infectious stress by ETEC . It was noted that major stressors altered the permeability of intestinal barriers and profiles of genes and proteins of pro-inflammatory cytokines and chemokines in mucosal system in pigs . However , it is not sufficient to fully explain the mechanism of the gut immune system in pigs under stress conditions . Correlation and interaction of gut and systemic immune system under major stressors should be better defined to overcome aforementioned obstacles . ( This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/ ) , which permits unrestricted non-commercial use , distribution , and reproduction in any medium , provided the original work is properly cited .", "gold_segments": [{"segment_text": "Modern livestock production became highly intensive and large scaled to increase production efficiency .", "label": "background"}, {"segment_text": "This production environment could add stressors affecting the health and growth of animals .", "label": "background"}, {"segment_text": "Major stressors can include environment ( air quality and temperature ) , nutrition , and infection .", "label": "background"}, {"segment_text": "These stressors can reduce growth performance and alter immune systems at systemic and local levels including the gastrointestinal tract .", "label": "background"}, {"segment_text": "Heat stress increases the permeability ,", "label": "background"}, {"segment_text": "oxidative stress , and inflammatory responses in the gut .", "label": "background"}, {"segment_text": "Nutritional stress from fasting , antinutritional compounds ,", "label": "background"}, {"segment_text": "and toxins induces the leakage and destruction of the tight junction proteins in the gut .", "label": "background"}, {"segment_text": "Fasting is shown to suppress pro-inflammatory cytokines ,", "label": "background"}, {"segment_text": "whereas deoxynivalenol increases the recruitment of intestinal pro-inflammatory cytokines and the level of lymphocytes in the gut .", "label": "background"}, {"segment_text": "Pathogenic and viral infections such as Enterotoxigenic E. coli ( ETEC ) and porcine epidemic diarrhea virus can lead to loosening the intestinal epithelial barrier .", "label": "background"}, {"segment_text": "On the other hand , supplementation of Lactobacillus or Saccharaomyces reduced infectious stress by ETEC .", "label": "background"}, {"segment_text": "It was noted that major stressors altered the permeability of intestinal barriers and profiles of genes and proteins of pro-inflammatory cytokines and chemokines in mucosal system in pigs .", "label": "background"}, {"segment_text": "However , it is not sufficient to fully explain the mechanism of the gut immune system in pigs under stress conditions .", "label": "background"}, {"segment_text": "Correlation and interaction of gut and systemic immune system under major stressors should be better defined to overcome aforementioned obstacles .", "label": "finding"}, {"segment_text": "(", "label": "other"}, {"segment_text": "This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/ ) ,", "label": "other"}, {"segment_text": "which permits unrestricted non-commercial use ,", "label": "other"}, {"segment_text": "distribution , and reproduction in any medium ,", "label": "other"}, {"segment_text": "provided the original work is properly cited .", "label": "other"}], "n_segments": 20}
{"paper_id": "e1eb29c0a697c2ffbf1d81746482b084b54f4df0", "title": "PCR sequencing of the spike genes of geographically and chronologically distinct human coronaviruses 229E", "coda_paper_id": 1009, "has_expert_labels": false, "abstract_text": "A reverse transcription nested PCR ( RT-PCR ) sequencing methodology was developed and used to generate sequence data from the spike genes of three geographically and chronologically distinct human coronaviruses 229E . These three coronaviruses were isolated originally from the USA in the 1960s ( human coronavirus 229E strain ATCC VR-74 ) , the UK in the 1990s ( human coronavirus 229E LRI 281 ) and Ghana ( human coronavirus 229E A162 ) . Upon translation and alignment with the published spike protein sequence of human coronavirus 229E ` LP ' ( isolated in the UK in the 1970s ) , it was found that variation within the translated protein sequences was rather limited . In particular , minimal variation was observed between the translated spike protein sequence of human coronaviruses 229E LP and ATCC VR-74 ( 1/1012 amino acid differences ) , whilst most variation was observed between the translated spike protein sequence of human coronaviruses 229E LP and A162 ( 47/1012 amino acid changes ) . Further , the translated spike protein sequence of human coronavirus 229E A162 showed three clusters of amino acid changes , situated within the 5 % half of the translated spike protein sequence .", "gold_segments": [{"segment_text": "A reverse transcription nested PCR ( RT-PCR ) sequencing methodology was developed and used to generate sequence data from the spike genes of three geographically and chronologically distinct human coronaviruses 229E .", "label": "background"}, {"segment_text": "These three coronaviruses were isolated originally from the USA in the 1960s ( human coronavirus 229E strain ATCC VR-74 ) ,", "label": "background"}, {"segment_text": "the UK in the 1990s ( human coronavirus 229E LRI 281 ) and Ghana ( human coronavirus 229E A162 ) .", "label": "background"}, {"segment_text": "Upon translation and alignment with the published spike protein sequence of human coronavirus 229E ` LP ' ( isolated in the UK in the 1970s ) ,", "label": "finding"}, {"segment_text": "it was found that variation within the translated protein sequences was rather limited .", "label": "finding"}, {"segment_text": "In particular , minimal variation was observed between the translated spike protein sequence of human coronaviruses 229E LP and ATCC VR-74 ( 1/1012 amino acid differences ) ,", "label": "finding"}, {"segment_text": "whilst most variation was observed between the translated spike protein sequence of human coronaviruses 229E LP and A162 ( 47/1012 amino acid changes ) .", "label": "finding"}, {"segment_text": "Further , the translated spike protein sequence of human coronavirus 229E A162 showed three clusters of amino acid changes ,", "label": "finding"}, {"segment_text": "situated within the 5 % half of the translated spike protein sequence .", "label": "finding"}], "n_segments": 9}
{"paper_id": "db055944a3acc538005fe7af772ec33c16b2fdd9", "title": "Vaccines for the future: learning from human immunology", "coda_paper_id": 1257, "has_expert_labels": false, "abstract_text": "Conventional vaccines have been extremely successful in preventing infections by pathogens expressing relatively conserved antigens through antibodymediated effector mechanisms . Thanks to vaccination some diseases have been eradicated and mortality due to infectious diseases has been significantly reduced . However , there are still many infections that are not preventable with vaccination , which represent a major cause of mortality worldwide . Some of these infections are caused by pathogens with a high degree of antigen variability that can not be controlled only by antibodies , but require a mix of humoral and cellular immune responses . Novel technologies for antigen discovery , expression and formulation allow now for the development of vaccines that can better cope with pathogen diversity and trigger multifunctional immune responses . In addition , the application of new genomic assays and systems biology approaches in human immunology can help to better identify vaccine correlates of protection . The availability of novel vaccine technologies , together with the knowledge of the distinct human immune responses that are required to prevent different types of infection , should help to rationally design effective vaccines where conventional approaches have failed .", "gold_segments": [{"segment_text": "Conventional vaccines have been extremely successful in preventing infections by pathogens expressing relatively conserved antigens through antibodymediated effector mechanisms .", "label": "background"}, {"segment_text": "Thanks to vaccination some diseases have been eradicated and mortality due to infectious diseases has been significantly reduced .", "label": "background"}, {"segment_text": "However , there are still many infections that are not preventable with vaccination ,", "label": "background"}, {"segment_text": "which represent a major cause of mortality worldwide .", "label": "background"}, {"segment_text": "Some of these infections are caused by pathogens with a high degree of antigen variability that can not be controlled only by antibodies ,", "label": "background"}, {"segment_text": "but require a mix of humoral and cellular immune responses .", "label": "background"}, {"segment_text": "Novel technologies for antigen discovery ,", "label": "background"}, {"segment_text": "expression and formulation allow now for the development of vaccines that can better cope with pathogen diversity and trigger multifunctional immune responses .", "label": "finding"}, {"segment_text": "In addition , the application of new genomic assays and systems biology approaches in human immunology can help to better identify vaccine correlates of protection .", "label": "finding"}, {"segment_text": "The availability of novel vaccine technologies ,", "label": "finding"}, {"segment_text": "together with the knowledge of the distinct human immune responses that are required to prevent different types of infection ,", "label": "finding"}, {"segment_text": "should help to rationally design effective vaccines where conventional approaches have failed .", "label": "finding"}], "n_segments": 12}
{"paper_id": "e4dc4fb77ff0a8a10cf07bf0cceb5ad06e722d0c", "title": "Generality of the Final Size Formula for an Epidemic of a Newly Invading Infectious Disease", "coda_paper_id": 1005, "has_expert_labels": false, "abstract_text": "The well-known formula for the final size of an epidemic was published by Kermack and McKendrick in 1927 . Their analysis was based on a simple susceptible-infected-recovered ( SIR ) model that assumes exponentially distributed infectious periods . More recent analyses have established that the standard final size formula is valid regardless of the distribution of infectious periods , but that it fails to be correct in the presence of certain kinds of heterogeneous mixing ( e.g. , if there is a core group , as for sexually transmitted diseases ) . We review previous work and establish more general conditions under which Kermack and McKendrick 's formula is valid . We show that the final size formula is unchanged if there is a latent stage , any number of distinct infectious stages and/or a stage during which infectives are isolated ( the durations of each stage can be drawn from any integrable distribution ) . We also consider the possibility that the transmission rates of infectious individuals are arbitrarily distributed-allowing , in particular , for the existence of super-spreaders-and prove that this potential complexity has no impact on the final size formula . Finally , we show that the final size formula is unchanged even for a general class of spatial contact structures . We conclude that whenever a new respiratory pathogen emerges , an estimate of the expected magnitude of the epidemic can be made as soon the basic reproduction number R 0 can be approximated , and this estimate is likely to be improved only by more accurate estimates of R 0 , not by knowledge of any other epidemiological details .", "gold_segments": [{"segment_text": "The well-known formula for the final size of an epidemic was published by Kermack and McKendrick in 1927 .", "label": "background"}, {"segment_text": "Their analysis was based on a simple susceptible-infected-recovered ( SIR ) model that assumes exponentially distributed infectious periods .", "label": "background"}, {"segment_text": "More recent analyses have established that the standard final size formula is valid regardless of the distribution of infectious periods ,", "label": "background"}, {"segment_text": "but that it fails to be correct in the presence of certain kinds of heterogeneous mixing ( e.g. , if there is a core group , as for sexually transmitted diseases ) .", "label": "background"}, {"segment_text": "We review previous work and establish more general conditions under which Kermack and McKendrick 's formula is valid .", "label": "purpose"}, {"segment_text": "We show that the final size formula is unchanged if there is a latent stage ,", "label": "finding"}, {"segment_text": "any number of distinct infectious stages and/or a stage during which infectives are isolated ( the durations of each stage can be drawn from any integrable distribution ) .", "label": "finding"}, {"segment_text": "We also consider the possibility that the transmission rates of infectious individuals are arbitrarily distributed-allowing ,", "label": "finding"}, {"segment_text": "in particular , for the existence of super-spreaders-and prove that this potential complexity has no impact on the final size formula .", "label": "finding"}, {"segment_text": "Finally , we show that the final size formula is unchanged even for a general class of spatial contact structures .", "label": "finding"}, {"segment_text": "We conclude that whenever a new respiratory pathogen emerges ,", "label": "finding"}, {"segment_text": "an estimate of the expected magnitude of the epidemic can be made as soon the basic reproduction number R 0 can be approximated ,", "label": "finding"}, {"segment_text": "and this estimate is likely to be improved only by more accurate estimates of R 0 ,", "label": "finding"}, {"segment_text": "not by knowledge of any other epidemiological details .", "label": "finding"}], "n_segments": 14}
{"paper_id": "5caced13bcb8a42cca41369c5a71ae7df5381ca8", "title": "Mucosal immune responses induced by oral administration recombinant Bacillus subtilis expressing the COE antigen of PEDV in newborn piglets", "coda_paper_id": 1691, "has_expert_labels": false, "abstract_text": "Porcine epidemic diarrhea ( PED ) is a highly contagious disease in newborn piglets and causes substantial economic losses in the world . PED virus ( PEDV ) spreads by fecal-oral contact and can be prevented by oral immunization . Therefore , it is necessary to develop an effective oral vaccine against PEDV infection . Currently , Bacillus subtilis as recombinant vaccine carrier has been used for antigen delivery and proved well in immune effect and safety . The present study evaluated the immunogenicity of recombinant Bacillus subtilis ( B. subtilis-RC ) in piglets via oral administration . After oral immunization in piglets , B. subtilis-RC significantly increased the local mucosal immune responses . Oral administration with B. subtilis-RC significantly improved the level of specific mucosal immunoglobulin A ( IgA ) antibodies against PEDV infection , through enlarging the area of Peyer 's patches ( PPs ) and increasing the number of ileum IgA + secreting ( SIgA ) cells . In the meantime , B. subtilis-RC remarkably increased the number of intraepithelial lymphocytes ( IELs ) . We also observed that oral administration of B. subtilis-RC significantly increased CD3 + T lymphocytes ' numbers and up-regulated the ratio of CD4 + / CD8 + T cells . Furthermore , high titers of specific serum immunoglobulin G ( IgG ) revealed satisfactory systemic immune response against PEDV infection . In summary , our study demonstrated that oral administration of B. subtilis-RC could trigger a high level of local and systemic immune responses and would be a promising candidate vaccine against PEDV infection in piglets .", "gold_segments": [{"segment_text": "Porcine epidemic diarrhea ( PED ) is a highly contagious disease in newborn piglets and causes substantial economic losses in the world .", "label": "background"}, {"segment_text": "PED virus ( PEDV ) spreads by fecal-oral contact and can be prevented by oral immunization .", "label": "background"}, {"segment_text": "Therefore , it is necessary to develop an effective oral vaccine against PEDV infection .", "label": "background"}, {"segment_text": "Currently , Bacillus subtilis as recombinant vaccine carrier has been used for antigen delivery and proved well in immune effect and safety .", "label": "background"}, {"segment_text": "The present study evaluated the immunogenicity of recombinant Bacillus subtilis ( B. subtilis-RC ) in piglets via oral administration .", "label": "purpose"}, {"segment_text": "After oral immunization in piglets ,", "label": "method"}, {"segment_text": "B. subtilis-RC significantly increased the local mucosal immune responses .", "label": "finding"}, {"segment_text": "Oral administration with B. subtilis-RC significantly improved the level of specific mucosal immunoglobulin A ( IgA ) antibodies against PEDV infection ,", "label": "finding"}, {"segment_text": "through enlarging the area of Peyer 's patches ( PPs ) and increasing the number of ileum IgA + secreting ( SIgA ) cells .", "label": "finding"}, {"segment_text": "In the meantime , B. subtilis-RC remarkably increased the number of intraepithelial lymphocytes ( IELs ) .", "label": "finding"}, {"segment_text": "We also observed that oral administration of B. subtilis-RC significantly increased CD3 + T lymphocytes ' numbers and up-regulated the ratio of CD4 + / CD8 + T cells .", "label": "finding"}, {"segment_text": "Furthermore , high titers of specific serum immunoglobulin G ( IgG ) revealed satisfactory systemic immune response against PEDV infection .", "label": "finding"}, {"segment_text": "In summary , our study demonstrated that oral administration of B. subtilis-RC could trigger a high level of local and systemic immune responses and would be a promising candidate vaccine against PEDV infection in piglets .", "label": "finding"}], "n_segments": 13}
{"paper_id": "95aec306660c1b7519e9f019d92cc3a8206481e4", "title": "The influence of locked nucleic acid residues on the thermodynamic properties of 2 0 -O-methyl RNA/RNA heteroduplexes", "coda_paper_id": 1802, "has_expert_labels": false, "abstract_text": "The influence of locked nucleic acid ( LNA ) residues on the thermodynamic properties of 2 0 - O-methyl RNA/RNA heteroduplexes is reported . Optical melting studies indicate that LNA incorporated into an otherwise 2 0 - O-methyl RNA oligonucleotide usually , but not always , enhances the stabilities of complementary duplexes formed with RNA . Several trends are apparent , including : ( i ) a 3 0 terminal U LNA and 5 0 terminal LNAs are less stabilizing than interior and other 3 0 terminal LNAs ; ( ii ) most of the stability enhancement is achieved when LNA nucleotides are separated by at least one 2 0 - O-methyl nucleotide ; and ( iii ) the effects of LNA substitutions are approximately additive when the LNA nucleotides are separated by at least one 2 0 - O-methyl nucleotide . An equation is proposed to approximate the stabilities of complementary duplexes formed with RNA when at least one 2 0 - O-methyl nucleotide separates LNA nucleotides . The sequence dependence of 2 0 - Omethyl RNA/RNA duplexes appears to be similar to that of RNA/RNA duplexes , and preliminary nearestneighbor free energy increments at 37 C are presented for 2 0 - O-methyl RNA/RNA duplexes . Internal mismatches with LNA nucleotides significantly destabilize duplexes with RNA .", "gold_segments": [{"segment_text": "The influence of locked nucleic acid ( LNA ) residues on the thermodynamic properties of 2 0 - O-methyl RNA/RNA heteroduplexes is reported .", "label": "background"}, {"segment_text": "Optical melting studies indicate that LNA incorporated into an otherwise 2 0 - O-methyl RNA oligonucleotide usually ,", "label": "background"}, {"segment_text": "but not always , enhances the stabilities of complementary duplexes formed with RNA .", "label": "background"}, {"segment_text": "Several trends are apparent , including : ( i ) a 3 0 terminal U LNA and 5 0 terminal LNAs are less stabilizing than interior and other 3 0 terminal LNAs ; ( ii ) most of the stability enhancement is achieved when LNA nucleotides are separated by at least one 2 0 - O-methyl nucleotide ; and ( iii ) the effects of LNA substitutions are approximately additive when the LNA nucleotides are separated by at least one 2 0 - O-methyl nucleotide .", "label": "background"}, {"segment_text": "An equation is proposed to approximate the stabilities of complementary duplexes formed with RNA when at least one 2 0 - O-methyl nucleotide separates LNA nucleotides .", "label": "finding"}, {"segment_text": "The sequence dependence of 2 0 - Omethyl RNA/RNA duplexes appears to be similar to that of RNA/RNA duplexes ,", "label": "finding"}, {"segment_text": "and preliminary nearestneighbor free energy increments at 37 C are presented for 2 0 - O-methyl RNA/RNA duplexes .", "label": "finding"}, {"segment_text": "Internal mismatches with LNA nucleotides significantly destabilize duplexes with RNA .", "label": "finding"}], "n_segments": 8}
{"paper_id": "ce6af0bb9b796bf3ddc44ddabdce04a7584957d5", "title": "Antiviral activity and possible mode of action of ellagic acid identified in Lagerstroemia speciosa leaves toward human rhinoviruses", "coda_paper_id": 1052, "has_expert_labels": false, "abstract_text": "Background : Human rhinoviruses ( HRVs ) are responsible for more than half of all cases of the common cold and cause billions of USD annually in medical visits and school and work absenteeism . An assessment was made of the cytotoxic and antiviral activities and possible mode of action of the tannin ellagic acid from the leaves of Lagerstroemia speciosa toward HeLa cells and three rhinoviruses , HRV-2 , -3 , and -4 . The antiviral property and mechanism of action of ellagic acid were evaluated using a sulforhodamine B assay and real-time reverse transcription-PCR ( RT-PCR ) with SYBR Green dye . Results were compared with those of the currently used broad-spectrum antiviral agent , ribavirin . Results : As judged by 50 % inhibitory concentration values , natural ellagic acid was 1.8 , 2.3 , and 2.2 times more toxic toward HRV-2 ( 38 μg/mL ) , HRV-3 ( 31 μg/mL ) , and HRV-4 ( 29 μg/mL ) than ribavirin , respectively . The inhibition rate of preincubation with 50 μg/mL ellagic acid was 17 % , whereas continuous presence of ellagic acid during infection led to a significant increase in the inhibition ( 70 % ) . Treatment with 50 μg/mL ellagic acid considerably suppressed HRV-4 infection only when added just after the virus inoculation ( 0 h ) ( 87 % inhibition ) , but not before − 1 h or after 1 h or later ( < 20 % inhibition ) . These findings suggest that ellagic acid does not interact with the HRV-4 particles and may directly interact with the human cells in the early stage of HRV infections to protect the cells from the virus destruction . Furthermore , RT-PCR analysis revealed that 50 μg/mL ellagic acid strongly inhibited the RNA replication of HRV-4 in HeLa cells , suggesting that ellagic acid inhibits virus replication by targeting on cellular molecules , rather than virus molecules . Conclusions : Global efforts to reduce the level of antibiotics justify further studies on L. speciosa leaf-derived materials containing ellagic acid as potential anti-HRV products or a lead molecule for the prevention or treatment of HRV infection .", "gold_segments": [{"segment_text": "Background : Human rhinoviruses ( HRVs ) are responsible for more than half of all cases of the common cold and cause billions of USD annually in medical visits and school and work absenteeism .", "label": "background"}, {"segment_text": "An assessment was made of the cytotoxic and antiviral activities and possible mode of action of the tannin ellagic acid from the leaves of Lagerstroemia speciosa toward HeLa cells and three rhinoviruses ,", "label": "background"}, {"segment_text": "HRV-2 , -3 , and -4 .", "label": "background"}, {"segment_text": "The antiviral property and mechanism of action of ellagic acid were evaluated using a sulforhodamine B assay and real-time reverse transcription-PCR ( RT-PCR ) with SYBR Green dye .", "label": "background"}, {"segment_text": "Results were compared with those of the currently used broad-spectrum antiviral agent , ribavirin .", "label": "finding"}, {"segment_text": "Results : As judged by 50 % inhibitory concentration values ,", "label": "finding"}, {"segment_text": "natural ellagic acid was 1.8 ,", "label": "finding"}, {"segment_text": "2.3 , and 2.2 times more toxic toward HRV-2 ( 38 μg/mL ) ,", "label": "finding"}, {"segment_text": "HRV-3 ( 31 μg/mL ) ,", "label": "finding"}, {"segment_text": "and HRV-4 ( 29 μg/mL ) than ribavirin , respectively .", "label": "finding"}, {"segment_text": "The inhibition rate of preincubation with 50 μg/mL ellagic acid was 17 % ,", "label": "finding"}, {"segment_text": "whereas continuous presence of ellagic acid during infection led to a significant increase in the inhibition ( 70 % ) .", "label": "finding"}, {"segment_text": "Treatment with 50 μg/mL ellagic acid considerably suppressed HRV-4 infection only when added just after the virus inoculation ( 0 h ) ( 87 % inhibition ) ,", "label": "finding"}, {"segment_text": "but not before − 1 h or after 1 h or later ( < 20 % inhibition ) .", "label": "finding"}, {"segment_text": "These findings suggest that ellagic acid does not interact with the HRV-4 particles and may directly interact with the human cells in the early stage of HRV infections to protect the cells from the virus destruction .", "label": "finding"}, {"segment_text": "Furthermore , RT-PCR analysis revealed that 50 μg/mL ellagic acid strongly inhibited the RNA replication of HRV-4 in HeLa cells ,", "label": "finding"}, {"segment_text": "suggesting that ellagic acid inhibits virus replication by targeting on cellular molecules , rather than virus molecules .", "label": "finding"}, {"segment_text": "Conclusions : Global efforts to reduce the level of antibiotics justify further studies on L. speciosa leaf-derived materials containing ellagic acid as potential anti-HRV products or a lead molecule for the prevention or treatment of HRV infection .", "label": "finding"}], "n_segments": 18}
{"paper_id": "2f0c5336664ae52d38bb63174353b3b6a3a0f665", "title": "Expression and functional characterization of the putative protein 8b of the severe acute respiratory syndrome-associated coronavirus", "coda_paper_id": 1509, "has_expert_labels": false, "abstract_text": "SARS 8b is one of the putative accessory proteins of the severe acute respiratory syndrome-associated coronavirus ( SARS-CoV ) with unknown functions . In this study , the cellular localization and activity of this estimated 9.6 kDa protein were examined . Confocal microscopy results indicated that SARS 8b is localized in both nucleus and cytoplasm of mammalian cells . Functional study revealed that overexpression of SARS 8b induced DNA synthesis . Coexpression of SARS 8b and SARS 6 , a previously characterized SARS-CoV accessory protein , did not elicit synergistic effects on DNA synthesis .", "gold_segments": [{"segment_text": "SARS 8b is one of the putative accessory proteins of the severe acute respiratory syndrome-associated coronavirus ( SARS-CoV ) with unknown functions .", "label": "background"}, {"segment_text": "In this study , the cellular localization and activity of this estimated 9.6 kDa protein were examined .", "label": "purpose"}, {"segment_text": "Confocal microscopy results indicated that SARS 8b is localized in both nucleus and cytoplasm of mammalian cells .", "label": "finding"}, {"segment_text": "Functional study revealed that overexpression of SARS 8b induced DNA synthesis .", "label": "finding"}, {"segment_text": "Coexpression of SARS 8b and SARS 6 ,", "label": "finding"}, {"segment_text": "a previously characterized SARS-CoV accessory protein ,", "label": "finding"}, {"segment_text": "did not elicit synergistic effects on DNA synthesis .", "label": "finding"}], "n_segments": 7}
{"paper_id": "12a2d60b1d2fbe08e499962d5c6c5bde0bdfbabf", "title": "Influence of viral load in the outcome of hospitalized patients with influenza virus infection", "coda_paper_id": 1607, "has_expert_labels": false, "abstract_text": "The role of viral load in the outcome of patients requiring hospital admission due to influenza is not well established . We aim to assess if there is an association between the viral load and the outcome in hospitalized patients with a confirmed influenza virus infection . A retrospective observational study including all adult patients who were hospitalized in our center with a confirmed influenza virus infection from January to May 2016 . Viral load was measured by real-time reverse-transcriptase-polymerase chain reaction ( rRT-PCR ) cycle threshold ( Ct ) value on upper respiratory tract samples . Its value was categorized into three groups ( low Ct , ≤ 20 ; intermediate Ct , > 20-30 ; and high Ct , > 30 ) . Two hundred thirty-nine patients were included . Influenza A / H1N1pdm09 was isolated in 207 cases ( 86.6 % ) . The mean Ct value was 26.69 ± 5.81 . The viral load was higher in the unvaccinated group when compared with the vaccinated patients ( Ct 25.17 ± 5.55 vs. 27.58 ± 4.97 , p = 0.004 ) . Only 27 patients ( 11.29 % ) presented a high viral load . Patients with a high viral load more often showed abnormal findings on chest X-ray ( p = 0.015 ) and lymphopenia ( p = 0.097 ) . By contrast , there were no differences between the three groups ( according to viral load ) , in associated pneumonia , respiratory failure , need for mechanical ventilation , sepsis , or in-hospital mortality . Our findings suggest that in patients admitted to the hospital with confirmed influenza virus infection ( mostly A/H1N1pdm09 ) , a high viral load is associated with a higher presence of abnormal findings on chest X-ray but not with a significant worse prognosis . In these cases , standardized quantitative PCR could be useful .", "gold_segments": [{"segment_text": "The role of viral load in the outcome of patients requiring hospital admission due to influenza is not well established .", "label": "background"}, {"segment_text": "We aim to assess if there is an association between the viral load and the outcome in hospitalized patients with a confirmed influenza virus infection .", "label": "purpose"}, {"segment_text": "A retrospective observational study including all adult patients who were hospitalized in our center with a confirmed influenza virus infection from January to May 2016 .", "label": "method"}, {"segment_text": "Viral load was measured by real-time reverse-transcriptase-polymerase chain reaction ( rRT-PCR ) cycle threshold ( Ct ) value on upper respiratory tract samples .", "label": "method"}, {"segment_text": "Its value was categorized into three groups ( low Ct , ≤ 20 ; intermediate Ct , > 20-30 ; and high Ct , > 30 ) .", "label": "method"}, {"segment_text": "Two hundred thirty-nine patients were included .", "label": "method"}, {"segment_text": "Influenza A / H1N1pdm09 was isolated in 207 cases ( 86.6 % ) .", "label": "finding"}, {"segment_text": "The mean Ct value was 26.69 ± 5.81 .", "label": "finding"}, {"segment_text": "The viral load was higher in the unvaccinated group when compared with the vaccinated patients ( Ct 25.17 ± 5.55 vs. 27.58 ± 4.97 , p = 0.004 ) .", "label": "finding"}, {"segment_text": "Only 27 patients ( 11.29 % ) presented a high viral load .", "label": "finding"}, {"segment_text": "Patients with a high viral load more often showed abnormal findings on chest X-ray ( p = 0.015 ) and lymphopenia ( p = 0.097 ) .", "label": "finding"}, {"segment_text": "By contrast , there were no differences between the three groups ( according to viral load ) ,", "label": "finding"}, {"segment_text": "in associated pneumonia , respiratory failure ,", "label": "finding"}, {"segment_text": "need for mechanical ventilation , sepsis , or in-hospital mortality .", "label": "finding"}, {"segment_text": "Our findings suggest that in patients admitted to the hospital with confirmed influenza virus infection ( mostly A/H1N1pdm09 ) ,", "label": "finding"}, {"segment_text": "a high viral load is associated with a higher presence of abnormal findings on chest X-ray but not with a significant worse prognosis .", "label": "finding"}, {"segment_text": "In these cases , standardized quantitative PCR could be useful .", "label": "finding"}], "n_segments": 17}
{"paper_id": "5b25c21a882848393a88f2036871db32f76c7a80", "title": "Construction and next-generation sequencing analysis of a large phage-displayed V NAR single-domain antibody library from six naïve nurse sharks", "coda_paper_id": 1748, "has_expert_labels": false, "abstract_text": "Methods : Here , we developed a library construction method based on polymerase chain reaction ( PCR ) - Extension Assembly and Self-Ligation ( named `` EASeL '' ) to construct a large V NAR antibody library with a size of 1.2 × 10 10 from six naïve adult nurse sharks ( Ginglymostoma cirratum ) . Results : The next-generation sequencing analysis of 1.19 million full-length V NAR s revealed that this library is highly diversified because it covers all four classical V NAR types ( Types I-IV ) including 11 % of classical Type I and 57 % of classical Type II . About 30 % of the total V NAR s could not be categorized as any of the classical types . The high variability of complementarity determining region ( CDR ) 3 length and cysteine numbers are important for the diversity of V NAR s. To validate the use of the shark V NAR library for antibody discovery , we isolated a panel of V NAR phage binders to cancer therapy-related antigens , including glypican-3 , human epidermal growth factor receptor 2 ( HER2 ) , and programmed cell death-1 ( PD1 ) . Additionally , we identified binders to viral antigens that included the Middle East respiratory syndrome ( MERS ) and severe acute respiratory syndrome ( SARS ) spike proteins . The isolated shark single-domain antibodies including Type I and Type II V NAR s were produced in Escherichia coli and validated for their antigen binding . A Type II V NAR ( PE38-B6 ) has a high affinity ( K d = 10.1 nM ) for its antigen . Statement of Significance : A method called `` EASeL '' for overlap extension PCR combined with selfligation has been established for constructing a large phage-displayed V NAR single-domain antibody library from six nurse sharks . The shark single-domain library provides an alternative platform for selecting therapeutic antibodies for treating cancer and other human diseases .", "gold_segments": [{"segment_text": "Methods : Here , we developed a library construction method based on polymerase chain reaction ( PCR ) - Extension Assembly and Self-Ligation ( named `` EASeL '' ) to construct a large V NAR antibody library with a size of 1.2 × 10 10 from six naïve adult nurse sharks ( Ginglymostoma cirratum ) .", "label": "method"}, {"segment_text": "Results : The next-generation sequencing analysis of 1.19 million full-length V NAR s revealed that this library is highly diversified because it covers all four classical V NAR types ( Types I-IV ) including 11 % of classical Type I and 57 % of classical Type II .", "label": "finding"}, {"segment_text": "About 30 % of the total V NAR s could not be categorized as any of the classical types .", "label": "finding"}, {"segment_text": "The high variability of complementarity determining region ( CDR ) 3 length and cysteine numbers are important for the diversity of V NAR s. To validate the use of the shark V NAR library for antibody discovery ,", "label": "finding"}, {"segment_text": "we isolated a panel of V NAR phage binders to cancer therapy-related antigens ,", "label": "finding"}, {"segment_text": "including glypican-3 , human epidermal growth factor receptor 2 ( HER2 ) ,", "label": "finding"}, {"segment_text": "and programmed cell death-1 ( PD1 ) .", "label": "finding"}, {"segment_text": "Additionally , we identified binders to viral antigens that included the Middle East respiratory syndrome ( MERS ) and severe acute respiratory syndrome ( SARS ) spike proteins .", "label": "finding"}, {"segment_text": "The isolated shark single-domain antibodies including Type I and Type II V NAR s were produced in Escherichia coli and validated for their antigen binding .", "label": "finding"}, {"segment_text": "A Type II V NAR ( PE38-B6 ) has a high affinity ( K d = 10.1 nM ) for its antigen .", "label": "finding"}, {"segment_text": "Statement of Significance : A method called `` EASeL '' for overlap extension PCR combined with selfligation has been established for constructing a large phage-displayed V NAR single-domain antibody library from six nurse sharks .", "label": "finding"}, {"segment_text": "The shark single-domain library provides an alternative platform for selecting therapeutic antibodies for treating cancer and other human diseases .", "label": "finding"}], "n_segments": 12}
{"paper_id": "d132d58ca7cebfdb99890a91cc5248a76cc1d08e", "title": "Global versus focused isolation during the SARS-CoV-2 pandemic- A cost-effectiveness analysis", "coda_paper_id": 1147, "has_expert_labels": false, "abstract_text": "Background : The novel coronavirus ( SARS-CoV-2 ) pandemic is driving many countries to adopt global isolation measures in an attempt to slow-down its spread . These extreme measures are associated with extraordinary economic costs . Objective : To compare the cost-effectiveness of global isolation of the whole population to focused isolation of individuals at high risk of being exposed , augmented by thorough PCR testing . Design : We applied a modified Susceptible , Exposed , Infectious , Removed ( SEIR ) model to compare two different strategies in controlling the SARS-CoV-2 spread . Data sources and target population : We modeled the dynamics in Israel , a small country with ~ 9 million people . Interventions : 1 . Global isolation of the whole population ( strategy 1 ) 2 . Focused isolation of people at high risk of exposure with extensive PCR testing ( strategy 2 ) . Outcome measures : Number of deaths and the cost per one avoided death in strategy 1 vs 2 . The number of expected deaths is 389 in strategy 1versus 432 in strategy 2 . The incremental cost-effectiveness ratio ( ICER ) in case of adhering to global isolation will be $ 102,383,282 to prevent one case of death . The ICER value is between $ 22.5 million to over $ 280 million per one avoided death . Conclusions : According to our model , global isolation will save ~ 43 more lives compared to a strategy of focused isolation and extensive screening . This benefit is implicated in tremendous costs that might result in overwhelming economic effects . Limitations : Compartment models do not necessarily fit to countries with heterogeneous populations . In addition , we rely on current published parameters that might not reliably reflect infection dynamics . All rights reserved . No reuse allowed without permission . the author/funder , who has granted medRxiv a license to display the preprint in perpetuity .", "gold_segments": [{"segment_text": "Background : The novel coronavirus ( SARS-CoV-2 ) pandemic is driving many countries to adopt global isolation measures in an attempt to slow-down its spread .", "label": "background"}, {"segment_text": "These extreme measures are associated with extraordinary economic costs .", "label": "background"}, {"segment_text": "Objective : To compare the cost-effectiveness of global isolation of the whole population to focused isolation of individuals at high risk of being exposed ,", "label": "purpose"}, {"segment_text": "augmented by thorough PCR testing .", "label": "purpose"}, {"segment_text": "Design : We applied a modified Susceptible ,", "label": "method"}, {"segment_text": "Exposed , Infectious , Removed ( SEIR ) model to compare two different strategies in controlling the SARS-CoV-2 spread .", "label": "method"}, {"segment_text": "Data sources and target population : We modeled the dynamics in Israel ,", "label": "method"}, {"segment_text": "a small country with ~ 9 million people .", "label": "method"}, {"segment_text": "Interventions : 1 .", "label": "method"}, {"segment_text": "Global isolation of the whole population ( strategy 1 ) 2 .", "label": "method"}, {"segment_text": "Focused isolation of people at high risk of exposure with extensive PCR testing ( strategy 2 ) .", "label": "method"}, {"segment_text": "Outcome measures : Number of deaths and the cost per one avoided death in strategy 1 vs 2 .", "label": "finding"}, {"segment_text": "The number of expected deaths is 389 in strategy 1versus 432 in strategy 2 .", "label": "finding"}, {"segment_text": "The incremental cost-effectiveness ratio ( ICER ) in case of adhering to global isolation will be $ 102,383,282 to prevent one case of death .", "label": "finding"}, {"segment_text": "The ICER value is between $ 22.5 million to over $ 280 million per one avoided death .", "label": "finding"}, {"segment_text": "Conclusions : According to our model ,", "label": "finding"}, {"segment_text": "global isolation will save ~ 43 more lives compared to a strategy of focused isolation and extensive screening .", "label": "finding"}, {"segment_text": "This benefit is implicated in tremendous costs that might result in overwhelming economic effects .", "label": "finding"}, {"segment_text": "Limitations : Compartment models do not necessarily fit to countries with heterogeneous populations .", "label": "finding"}, {"segment_text": "In addition , we rely on current published parameters that might not reliably reflect infection dynamics .", "label": "finding"}, {"segment_text": "All rights reserved .", "label": "other"}, {"segment_text": "No reuse allowed without permission .", "label": "other"}, {"segment_text": "the author/funder , who has granted medRxiv a license to display the preprint in perpetuity .", "label": "other"}], "n_segments": 23}
{"paper_id": "e9d32ac6db6f898b035aab6d4357342c3ae2442b", "title": "A Surveillance System to Reduce Transmission of Pandemic H1N1 (2009) Influenza in a 2600-Bed Medical Center", "coda_paper_id": 1036, "has_expert_labels": false, "abstract_text": "Background : Concerns have been raised about how the transmission of emerging infectious diseases from patients to healthcare workers ( HCWs ) and vice versa could be recognized and prevented in a timely manner . An effective strategy to block transmission of pandemic H1N1 ( 2009 ) influenza in HCWs is important .", "gold_segments": [{"segment_text": "Background : Concerns have been raised about how the transmission of emerging infectious diseases from patients to healthcare workers ( HCWs ) and vice versa could be recognized and prevented in a timely manner .", "label": "background"}, {"segment_text": "An effective strategy to block transmission of pandemic H1N1 ( 2009 ) influenza in HCWs is important .", "label": "background"}], "n_segments": 2}
{"paper_id": "edd296f69419b4b079b0ab5dcc89f48e9d9f82f3", "title": "SCIENCE CHINA Isolation and characterization of dengue virus serotype 2 from the large dengue outbreak in Guangdong, China in 2014 Isolation and characterization of dengue virus serotype 2 from the large dengue outbreak in Guangdong", "coda_paper_id": 1109, "has_expert_labels": false, "abstract_text": "Dengue has been well recognized as a global public health threat , but only sporadic epidemics and imported cases were reported in recent decades in China . Since July 2014 , an unexpected large dengue outbreak has occurred in Guangdong province , China , resulting in more than 40000 patients including six deaths . To clarify and characterize the causative agent of this outbreak , the acute phase serum from a patient diagnosed with severe dengue was subjected to virus isolation and high-throughput sequencing ( HTS ) . Traditional real-time RT-PCR and HTS with Ion Torrent PGM detected the presence of dengue virus serotype 2 ( DENV-2 ) . A clinical DENV-2 isolate GZ05/2014 was obtained by culturing the patient serum in mosquito C6/36 cells . The complete genome of GZ05/2014 was determined and deposited in GenBank under the access number KP012546 . Phylogenetic analysis based on the complete envelope gene showed that the newly DENV-2 isolate belonged to Cosmopolitan genotype and clustered closely with other Guangdong strains isolated in the past decade . No amino acid mutations that are obviously known to increase virulence or replication were identified throughout the genome of GZ05/2014 . The high homology of Guangdong DENV-2 strains indicated the possibility of establishment of local DENV-2 circulation in Guangdong , China . These results help clarify the origin of this epidemic and predict the future status of dengue in China . dengue virus serotype 2 , virus isolation , phylogenetic analysis , envelope gene Citation :", "gold_segments": [{"segment_text": "Dengue has been well recognized as a global public health threat ,", "label": "background"}, {"segment_text": "but only sporadic epidemics and imported cases were reported in recent decades in China .", "label": "background"}, {"segment_text": "Since July 2014 , an unexpected large dengue outbreak has occurred in Guangdong province ,", "label": "background"}, {"segment_text": "China , resulting in more than 40000 patients including six deaths .", "label": "background"}, {"segment_text": "To clarify and characterize the causative agent of this outbreak ,", "label": "purpose"}, {"segment_text": "the acute phase serum from a patient diagnosed with severe dengue was subjected to virus isolation and high-throughput sequencing ( HTS ) .", "label": "method"}, {"segment_text": "Traditional real-time RT-PCR and HTS with Ion Torrent PGM detected the presence of dengue virus serotype 2 ( DENV-2 ) .", "label": "method"}, {"segment_text": "A clinical DENV-2 isolate GZ05/2014 was obtained by culturing the patient serum in mosquito C6/36 cells .", "label": "method"}, {"segment_text": "The complete genome of GZ05/2014 was determined and deposited in GenBank under the access number KP012546 .", "label": "method"}, {"segment_text": "Phylogenetic analysis based on the complete envelope gene showed that the newly DENV-2 isolate belonged to Cosmopolitan genotype and clustered closely with other Guangdong strains isolated in the past decade .", "label": "finding"}, {"segment_text": "No amino acid mutations that are obviously known to increase virulence or replication were identified throughout the genome of GZ05/2014 .", "label": "finding"}, {"segment_text": "The high homology of Guangdong DENV-2 strains indicated the possibility of establishment of local DENV-2 circulation in Guangdong , China .", "label": "finding"}, {"segment_text": "These results help clarify the origin of this epidemic and predict the future status of dengue in China .", "label": "finding"}, {"segment_text": "dengue virus serotype 2 , virus isolation ,", "label": "other"}, {"segment_text": "phylogenetic analysis , envelope gene Citation :", "label": "other"}], "n_segments": 15}
{"paper_id": "f318f02676fa086210640feb3fb488ae9522ba95", "title": "Biological Crystallography Structure of the C-terminal domain of nsp4 from feline coronavirus", "coda_paper_id": 1363, "has_expert_labels": false, "abstract_text": "Coronaviruses are a family of positive-stranded RNA viruses that includes important pathogens of humans and other animals . The large coronavirus genome ( 26-31 kb ) encodes 15-16 nonstructural proteins ( nsps ) that are derived from two replicase polyproteins by autoproteolytic processing . The nsps assemble into the viral replication-transcription complex and nsp3 , nsp4 and nsp6 are believed to anchor this enzyme complex to modified intracellular membranes . The largest part of the coronavirus nsp4 subunit is hydrophobic and is predicted to be embedded in the membranes . In this report , a conserved C-terminal domain ( $ 100 amino-acid residues ) has been delineated that is predicted to face the cytoplasm and has been isolated as a soluble domain using library-based construct screening . A prototypical crystal structure at 2.8 Å resolution was obtained using nsp4 from feline coronavirus . Unmodified and SeMet-substituted proteins were crystallized under similar conditions , resulting in tetragonal crystals that belonged to space group P4 3 . The phase problem was initially solved by single isomorphous replacement with anomalous scattering ( SIRAS ) , followed by molecular replacement using a SIRAS-derived composite model . The structure consists of a single domain with a predominantly - helical content displaying a unique fold that could be engaged in proteinprotein interactions .", "gold_segments": [{"segment_text": "Coronaviruses are a family of positive-stranded RNA viruses that includes important pathogens of humans and other animals .", "label": "background"}, {"segment_text": "The large coronavirus genome ( 26-31 kb ) encodes 15-16 nonstructural proteins ( nsps ) that are derived from two replicase polyproteins by autoproteolytic processing .", "label": "background"}, {"segment_text": "The nsps assemble into the viral replication-transcription complex and nsp3 ,", "label": "background"}, {"segment_text": "nsp4 and nsp6 are believed to anchor this enzyme complex to modified intracellular membranes .", "label": "background"}, {"segment_text": "The largest part of the coronavirus nsp4 subunit is hydrophobic and is predicted to be embedded in the membranes .", "label": "background"}, {"segment_text": "In this report , a conserved C-terminal domain ( $ 100 amino-acid residues ) has been delineated that is predicted to face the cytoplasm and has been isolated as a soluble domain using library-based construct screening .", "label": "method"}, {"segment_text": "A prototypical crystal structure at 2.8 Å resolution was obtained using nsp4 from feline coronavirus .", "label": "method"}, {"segment_text": "Unmodified and SeMet-substituted proteins were crystallized under similar conditions ,", "label": "method"}, {"segment_text": "resulting in tetragonal crystals that belonged to space group P4 3 .", "label": "finding"}, {"segment_text": "The phase problem was initially solved by single isomorphous replacement with anomalous scattering ( SIRAS ) ,", "label": "finding"}, {"segment_text": "followed by molecular replacement using a SIRAS-derived composite model .", "label": "finding"}, {"segment_text": "The structure consists of a single domain with a predominantly - helical content displaying a unique fold that could be engaged in proteinprotein interactions .", "label": "finding"}], "n_segments": 12}
{"paper_id": "55e303047b9d479c0af87287ab1a570a33949178", "title": "Viral and bacterial infections associated with camel (Camelus dromedarius) calf diarrhea in North Province, Saudi Arabia", "coda_paper_id": 1461, "has_expert_labels": false, "abstract_text": "Diarrhea and deaths in new-born camel calves were noticed by veterinary investigators and pastoralist in Saudi Arabia to be very high . Hence , it is thought to be necessary to investigate this problem from the virological and bacteriological point of view . The role of pathogenic bacteria and viruses in six different towns of North Province ( Al-Assafia , Arar , Domat Aljandal , Hail , Skaka and Khoa ) in Saudi Arabia was studied . Survey was conducted in diarrheic camel calves aged 12 months or younger . In our study calf diarrhea was reported in 184 out of 2308 camels examined clinically during one year , the prevalence of diarrhea was found to be 8.0 % in calves ranging from one month to one year . In the present study group A rotavirus and Brucella abortus were detected in 14.7 % and 8.98 % , respectively , using ELISA technique . Escherichia coli was isolated from diarrheic calf camel ( 58.2 % ) 99/170 samples during dry and wet season . Salmonella spp. and Enterococcus spp. were detected in 12 % and 8.8 % of the specimens , respectively . In this study enterotoxogenic E. coli ( ET E. coli ) was isolated from 7 % of diarrheic camel , which indicates the strong correlation between the camel calf diarrhea and the detection of enterotoxogenic E. coli . This study represented the first report for the detection of group A rotavirus and B. abortus antigen and antibodies in calf", "gold_segments": [{"segment_text": "Diarrhea and deaths in new-born camel calves were noticed by veterinary investigators and pastoralist in Saudi Arabia to be very high .", "label": "background"}, {"segment_text": "Hence , it is thought to be necessary to investigate this problem from the virological and bacteriological point of view .", "label": "background"}, {"segment_text": "The role of pathogenic bacteria and viruses in six different towns of North Province ( Al-Assafia , Arar , Domat Aljandal , Hail , Skaka and Khoa ) in Saudi Arabia was studied .", "label": "background"}, {"segment_text": "Survey was conducted in diarrheic camel calves aged 12 months or younger .", "label": "method"}, {"segment_text": "In our study calf diarrhea was reported in 184 out of 2308 camels examined clinically during one year ,", "label": "finding"}, {"segment_text": "the prevalence of diarrhea was found to be 8.0 % in calves ranging from one month to one year .", "label": "finding"}, {"segment_text": "In the present study group A rotavirus and Brucella abortus were detected in 14.7 % and 8.98 % ,", "label": "finding"}, {"segment_text": "respectively , using ELISA technique .", "label": "finding"}, {"segment_text": "Escherichia coli was isolated from diarrheic calf camel ( 58.2 % ) 99/170 samples during dry and wet season .", "label": "finding"}, {"segment_text": "Salmonella spp. and Enterococcus spp. were detected in 12 % and 8.8 % of the specimens , respectively .", "label": "finding"}, {"segment_text": "In this study enterotoxogenic E. coli ( ET E. coli ) was isolated from 7 % of diarrheic camel ,", "label": "finding"}, {"segment_text": "which indicates the strong correlation between the camel calf diarrhea and the detection of enterotoxogenic E. coli .", "label": "finding"}, {"segment_text": "This study represented the first report for the detection of group A rotavirus and B. abortus antigen and antibodies in calf", "label": "finding"}], "n_segments": 13}
{"paper_id": "b9fbe0887c389e6c5202eaf5d7e21c9d19ab6bc6", "title": "Porcine epidemic diarrhea: A retrospect from Europe and matters of debate", "coda_paper_id": 1431, "has_expert_labels": false, "abstract_text": "Europe CV777 Virulence Historical review a b s t r a c t A retrospect is given on the emergence of porcine epidemic diarrhea ( PED ) during the early seventies in Europe . While , at first , it appeared as a disease affecting feeder pigs , fattening-and adult swine , it later also became pathogenic for neonatal and suckling pigs hereby drastically increasing its economic impact . Isolation of the causative virus revealed a new porcine coronavirus , the origin of which has never been clarified . Pathogenesis studies with the prototype strain CV777 showed severe villous atrophy in neonatal pigs and the virus-animal interactions showed many similarities with transmissible gastro-enteritis virus ( TGEV ) , another porcine coronavirus . Disease patterns in field outbreaks showed muchvariation but , while farm related factors played a role , possible genetic variations of virus strains in Europe have not been examined and are thus unknown . CV777 in experimental pigs caused diarrheal disease and mortality rates similar to those later encountered in Asia and more recently with the `` original '' US strains even though genomic typing of the prototype European strain have shown that it belongs to the S-INDEL strains . In Europe , PED has become endemic during the eighties and nineties and subsequently regressed so that , after 2000 , swine populations in many countries have largely become seronegative . Sporadic outbreaks have recently reappeared showing a large variety of clinical outcomes .", "gold_segments": [{"segment_text": "Europe CV777 Virulence Historical review a b s t r a c t A retrospect is given on the emergence of porcine epidemic diarrhea ( PED ) during the early seventies in Europe .", "label": "background"}, {"segment_text": "While , at first , it appeared as a disease affecting feeder pigs ,", "label": "background"}, {"segment_text": "fattening-and adult swine , it later also became pathogenic for neonatal and suckling pigs hereby drastically increasing its economic impact .", "label": "background"}, {"segment_text": "Isolation of the causative virus revealed a new porcine coronavirus ,", "label": "background"}, {"segment_text": "the origin of which has never been clarified .", "label": "background"}, {"segment_text": "Pathogenesis studies with the prototype strain CV777 showed severe villous atrophy in neonatal pigs and the virus-animal interactions showed many similarities with transmissible gastro-enteritis virus ( TGEV ) , another porcine coronavirus .", "label": "background"}, {"segment_text": "Disease patterns in field outbreaks showed muchvariation but ,", "label": "background"}, {"segment_text": "while farm related factors played a role ,", "label": "background"}, {"segment_text": "possible genetic variations of virus strains in Europe have not been examined and are thus unknown .", "label": "background"}, {"segment_text": "CV777 in experimental pigs caused diarrheal disease and mortality rates similar to those later encountered in Asia and more recently with the `` original '' US strains even though genomic typing of the prototype European strain have shown that it belongs to the S-INDEL strains .", "label": "finding"}, {"segment_text": "In Europe , PED has become endemic during the eighties and nineties and subsequently regressed so that ,", "label": "finding"}, {"segment_text": "after 2000 , swine populations in many countries have largely become seronegative .", "label": "finding"}, {"segment_text": "Sporadic outbreaks have recently reappeared showing a large variety of clinical outcomes .", "label": "finding"}], "n_segments": 13}
{"paper_id": "64478db449af8e4a5645c17f548649a0159da0c6", "title": "Individual and temporal variation in pathogen load predicts long- 1 term impacts of an emerging infectious disease", "coda_paper_id": 1108, "has_expert_labels": false, "abstract_text": "Emerging infectious diseases increasingly threaten wildlife populations . Most studies focus 27 on managing short-term epidemic properties , such as controlling early outbreaks . Predicting 28 long-term endemic characteristics with limited retrospective data is more challenging . We 29 used individual-based modelling informed by individual variation in pathogen load and 30 transmissibility to predict long-term impacts of a lethal , transmissible cancer on Tasmanian 31 devil ( Sarcophilus harrisii ) populations . For this , we employed Approximate Bayesian 32 Computation to identify model scenarios that best matched known epidemiological and 33 demographic system properties derived from ten years of data after disease emergence , 34 enabling us to forecast future system dynamics . We show that the dramatic devil population 35 declines observed thus far are likely attributable to transient dynamics . Only 21 % of 36 matching scenarios led to devil extinction within 100 years following devil facial tumour 37 disease ( DFTD ) introduction , whereas DFTD faded out in 57 % of simulations . In the 38 remaining 22 % of simulations , disease and host coexisted for at least 100 years , usually with 39 long-period oscillations . Our findings show that pathogen extirpation or host-pathogen 40 coexistence are much more likely than the DFTD-induced devil extinction , with crucial 41 management ramifications . Accounting for individual-level disease progression and the long-42 term outcome of devil-DFTD interactions at the population-level , our findings suggest that 43 immediate management interventions are unlikely to be necessary to ensure the persistence of 44 Tasmanian devil populations . This is because strong population declines of devils after 45 disease emergence do not necessarily translate into long-term population declines at 46 equilibria . Our modelling approach is widely applicable to other host-pathogen systems to 47 predict disease impact beyond transient dynamics .", "gold_segments": [{"segment_text": "Emerging infectious diseases increasingly threaten wildlife populations .", "label": "background"}, {"segment_text": "Most studies focus 27 on managing short-term epidemic properties ,", "label": "background"}, {"segment_text": "such as controlling early outbreaks .", "label": "background"}, {"segment_text": "Predicting 28 long-term endemic characteristics with limited retrospective data is more challenging .", "label": "background"}, {"segment_text": "We 29 used individual-based modelling informed by individual variation in pathogen load and 30 transmissibility to predict long-term impacts of a lethal ,", "label": "method"}, {"segment_text": "transmissible cancer on Tasmanian 31 devil ( Sarcophilus harrisii ) populations .", "label": "method"}, {"segment_text": "For this , we employed Approximate Bayesian 32 Computation to identify model scenarios that best matched known epidemiological and 33 demographic system properties derived from ten years of data after disease emergence ,", "label": "method"}, {"segment_text": "34 enabling us to forecast future system dynamics .", "label": "method"}, {"segment_text": "We show that the dramatic devil population 35 declines observed thus far are likely attributable to transient dynamics .", "label": "finding"}, {"segment_text": "Only 21 % of 36 matching scenarios led to devil extinction within 100 years following devil facial tumour 37 disease ( DFTD ) introduction ,", "label": "finding"}, {"segment_text": "whereas DFTD faded out in 57 % of simulations .", "label": "finding"}, {"segment_text": "In the 38 remaining 22 % of simulations ,", "label": "finding"}, {"segment_text": "disease and host coexisted for at least 100 years ,", "label": "finding"}, {"segment_text": "usually with 39 long-period oscillations .", "label": "finding"}, {"segment_text": "Our findings show that pathogen extirpation or host-pathogen 40 coexistence are much more likely than the DFTD-induced devil extinction ,", "label": "finding"}, {"segment_text": "with crucial 41 management ramifications .", "label": "finding"}, {"segment_text": "Accounting for individual-level disease progression and the long-42 term outcome of devil-DFTD interactions at the population-level ,", "label": "finding"}, {"segment_text": "our findings suggest that 43 immediate management interventions are unlikely to be necessary to ensure the persistence of 44", "label": "finding"}, {"segment_text": "Tasmanian devil populations .", "label": "finding"}, {"segment_text": "This is because strong population declines of devils after 45 disease emergence do not necessarily translate into long-term population declines at 46 equilibria .", "label": "finding"}, {"segment_text": "Our modelling approach is widely applicable to other host-pathogen systems to 47 predict disease impact beyond transient dynamics .", "label": "finding"}], "n_segments": 21}
{"paper_id": "739e01113e6c837a1fb973b1ab7e434cc9c27904", "title": "Differential Effects of IL-12 on Tregs and Non-Treg T Cells: Roles of IFN-c, IL-2 and IL-2R", "coda_paper_id": 1417, "has_expert_labels": false, "abstract_text": "Complex interactions between effector T cells and Foxp3 + regulatory T cells ( Treg ) contribute to clinical outcomes in cancer , and autoimmune and infectious diseases . Previous work showed that IL-12 reversed Treg-mediated suppression of CD4 + Foxp3 2 T cell ( Tconv ) proliferation . We and others have also shown that Tregs express T-bet and IFN-c at sites of Th1 inflammation and that IL-12 induces IFN-c production by Tregs in vitro . To investigate whether loss of immunosuppression occurs when IFN-c is expressed by Tregs we treated mouse lymphocyte cultures with IL-12 . IFN-c expression did not decrease the ability of Tregs to suppress Tconv proliferation . Rather , IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs . We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells , diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells . Together , these IL-12 mediated changes favored the outgrowth of non-Tregs . Additionally , we showed that treatment with a second cytokine , IL-27 , decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation . Notably , IL-27 only slightly modified levels of IL-2R on non-Treg T cells . Together , these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-c expression in IL-12-mediated reversal of Treg immunosuppression .", "gold_segments": [{"segment_text": "Complex interactions between effector T cells and Foxp3 + regulatory T cells ( Treg ) contribute to clinical outcomes in cancer ,", "label": "background"}, {"segment_text": "and autoimmune and infectious diseases .", "label": "background"}, {"segment_text": "Previous work showed that IL-12 reversed Treg-mediated suppression of CD4 + Foxp3 2 T cell ( Tconv ) proliferation .", "label": "background"}, {"segment_text": "We and others have also shown that Tregs express T-bet and IFN-c at sites of Th1 inflammation and that IL-12 induces IFN-c production by Tregs in vitro .", "label": "background"}, {"segment_text": "To investigate whether loss of immunosuppression occurs when IFN-c is expressed by Tregs we treated mouse lymphocyte cultures with IL-12 .", "label": "purpose"}, {"segment_text": "IFN-c expression did not decrease the ability of Tregs to suppress Tconv proliferation .", "label": "finding"}, {"segment_text": "Rather , IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs .", "label": "finding"}, {"segment_text": "We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells ,", "label": "finding"}, {"segment_text": "diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells .", "label": "finding"}, {"segment_text": "Together , these IL-12 mediated changes favored the outgrowth of non-Tregs .", "label": "finding"}, {"segment_text": "Additionally , we showed that treatment with a second cytokine ,", "label": "finding"}, {"segment_text": "IL-27 , decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation .", "label": "finding"}, {"segment_text": "Notably , IL-27 only slightly modified levels of IL-2R on non-Treg T cells .", "label": "finding"}, {"segment_text": "Together , these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-c expression in IL-12-mediated reversal of Treg immunosuppression .", "label": "finding"}], "n_segments": 14}
{"paper_id": "63cb88b9fee3f16bcf3666b4665e445325addf9d", "title": "Lytic HSV-1 infection induces the multifunctional transcription factor Early Growth Response-1 (EGR-1) in rabbit corneal cells", "coda_paper_id": 1194, "has_expert_labels": false, "abstract_text": "Background : Herpes simplex virus type-1 ( HSV-1 ) infections can cause a number of diseases ranging from simple cold sores to dangerous keratitis and lethal encephalitis . The interaction between virus and host cells , critical for viral replication , is being extensively investigated by many laboratories . In this study , we tested the hypothesis that HSV-1 lytic infection triggers the expression of important multi-functional transcription factor Egr1 . The mechanisms of induction are mediated , at least in part , by signaling pathways such as NFB and CREB . Methods : SIRC , VERO , and 293HEK cell lines were infected with HSV-1 , and the Egr-1 transcript and protein were detected by RT-PCR and Western blot , respectively . The localization and expression profile of Egr-1 were investigated further by immunofluorescence microscopy analyses . The recruitment of transcription factors to the Egr-1 promoter during infection was studied by chromatin immunoprecipitation ( ChIP ) . Various inhibitors and dominant-negative mutant were used to assess the mechanisms of Egr-1 induction and their effects were addressed by immunofluorescence microscopy . Results : Western blot analyses showed that Egr-1 was absent in uninfected cells ; however , the protein was detected 24-72 hours post treatment , and the response was directly proportional to the titer of the virus used for infection . Using recombinant HSV-1 expressing EGFP , Egr-1 was detected only in the infected cells . ChIP assays demonstrated that NFкB and cAMP response element binding protein ( CREB ) were recruited to the Egr-1 promoter upon infection . Additional studies showed that inhibitors of NFкB and dominant-negative CREB repressed the Egr-1 induction by HSV-1 infection . Conclusion : Collectively , these results demonstrate that Egr-1 is expressed rapidly upon HSV-1 infection and that this novel induction could be due to the NFкB/CREB-mediated transactivation . Egr-1 induction might play a key role in the viral gene expression , replication , inflammation , and the disease progression .", "gold_segments": [{"segment_text": "Background : Herpes simplex virus type-1 ( HSV-1 ) infections can cause a number of diseases ranging from simple cold sores to dangerous keratitis and lethal encephalitis .", "label": "background"}, {"segment_text": "The interaction between virus and host cells ,", "label": "background"}, {"segment_text": "critical for viral replication , is being extensively investigated by many laboratories .", "label": "background"}, {"segment_text": "In this study , we tested the hypothesis that HSV-1 lytic infection triggers the expression of important multi-functional transcription factor Egr1 .", "label": "purpose"}, {"segment_text": "The mechanisms of induction are mediated ,", "label": "purpose"}, {"segment_text": "at least in part , by signaling pathways such as NFB and CREB .", "label": "purpose"}, {"segment_text": "Methods : SIRC , VERO ,", "label": "method"}, {"segment_text": "and 293HEK cell lines were infected with HSV-1 ,", "label": "method"}, {"segment_text": "and the Egr-1 transcript and protein were detected by RT-PCR and Western blot , respectively .", "label": "method"}, {"segment_text": "The localization and expression profile of Egr-1 were investigated further by immunofluorescence microscopy analyses .", "label": "method"}, {"segment_text": "The recruitment of transcription factors to the Egr-1 promoter during infection was studied by chromatin immunoprecipitation ( ChIP ) .", "label": "method"}, {"segment_text": "Various inhibitors and dominant-negative mutant were used to assess the mechanisms of Egr-1 induction and their effects were addressed by immunofluorescence microscopy .", "label": "method"}, {"segment_text": "Results : Western blot analyses showed that Egr-1 was absent in uninfected cells ; however ,", "label": "finding"}, {"segment_text": "the protein was detected 24-72 hours post treatment ,", "label": "finding"}, {"segment_text": "and the response was directly proportional to the titer of the virus used for infection .", "label": "finding"}, {"segment_text": "Using recombinant HSV-1 expressing EGFP ,", "label": "finding"}, {"segment_text": "Egr-1 was detected only in the infected cells .", "label": "finding"}, {"segment_text": "ChIP assays demonstrated that NFкB and cAMP response element binding protein ( CREB ) were recruited to the Egr-1 promoter upon infection .", "label": "finding"}, {"segment_text": "Additional studies showed that inhibitors of NFкB and dominant-negative CREB repressed the Egr-1 induction by HSV-1 infection .", "label": "finding"}, {"segment_text": "Conclusion : Collectively , these results demonstrate that Egr-1 is expressed rapidly upon HSV-1 infection and that this novel induction could be due to the NFкB/CREB-mediated transactivation .", "label": "finding"}, {"segment_text": "Egr-1 induction might play a key role in the viral gene expression ,", "label": "finding"}, {"segment_text": "replication , inflammation , and the disease progression .", "label": "finding"}], "n_segments": 22}
{"paper_id": "4fca609594e9a1b98931ae5b431e489db84a98ef", "title": "High-resolution computed tomography manifestations of COVID-19 infections in patients of different ages", "coda_paper_id": 1762, "has_expert_labels": false, "abstract_text": "Purpose : We aimed to compare chest HRCT lung signs identified in scans of differently aged patients with COVID-19 infections . Methods : Case data of patients diagnosed with COVID-19 infection in Hangzhou City , Zhejiang Province in China were collected , and chest HRCT signs of infected patients in four age groups ( < 18 years , 18-44 years , 45-59 years , ≥ 60 years ) were compared . Results : Small patchy , ground-glass opacity ( GGO ) , and consolidations were the main HRCT signs in 98 patients with confirmed COVID-19 infections . Patients aged 45-59 years and aged ≥ 60 years had more bilateral lung , lung lobe , and lung field involvement , and greater lesion numbers than patients < 18 years . GGO accompanied with the interlobular septa thickening or a crazy-paving pattern , consolidation , and air bronchogram sign were more common in patients aged 45-59 years , and ≥ 60 years , than in those aged < 18 years , and aged 18-44 years . Conclusions : Chest HRCT manifestations in patients with COVID-19 are related to patient 's age , and HRCT signs may be milder in younger patients .", "gold_segments": [{"segment_text": "Purpose : We aimed to compare chest HRCT lung signs identified in scans of differently aged patients with COVID-19 infections .", "label": "purpose"}, {"segment_text": "Methods : Case data of patients diagnosed with COVID-19 infection in Hangzhou City ,", "label": "method"}, {"segment_text": "Zhejiang Province in China were collected ,", "label": "method"}, {"segment_text": "and chest HRCT signs of infected patients in four age groups ( < 18 years , 18-44 years , 45-59 years , ≥ 60 years ) were compared .", "label": "method"}, {"segment_text": "Results : Small patchy , ground-glass opacity ( GGO ) ,", "label": "finding"}, {"segment_text": "and consolidations were the main HRCT signs in 98 patients with confirmed COVID-19 infections .", "label": "finding"}, {"segment_text": "Patients aged 45-59 years and aged ≥ 60 years had more bilateral lung ,", "label": "finding"}, {"segment_text": "lung lobe , and lung field involvement ,", "label": "finding"}, {"segment_text": "and greater lesion numbers than patients < 18 years .", "label": "finding"}, {"segment_text": "GGO accompanied with the interlobular septa thickening or a crazy-paving pattern ,", "label": "finding"}, {"segment_text": "consolidation , and air bronchogram sign were more common in patients aged 45-59 years ,", "label": "finding"}, {"segment_text": "and ≥ 60 years , than in those aged < 18 years , and aged 18-44 years .", "label": "finding"}, {"segment_text": "Conclusions : Chest HRCT manifestations in patients with COVID-19 are related to patient 's age ,", "label": "finding"}, {"segment_text": "and HRCT signs may be milder in younger patients .", "label": "finding"}], "n_segments": 14}
{"paper_id": "aad248c894ac1b35e2adad9e23c9cf40dc3c20aa", "title": "Matrix stiffness modulates infection of endothelial cells by Listeria monocytogenes via expression of cell surface vimentin", "coda_paper_id": 1030, "has_expert_labels": false, "abstract_text": "Extracellular matrix stiffness ( ECM ) is one of the many mechanical forces acting on mammalian adherent cells and an important determinant of cellular function . While the effect of ECM stiffness on many aspects of cellular behavior has been studied previously , how ECM stiffness might mediate susceptibility of host cells to infection by bacterial pathogens is hitherto unexplored . To address this open question , we manufactured hydrogels of varying physiologically relevant stiffness and seeded human microvascular endothelial cells ( HMEC-1 ) on them . We then infected HMEC-1 with the bacterial pathogen Listeria monocytogenes ( Lm ) and found that adhesion of Lm to host cells increases monotonically with increasing matrix stiffness , an effect that requires the activity of focal adhesion kinase ( FAK ) . We identified cell surface vimentin as a candidate surface receptor mediating stiffness-dependent adhesion of Lm to HMEC-1 and found that bacterial infection of these host cells is decreased when the amount of surface vimentin is reduced . Our results provide the first evidence that ECM stiffness can mediate the susceptibility of mammalian host cells to infection by a bacterial pathogen . Monitoring Editor", "gold_segments": [{"segment_text": "Extracellular matrix stiffness ( ECM ) is one of the many mechanical forces acting on mammalian adherent cells and an important determinant of cellular function .", "label": "background"}, {"segment_text": "While the effect of ECM stiffness on many aspects of cellular behavior has been studied previously ,", "label": "background"}, {"segment_text": "how ECM stiffness might mediate susceptibility of host cells to infection by bacterial pathogens is hitherto unexplored .", "label": "background"}, {"segment_text": "To address this open question ,", "label": "background"}, {"segment_text": "we manufactured hydrogels of varying physiologically relevant stiffness and seeded human microvascular endothelial cells ( HMEC-1 ) on them .", "label": "method"}, {"segment_text": "We then infected HMEC-1 with the bacterial pathogen Listeria monocytogenes ( Lm ) and found that adhesion of Lm to host cells increases monotonically with increasing matrix stiffness ,", "label": "method"}, {"segment_text": "an effect that requires the activity of focal adhesion kinase ( FAK ) .", "label": "method"}, {"segment_text": "We identified cell surface vimentin as a candidate surface receptor mediating stiffness-dependent adhesion of Lm to HMEC-1 and found that bacterial infection of these host cells is decreased when the amount of surface vimentin is reduced .", "label": "finding"}, {"segment_text": "Our results provide the first evidence that ECM stiffness can mediate the susceptibility of mammalian host cells to infection by a bacterial pathogen .", "label": "finding"}, {"segment_text": "Monitoring Editor", "label": "other"}], "n_segments": 10}
{"paper_id": "c0e510aa2560a27325d969cf822787cb14746c39", "title": "The Control of Microbiological Problems* Methods for controlling the microbiological problems include control of the contamination sources and control of microbiological populations (Blanco et al", "coda_paper_id": 1006, "has_expert_labels": false, "abstract_text": ". The treatment of fresh water and additives , control of the residence time in the storage tanks , and control of the stagnant flow areas should be done to control the contamination sources and the microbiological populations . Systematic maintenance and cleaning of the system by using different chemicals or treatments to reduce the formation of deposits and to eliminate the already formed deposits is required . A microbiological control program requires a good knowledge of the system and the main sources of contamination . Once the sources of contamination have been reduced , the paper manufacturer can control the microbiological populations of the system . Good housekeeping and regular inspection of all areas , effective boilouts , and regularly scheduled washup reduces slime development . To reduce the number of maintenance shutdowns in the paper machines , chemical products are introduced into the system to get rid of the microorganisms by preventing their growth or by reducing the harmful effects they produce . The chemical products most commonly used are dispersants and biocides . Other control methods are the enzymatic degradation of microbiological deposits and controlling the population by limiting nutrients", "gold_segments": [{"segment_text": ".", "label": "other"}, {"segment_text": "The treatment of fresh water and additives ,", "label": "background"}, {"segment_text": "control of the residence time in the storage tanks ,", "label": "background"}, {"segment_text": "and control of the stagnant flow areas should be done to control the contamination sources and the microbiological populations .", "label": "background"}, {"segment_text": "Systematic maintenance and cleaning of the system by using different chemicals or treatments to reduce the formation of deposits and to eliminate the already formed deposits is required .", "label": "background"}, {"segment_text": "A microbiological control program requires a good knowledge of the system and the main sources of contamination .", "label": "background"}, {"segment_text": "Once the sources of contamination have been reduced ,", "label": "background"}, {"segment_text": "the paper manufacturer can control the microbiological populations of the system .", "label": "background"}, {"segment_text": "Good housekeeping and regular inspection of all areas ,", "label": "background"}, {"segment_text": "effective boilouts , and regularly scheduled washup reduces slime development .", "label": "background"}, {"segment_text": "To reduce the number of maintenance shutdowns in the paper machines ,", "label": "method"}, {"segment_text": "chemical products are introduced into the system to get rid of the microorganisms by preventing their growth or by reducing the harmful effects they produce .", "label": "method"}, {"segment_text": "The chemical products most commonly used are dispersants and biocides .", "label": "method"}, {"segment_text": "Other control methods are the enzymatic degradation of microbiological deposits and controlling the population by limiting nutrients", "label": "method"}], "n_segments": 14}
{"paper_id": "ee223f7ec225197050033b2433c8790bac10b5e3", "title": "Study on nucleic acid (CT-DNA and yeast tRNA) binding behaviors and cytotoxic properties of a heterodinuclear Ru(II)-Co(III) polypyridyl complex", "coda_paper_id": 1588, "has_expert_labels": false, "abstract_text": "A heterodinuclear ( Ru ( II ) , Co ( III ) ) metal polypyridyl complex ( ( phen ) 2 Ru ( bpibH 2 ) Co ( phen ) 2 ) 5 + ( phen = 1,10 phenanthroline , bpibH 2 = 1,4-bis ( ( 1,10 ) phebanthroline - ( 5,6-d ) imidazol-2-yl ) - benzene ) has been designed and synthesized . The comparative study on the interactions of the Ru ( II ) - Co ( III ) complex with calf thymus DNA ( CT-DNA ) and yeast tRNA has been investigated by UV-visible spectroscopy , fluorescence spectroscopy , viscosity , as well as equilibrium dialysis and circular dichroism ( CD ) . The antitumor activities of the complex have been evaluated by MTT ( 3 - ( 4,5-dimethylthiazol-2-yl ) -2,5-diphenyltetrazolium bromide ) method and Giemsa staining experiment . These results indicate that the structures of nucleic acids have significant effects on the binding behaviors of metal complexes . Furthermore , the complex demonstrates different antitumor activity against selected tumor cell lines in vitro , and can make the cell apoptosis .", "gold_segments": [{"segment_text": "A heterodinuclear ( Ru ( II ) ,", "label": "method"}, {"segment_text": "Co ( III ) ) metal polypyridyl complex ( ( phen ) 2 Ru ( bpibH 2 ) Co ( phen ) 2 ) 5 + ( phen = 1,10 phenanthroline , bpibH 2 = 1,4-bis ( ( 1,10 ) phebanthroline - ( 5,6-d ) imidazol-2-yl ) - benzene ) has been designed and synthesized .", "label": "method"}, {"segment_text": "The comparative study on the interactions of the Ru ( II ) - Co ( III ) complex with calf thymus DNA ( CT-DNA ) and yeast tRNA has been investigated by UV-visible spectroscopy ,", "label": "method"}, {"segment_text": "fluorescence spectroscopy , viscosity , as well as equilibrium dialysis and circular dichroism ( CD ) .", "label": "method"}, {"segment_text": "The antitumor activities of the complex have been evaluated by MTT ( 3 - ( 4,5-dimethylthiazol-2-yl ) -2,5-diphenyltetrazolium bromide ) method and Giemsa staining experiment .", "label": "method"}, {"segment_text": "These results indicate that the structures of nucleic acids have significant effects on the binding behaviors of metal complexes .", "label": "finding"}, {"segment_text": "Furthermore , the complex demonstrates different antitumor activity against selected tumor cell lines in vitro ,", "label": "finding"}, {"segment_text": "and can make the cell apoptosis .", "label": "finding"}], "n_segments": 8}
{"paper_id": "844952cd4f3326959a4bf2e50bc64ab436b8ded8", "title": "", "coda_paper_id": 1038, "has_expert_labels": false, "abstract_text": "Microbiologic infections acquired from animals , known as zoonoses , pose a risk to public health . An estimated 60 % of emerging human pathogens are zoonotic . Of these pathogens , > 71 % have wildlife origins . These pathogens can switch hosts by acquiring new genetic combinations that have altered pathogenic potential or by changes in behavior or socioeconomic , environmental , or ecologic characteristics of the hosts . We discuss causal factors that infl uence the dynamics associated with emergence or reemergence of zoonoses , particularly in the industrialized world , and highlight selected examples to provide a comprehensive view of their range and diversity .", "gold_segments": [{"segment_text": "Microbiologic infections acquired from animals ,", "label": "background"}, {"segment_text": "known as zoonoses , pose a risk to public health .", "label": "background"}, {"segment_text": "An estimated 60 % of emerging human pathogens are zoonotic .", "label": "background"}, {"segment_text": "Of these pathogens , > 71 % have wildlife origins .", "label": "background"}, {"segment_text": "These pathogens can switch hosts by acquiring new genetic combinations that have altered pathogenic potential or by changes in behavior or socioeconomic ,", "label": "background"}, {"segment_text": "environmental , or ecologic characteristics of the hosts .", "label": "background"}, {"segment_text": "We discuss causal factors that infl uence the dynamics associated with emergence or reemergence of zoonoses ,", "label": "purpose"}, {"segment_text": "particularly in the industrialized world ,", "label": "purpose"}, {"segment_text": "and highlight selected examples to provide a comprehensive view of their range and diversity .", "label": "purpose"}], "n_segments": 9}
{"paper_id": "a0617aeba1fe75917aa23e6597ee84bf932b012f", "title": "Chemical and Physical Signatures for Microbial Forensics", "coda_paper_id": 1971, "has_expert_labels": false, "abstract_text": "This chapter is meant to ( 1 ) review classical methods used to characterize and classify microbes and ( 2 ) introduce new molecular methods used in microbial characterization . The fundamental composition of microbes is discussed as well as their importance in classifi cation of microbes into genus and species . Classical microbiological methods in general seek to defi ne the common features of specifi c bacterial groups as a means of classifi cation and identifi cation of microbes . Thus , the focus was to describe the common features which discriminated closely related groups of organisms . In contrast , the newer molecular methods often seek to expand the classification of microbes not only as a means to organize microbial phylogeny but also to differentiate signatures between microbes identifi ed within a species in greater detail . Molecular biology tools are used both as an adjunct to established methods and as replacement for classical methods for detection , discrimination , or identifi cation of bacterial and viral species . 2.1", "gold_segments": [{"segment_text": "This chapter is meant to ( 1 ) review classical methods used to characterize and classify microbes and ( 2 ) introduce new molecular methods used in microbial characterization .", "label": "purpose"}, {"segment_text": "The fundamental composition of microbes is discussed as well as their importance in classifi cation of microbes into genus and species .", "label": "background"}, {"segment_text": "Classical microbiological methods in general seek to defi ne the common features of specifi c bacterial groups as a means of classifi cation and identifi cation of microbes .", "label": "background"}, {"segment_text": "Thus , the focus was to describe the common features which discriminated closely related groups of organisms .", "label": "background"}, {"segment_text": "In contrast , the newer molecular methods often seek to expand the classification of microbes not only as a means to organize microbial phylogeny but also to differentiate signatures between microbes identifi ed within a species in greater detail .", "label": "background"}, {"segment_text": "Molecular biology tools are used both as an adjunct to established methods and as replacement for classical methods for detection ,", "label": "background"}, {"segment_text": "discrimination , or identifi cation of bacterial and viral species .", "label": "background"}, {"segment_text": "2.1", "label": "other"}], "n_segments": 8}
{"paper_id": "7b6d4793dd3746e9292feba95dab38ff505905be", "title": "Defining high-value information for COVID-19 decision-making COVID-19 Statistics, Policy modeling and Epidemiology Collective (C-SPEC) 1", "coda_paper_id": 1979, "has_expert_labels": false, "abstract_text": "Initial projections from the first generation of COVID-19 models focused public attention on worst-case scenarios in the absence of decisive policy action . These underscored the imperative for strong and immediate measures to slow the spread of infection . In the coming weeks , however , as policymakers continue enlisting models to inform decisions on COVID-19 , answers to the most difficult and pressing policy questions will be much more sensitive to underlying uncertainties . In this study , we demonstrate a model-based approach to assessing the potential value of reducing critical uncertainties most salient to COVID-19 decision-making and discuss priorities for acquiring new data to reduce these uncertainties . We demonstrate how information about the impact of non-pharmaceutical interventions could narrow prediction intervals around hospitalizations over the next few weeks , while information about the prevalence of undetected cases could narrow prediction intervals around the timing and height of the peak of the epidemic .", "gold_segments": [{"segment_text": "Initial projections from the first generation of COVID-19 models focused public attention on worst-case scenarios in the absence of decisive policy action .", "label": "background"}, {"segment_text": "These underscored the imperative for strong and immediate measures to slow the spread of infection .", "label": "background"}, {"segment_text": "In the coming weeks , however ,", "label": "background"}, {"segment_text": "as policymakers continue enlisting models to inform decisions on COVID-19 ,", "label": "background"}, {"segment_text": "answers to the most difficult and pressing policy questions will be much more sensitive to underlying uncertainties .", "label": "background"}, {"segment_text": "In this study , we demonstrate a model-based approach to assessing the potential value of reducing critical uncertainties most salient to COVID-19 decision-making and discuss priorities for acquiring new data to reduce these uncertainties .", "label": "purpose"}, {"segment_text": "We demonstrate how information about the impact of non-pharmaceutical interventions could narrow prediction intervals around hospitalizations over the next few weeks ,", "label": "purpose"}, {"segment_text": "while information about the prevalence of undetected cases could narrow prediction intervals around the timing and height of the peak of the epidemic .", "label": "purpose"}], "n_segments": 8}
{"paper_id": "311d140154026feab3f47bedda187565a9b1641f", "title": "Dual roles of calpain in facilitating Coxsackievirus B3 replication and prompting inflammation in acute myocarditis", "coda_paper_id": 1627, "has_expert_labels": false, "abstract_text": "Background : Viral myocarditis ( VMC ) treatment has long been lacking of effective methods . Our former studies indicated roles of calpain in VMC pathogenesis . This study aimed at verifying the potential of calpain in Coxsackievirus B3 ( CVB3 ) - induced myocarditis treatment . Methods : A transgenic mouse overexpressing the endogenous calpain inhibitor , calpastatin , was introduced in the study . VMC mouse model was established via intraperitoneal injection of CVB3 in transgenic and wild mouse respectively . Myocardial injury was assayed histologically ( HE staining and pathology grading ) and serologically ( myocardial damage markers of CK-MB and cTnI ) . CVB3 replication was observed in vivo and in vitro via the capsid protein VP1 detection or virus titration . Inflammation/fibrotic factors of MPO , perforin , IFNγ , IL17 , Smad3 and MMP2 were evaluated using western blot or immunohistology stain . Role of calpain in regulating fibroblast migration was studied in scratch assays . Results : Calpastatin overexpression ameliorated myocardial injury induced by CVB3 infection significantly in transgenic mouse indicated by reduced peripheral CK-MB and cTnI levels and improved histology injury . Comparing with CVB3-infected wild type mouse , the transgenic mouse heart tissue carried lower virus load . The inflammation factors of MPO , perforin , IFNγ and IL17 were down-regulated accompanied with fibrotic agents of Smad3 and MMP2 inhibition . And calpain participated in the migration of fibroblasts in vitro , which further proves its role in regulating fibrosis . Conclusion : Calpain plays dual roles of facilitating CVB3 replication and inflammation promotion . Calpain inhibition in CVB3-induced myocarditis showed significant treatment effect . Calpain might be a novel target for VMC treatment in clinical practices .", "gold_segments": [{"segment_text": "Background : Viral myocarditis ( VMC ) treatment has long been lacking of effective methods .", "label": "background"}, {"segment_text": "Our former studies indicated roles of calpain in VMC pathogenesis .", "label": "background"}, {"segment_text": "This study aimed at verifying the potential of calpain in Coxsackievirus B3 ( CVB3 ) - induced myocarditis treatment .", "label": "purpose"}, {"segment_text": "Methods : A transgenic mouse overexpressing the endogenous calpain inhibitor ,", "label": "method"}, {"segment_text": "calpastatin , was introduced in the study .", "label": "method"}, {"segment_text": "VMC mouse model was established via intraperitoneal injection of CVB3 in transgenic and wild mouse respectively .", "label": "method"}, {"segment_text": "Myocardial injury was assayed histologically ( HE staining and pathology grading ) and serologically ( myocardial damage markers of CK-MB and cTnI ) .", "label": "method"}, {"segment_text": "CVB3 replication was observed in vivo and in vitro via the capsid protein VP1 detection or virus titration .", "label": "method"}, {"segment_text": "Inflammation/fibrotic factors of MPO , perforin ,", "label": "method"}, {"segment_text": "IFNγ , IL17 , Smad3 and MMP2 were evaluated using western blot or immunohistology stain .", "label": "method"}, {"segment_text": "Role of calpain in regulating fibroblast migration was studied in scratch assays .", "label": "method"}, {"segment_text": "Results : Calpastatin overexpression ameliorated myocardial injury induced by CVB3 infection significantly in transgenic mouse indicated by reduced peripheral CK-MB and cTnI levels and improved histology injury .", "label": "finding"}, {"segment_text": "Comparing with CVB3-infected wild type mouse ,", "label": "finding"}, {"segment_text": "the transgenic mouse heart tissue carried lower virus load .", "label": "finding"}, {"segment_text": "The inflammation factors of MPO ,", "label": "finding"}, {"segment_text": "perforin , IFNγ and IL17 were down-regulated accompanied with fibrotic agents of Smad3 and MMP2 inhibition .", "label": "finding"}, {"segment_text": "And calpain participated in the migration of fibroblasts in vitro ,", "label": "finding"}, {"segment_text": "which further proves its role in regulating fibrosis .", "label": "finding"}, {"segment_text": "Conclusion : Calpain plays dual roles of facilitating CVB3 replication and inflammation promotion .", "label": "finding"}, {"segment_text": "Calpain inhibition in CVB3-induced myocarditis showed significant treatment effect .", "label": "finding"}, {"segment_text": "Calpain might be a novel target for VMC treatment in clinical practices .", "label": "finding"}], "n_segments": 21}
{"paper_id": "405178382d43ce2210f9573baba85368387e44f9", "title": "Composition bias and genome polarity of RNA viruses", "coda_paper_id": 1916, "has_expert_labels": false, "abstract_text": "I have observed a relationship between GC content in coding sequences of RNA viruses and their genome polarity . Positive-stranded RNA viruses have significantly higher GC contents than negative-stranded RNA viruses . Coding sequences of all negative-stranded RNA viruses are biased toward high A in coding strands ( high T in genomes ) , while two distinct patterns were observed among positive-stranded RNA genomes . This finding suggests that RNA viruses with different genome polarity are under different mutational pressure , which may be a consequence of the difference in the strategies of viral genome expression and replication . The GC content directly affects the viral codon adaptation index using highly expressed human genes as the reference set , which may theoretically predict the efficiency of viral gene expression in human cells .", "gold_segments": [{"segment_text": "I have observed a relationship between GC content in coding sequences of RNA viruses and their genome polarity .", "label": "method"}, {"segment_text": "Positive-stranded RNA viruses have significantly higher GC contents than negative-stranded RNA viruses .", "label": "finding"}, {"segment_text": "Coding sequences of all negative-stranded RNA viruses are biased toward high A in coding strands ( high T in genomes ) ,", "label": "finding"}, {"segment_text": "while two distinct patterns were observed among positive-stranded RNA genomes .", "label": "finding"}, {"segment_text": "This finding suggests that RNA viruses with different genome polarity are under different mutational pressure ,", "label": "finding"}, {"segment_text": "which may be a consequence of the difference in the strategies of viral genome expression and replication .", "label": "finding"}, {"segment_text": "The GC content directly affects the viral codon adaptation index using highly expressed human genes as the reference set ,", "label": "finding"}, {"segment_text": "which may theoretically predict the efficiency of viral gene expression in human cells .", "label": "finding"}], "n_segments": 8}
{"paper_id": "b16e9ad986a7b19e35e008a79293bba8fb2c6787", "title": "A Note on the Risk of Infections Invading Unaffected Regions", "coda_paper_id": 1863, "has_expert_labels": false, "abstract_text": "We present two probabilistic models to estimate the risk of introducing infectious diseases into previously unaffected countries/regions by infective travellers . We analyse two distinct situations , one dealing with a directly transmitted infection ( measles in Italy in 2017 ) and one dealing with a vector-borne infection ( Zika virus in Rio de Janeiro , which may happen in the future ) . To calculate the risk in the first scenario , we used a simple , nonhomogeneous birth process . The second model proposed in this paper provides a way to calculate the probability that local mosquitoes become infected by the arrival of a single infective traveller during his/her infectiousness period . The result of the risk of measles invasion of Italy was of 93 % and the result of the risk of Zika virus invasion of Rio de Janeiro was of 22 % .", "gold_segments": [{"segment_text": "We present two probabilistic models to estimate the risk of introducing infectious diseases into previously unaffected countries/regions by infective travellers .", "label": "background"}, {"segment_text": "We analyse two distinct situations ,", "label": "method"}, {"segment_text": "one dealing with a directly transmitted infection ( measles in Italy in 2017 ) and one dealing with a vector-borne infection ( Zika virus in Rio de Janeiro , which may happen in the future ) .", "label": "method"}, {"segment_text": "To calculate the risk in the first scenario ,", "label": "method"}, {"segment_text": "we used a simple , nonhomogeneous birth process .", "label": "method"}, {"segment_text": "The second model proposed in this paper provides a way to calculate the probability that local mosquitoes become infected by the arrival of a single infective traveller during his/her infectiousness period .", "label": "method"}, {"segment_text": "The result of the risk of measles invasion of Italy was of 93 % and the result of the risk of Zika virus invasion of Rio de Janeiro was of 22 % .", "label": "finding"}], "n_segments": 7}
{"paper_id": "bf0c1b6cbc176fc65868fcf129c2de48829a12dc", "title": "Journal of the Pediatric Infectious Diseases Society Expanding Existing Antimicrobial Stewardship Programs in Pediatrics: What Comes Next", "coda_paper_id": 1337, "has_expert_labels": false, "abstract_text": "The prevalence of pediatric antimicrobial stewardship programs ( ASPs ) is increasing in acute care facilities across the United States . Over the past several years , the evidence base used to inform effective stewardship practices has expanded , and regulatory interest in stewardship programs has increased . Here , we review approaches for established , hospital-based pediatric ASPs to adapt and report standardized metrics , broaden their reach to specialized populations , expand to undertake novel stewardship initiatives , and implement rapid diagnostics to continue their evolution in improving antimicrobial use and patient outcomes .", "gold_segments": [{"segment_text": "The prevalence of pediatric antimicrobial stewardship programs ( ASPs ) is increasing in acute care facilities across the United States .", "label": "background"}, {"segment_text": "Over the past several years ,", "label": "background"}, {"segment_text": "the evidence base used to inform effective stewardship practices has expanded ,", "label": "background"}, {"segment_text": "and regulatory interest in stewardship programs has increased .", "label": "background"}, {"segment_text": "Here , we review approaches for established ,", "label": "purpose"}, {"segment_text": "hospital-based pediatric ASPs to adapt and report standardized metrics ,", "label": "purpose"}, {"segment_text": "broaden their reach to specialized populations ,", "label": "purpose"}, {"segment_text": "expand to undertake novel stewardship initiatives ,", "label": "purpose"}, {"segment_text": "and implement rapid diagnostics to continue their evolution in improving antimicrobial use and patient outcomes .", "label": "finding"}], "n_segments": 9}
{"paper_id": "920282c7a0656a43143be9b656b36367cf871c08", "title": "Combination Therapy Using Chimeric Monoclonal Antibodies Protects Mice from Lethal H5N1 Infection and Prevents Formation of Escape Mutants", "coda_paper_id": 1826, "has_expert_labels": false, "abstract_text": "Background : Given that there is a possibility of a human H5N1 pandemic and the fact that the recent H5N1 viruses are resistant to the anti-viral drugs , newer strategies for effective therapy are warranted . Previous studies show that single mAbs in immune prophylaxis can be protective against H5N1 infection . But a single mAb may not be effective in neutralization of a broad range of different strains of H5N1 and control of potential neutralization escape mutants . Methods/Principal Findings : We selected two mAbs which recognized different epitopes on the hemagglutinin molecule . These two mAbs could each neutralize in vitro escape mutants to the other and in combination could effectively neutralize viruses from clades 0 , 1 , 2.1 , 2.2 , 2.3 , 4 , 7 and 8 of influenza A H5N1 viruses . This combination of chimeric mAbs when administered passively , pre or post challenge with 10 MLD50 ( 50 % mouse lethal dose ) HPAI H5N1 influenza A viruses could protect 100 % of the mice from two different clades of viruses ( clades 1 and 2.1 ) . We also tested the efficacy of a single dose of the combination of mAbs versus two doses . Two doses of the combination therapy not only affected early clearance of the virus from the lung but could completely prevent lung pathology of the H5N1 infected mice . No escape variants were detected after therapy . Conclusions/Significance : Our studies provide proof of concept that the synergistic action of two or more mAbs in combination is required for preventing the generation of escape mutants and also to enhance the therapeutic efficacy of passive therapy against H5N1 infection . Combination therapy may allow for a lower dose of antibody to be administered for passive therapy of influenza infection and hence can be made available at reduced economic costs during an outbreak .", "gold_segments": [{"segment_text": "Background : Given that there is a possibility of a human H5N1 pandemic and the fact that the recent H5N1 viruses are resistant to the anti-viral drugs ,", "label": "background"}, {"segment_text": "newer strategies for effective therapy are warranted .", "label": "background"}, {"segment_text": "Previous studies show that single mAbs in immune prophylaxis can be protective against H5N1 infection .", "label": "background"}, {"segment_text": "But a single mAb may not be effective in neutralization of a broad range of different strains of H5N1 and control of potential neutralization escape mutants .", "label": "background"}, {"segment_text": "Methods/Principal Findings : We selected two mAbs which recognized different epitopes on the hemagglutinin molecule .", "label": "method"}, {"segment_text": "These two mAbs could each neutralize in vitro escape mutants to the other and in combination could effectively neutralize viruses from clades 0 ,", "label": "method"}, {"segment_text": "1 , 2.1 , 2.2 ,", "label": "method"}, {"segment_text": "2.3 , 4 , 7 and 8 of influenza A H5N1 viruses .", "label": "method"}, {"segment_text": "This combination of chimeric mAbs when administered passively ,", "label": "finding"}, {"segment_text": "pre or post challenge with 10 MLD50 ( 50 % mouse lethal dose ) HPAI H5N1 influenza A viruses could protect 100 % of the mice from two different clades of viruses ( clades 1 and 2.1 ) .", "label": "finding"}, {"segment_text": "We also tested the efficacy of a single dose of the combination of mAbs versus two doses .", "label": "method"}, {"segment_text": "Two doses of the combination therapy not only affected early clearance of the virus from the lung but could completely prevent lung pathology of the H5N1 infected mice .", "label": "finding"}, {"segment_text": "No escape variants were detected after therapy .", "label": "finding"}, {"segment_text": "Conclusions/Significance : Our studies provide proof of concept that the synergistic action of two or more mAbs in combination is required for preventing the generation of escape mutants and also to enhance the therapeutic efficacy of passive therapy against H5N1 infection .", "label": "finding"}, {"segment_text": "Combination therapy may allow for a lower dose of antibody to be administered for passive therapy of influenza infection and hence can be made available at reduced economic costs during an outbreak .", "label": "finding"}], "n_segments": 15}
{"paper_id": "27d6ec2664104ba3347a3991ce63d20ebae32d39", "title": "Isolation of Middle East Respiratory Syndrome Coronavirus from a Patient of the 2015 Korean Outbreak", "coda_paper_id": 1929, "has_expert_labels": false, "abstract_text": "During the 2015 outbreak of Middle East respiratory syndrome coronavirus ( MERS-CoV ) in Korea , 186 persons were infected , resulting in 38 fatalities . We isolated MERS-CoV from the oropharyngeal sample obtained from a patient of the outbreak . Cytopathic effects showing detachment and rounding of cells were observed in Vero cell cultures 3 days after inoculation of the sample . Spherical virus particles were observed by transmission electron microscopy . Full-length genome sequence of the virus isolate was obtained and phylogenetic analyses showed that it clustered with clade B of MERS-CoV .", "gold_segments": [{"segment_text": "During the 2015 outbreak of Middle East respiratory syndrome coronavirus ( MERS-CoV ) in Korea ,", "label": "background"}, {"segment_text": "186 persons were infected , resulting in 38 fatalities .", "label": "background"}, {"segment_text": "We isolated MERS-CoV from the oropharyngeal sample obtained from a patient of the outbreak .", "label": "background"}, {"segment_text": "Cytopathic effects showing detachment and rounding of cells were observed in Vero cell cultures 3 days after inoculation of the sample .", "label": "finding"}, {"segment_text": "Spherical virus particles were observed by transmission electron microscopy .", "label": "finding"}, {"segment_text": "Full-length genome sequence of the virus isolate was obtained and phylogenetic analyses showed that it clustered with clade B of MERS-CoV .", "label": "finding"}], "n_segments": 6}
{"paper_id": "9b7bce91950139e59234302c89d3d98ad13ca6da", "title": "Roles for the Recycling Endosome, Rab8, and Rab11 in hantavirus release from epithelial cells", "coda_paper_id": 1951, "has_expert_labels": false, "abstract_text": "Hantavirus structural proteins are believed to localize to intracellular membranes often identified as Golgi membranes , in virus-infected cells . After virus budding into the Golgi luminal space , viruscontaining vesicles are transported to the plasma membrane via trafficking pathways that are not well defined . Using the New World hantavirus , Andes virus , we have investigated the role of various Rab proteins in the release of hantavirus particles from infected cells . Rabs 8 and 11 were found to colocalize with Andes virus proteins in virus infected cells and when expressed from cDNA , implicating the recycling endosome as an organelle important for hantavirus infection . Small interfering RNA-mediated downregulation of Rab11a alone or Rab11a and Rab11b together resulted in a decrease in infectious virus particle secretion from infected cells . Downregulation of Rab8a did not alter infectious virus release but reduction of both isoforms did . These data implicate the recycling endosome and the Rab proteins associated with vesicular transport to or from this intracellular organelle as an important pathway for hantavirus trafficking to the plasma membrane .", "gold_segments": [{"segment_text": "Hantavirus structural proteins are believed to localize to intracellular membranes often identified as Golgi membranes , in virus-infected cells .", "label": "background"}, {"segment_text": "After virus budding into the Golgi luminal space ,", "label": "background"}, {"segment_text": "viruscontaining vesicles are transported to the plasma membrane via trafficking pathways that are not well defined .", "label": "background"}, {"segment_text": "Using the New World hantavirus ,", "label": "method"}, {"segment_text": "Andes virus , we have investigated the role of various Rab proteins in the release of hantavirus particles from infected cells .", "label": "method"}, {"segment_text": "Rabs 8 and 11 were found to colocalize with Andes virus proteins in virus infected cells and when expressed from cDNA ,", "label": "finding"}, {"segment_text": "implicating the recycling endosome as an organelle important for hantavirus infection .", "label": "finding"}, {"segment_text": "Small interfering RNA-mediated downregulation of Rab11a alone or Rab11a and Rab11b together resulted in a decrease in infectious virus particle secretion from infected cells .", "label": "finding"}, {"segment_text": "Downregulation of Rab8a did not alter infectious virus release but reduction of both isoforms did .", "label": "finding"}, {"segment_text": "These data implicate the recycling endosome and the Rab proteins associated with vesicular transport to or from this intracellular organelle as an important pathway for hantavirus trafficking to the plasma membrane .", "label": "finding"}], "n_segments": 10}
{"paper_id": "638ba967f1c12d3d5c228dd04ea6aabca923b69c", "title": "Pharmaceutical and biomedical applications of surface engineered carbon nanotubes", "coda_paper_id": 1842, "has_expert_labels": false, "abstract_text": "Surface engineered carbon nanotubes ( CNTs ) are attracting recent attention of scientists owing to their vivid biomedical and pharmaceutical applications . The focus of this review is to highlight the important role of surface engineered CNTs in the highly challenging but rewarding area of nanotechnology . The major strength of this review lies in highlighting the exciting applications of CNTs to boost the research efforts , which unfortunately are otherwise scattered in the literature making the reading non-coherent and non-homogeneous . Reviews POST SCREEN", "gold_segments": [{"segment_text": "Surface engineered carbon nanotubes ( CNTs ) are attracting recent attention of scientists owing to their vivid biomedical and pharmaceutical applications .", "label": "background"}, {"segment_text": "The focus of this review is to highlight the important role of surface engineered CNTs in the highly challenging but rewarding area of nanotechnology .", "label": "purpose"}, {"segment_text": "The major strength of this review lies in highlighting the exciting applications of CNTs to boost the research efforts ,", "label": "purpose"}, {"segment_text": "which unfortunately are otherwise scattered in the literature making the reading non-coherent and non-homogeneous .", "label": "finding"}, {"segment_text": "Reviews POST SCREEN", "label": "other"}], "n_segments": 5}
{"paper_id": "fa9460f462e92e3ccbecc0e9fe406b886b7c1e35", "title": "The Moraxella adhesin UspA1 binds to its human CEACAM1 receptor by a deformable trimeric coiled-coil", "coda_paper_id": 1789, "has_expert_labels": false, "abstract_text": "Moraxella catarrhalis is a ubiquitous human-specific bacterium commonly associated with upper and lower respiratory tract infections , including otitis media , sinusitis and chronic obstructive pulmonary disease . The bacterium uses an autotransporter protein UspA1 to target an important human cellular receptor carcinoembryonic antigen-related cell adhesion molecule 1 ( CEACAM1 ) . Using X-ray crystallography , we show that the CEACAM1 receptor-binding region of UspA1 unusually consists of an extended , rod-like left-handed trimeric coiled-coil . Mutagenesis and binding studies of UspA1 and the N-domain of CEACAM1 have been used to delineate the interacting surfaces between ligand and receptor and guide assembly of the complex . However , solution scattering , molecular modelling and electron microscopy analyses all indicate that significant bending of the UspA1 coiled-coil stalk also occurs . This explains how UspA1 can engage CEACAM1 at a site far distant from its head group , permitting closer proximity of the respective cell surfaces during infection .", "gold_segments": [{"segment_text": "Moraxella catarrhalis is a ubiquitous human-specific bacterium commonly associated with upper and lower respiratory tract infections ,", "label": "background"}, {"segment_text": "including otitis media , sinusitis and chronic obstructive pulmonary disease .", "label": "background"}, {"segment_text": "The bacterium uses an autotransporter protein UspA1 to target an important human cellular receptor carcinoembryonic antigen-related cell adhesion molecule 1 ( CEACAM1 ) .", "label": "background"}, {"segment_text": "Using X-ray crystallography , we show that the CEACAM1 receptor-binding region of UspA1 unusually consists of an extended , rod-like left-handed trimeric coiled-coil .", "label": "background"}, {"segment_text": "Mutagenesis and binding studies of UspA1 and the N-domain of CEACAM1 have been used to delineate the interacting surfaces between ligand and receptor and guide assembly of the complex .", "label": "background"}, {"segment_text": "However , solution scattering , molecular modelling and electron microscopy analyses all indicate that significant bending of the UspA1 coiled-coil stalk also occurs .", "label": "finding"}, {"segment_text": "This explains how UspA1 can engage CEACAM1 at a site far distant from its head group ,", "label": "finding"}, {"segment_text": "permitting closer proximity of the respective cell surfaces during infection .", "label": "finding"}], "n_segments": 8}
{"paper_id": "b07181f9086788a6a4f7de90129118352320e993", "title": "SURVEY AND SUMMARY Miniaturized PCR chips for nucleic acid amplification and analysis: latest advances and future trends", "coda_paper_id": 1611, "has_expert_labels": false, "abstract_text": "The possibility of performing fast and small-volume nucleic acid amplification and analysis on a single chip has attracted great interest . Devices based on this idea , referred to as micro total analysis , microfluidic analysis , or simply ` Lab on a chip ' systems , have witnessed steady advances over the last several years . Here , we summarize recent research on chip substrates , surface treatments , PCR reaction volume and speed , architecture , approaches to eliminating cross-contamination and control and measurement of temperature and liquid flow . We also discuss product-detection methods , integration of functional components , biological samples used in PCR chips , potential applications and other practical issues related to implementation of lab-on-a-chip technologies . SUBSTRATES AND SURFACE TREATMENTS TO REDUCE BIOMOLECULE ADSORPTION Most PCR microchambers or microchannels are fabricated from silicon ( 10-25 ) or glass ( 26-36 ) substrate . Polymers , such as polydimethylsiloxane ( PDMS ) ( 37-55 ) , polycarbonate ( PC ) ( 56-63 ) and polymethylmethacrylate ( PMMA ) ( 64-68 ) have increasingly been utilized as alternative substrates . New substrates , such as SU-8", "gold_segments": [{"segment_text": "The possibility of performing fast and small-volume nucleic acid amplification and analysis on a single chip has attracted great interest .", "label": "background"}, {"segment_text": "Devices based on this idea ,", "label": "background"}, {"segment_text": "referred to as micro total analysis ,", "label": "background"}, {"segment_text": "microfluidic analysis , or simply ` Lab on a chip ' systems ,", "label": "background"}, {"segment_text": "have witnessed steady advances over the last several years .", "label": "background"}, {"segment_text": "Here , we summarize recent research on chip substrates ,", "label": "purpose"}, {"segment_text": "surface treatments , PCR reaction volume and speed ,", "label": "purpose"}, {"segment_text": "architecture , approaches to eliminating cross-contamination and control and measurement of temperature and liquid flow .", "label": "purpose"}, {"segment_text": "We also discuss product-detection methods ,", "label": "purpose"}, {"segment_text": "integration of functional components , biological samples used in PCR chips ,", "label": "purpose"}, {"segment_text": "potential applications and other practical issues related to implementation of lab-on-a-chip technologies .", "label": "purpose"}, {"segment_text": "SUBSTRATES AND SURFACE TREATMENTS TO REDUCE BIOMOLECULE ADSORPTION", "label": "finding"}, {"segment_text": "Most PCR microchambers or microchannels are fabricated from silicon ( 10-25 ) or glass ( 26-36 ) substrate .", "label": "finding"}, {"segment_text": "Polymers , such as polydimethylsiloxane ( PDMS ) ( 37-55 ) ,", "label": "finding"}, {"segment_text": "polycarbonate ( PC ) ( 56-63 ) and polymethylmethacrylate ( PMMA ) ( 64-68 ) have increasingly been utilized as alternative substrates .", "label": "finding"}, {"segment_text": "New substrates , such as SU-8", "label": "finding"}], "n_segments": 16}
{"paper_id": "5ce2148b1fe00d0eb0889498822638393a80f084", "title": "Nanoscale Structure Determination of Murray Valley Encephalitis and Powassan Virus Non-Coding RNAs", "coda_paper_id": 1200, "has_expert_labels": false, "abstract_text": "Viral infections are responsible for numerous deaths worldwide . Flaviviruses , which contain RNA as their genetic material , are one of the most pathogenic families of viruses . There is an increasing amount of evidence suggesting that their 5 ' and 3 ' non-coding terminal regions are critical for their survival . Information on their structural features is essential to gain detailed insights into their functions and interactions with host proteins . In this study , the 5 ' and 3 ' terminal regions of Murray Valley encephalitis virus and Powassan virus were examined using biophysical and computational modeling methods . First , we used size exclusion chromatography and analytical ultracentrifuge methods to investigate the purity of in-vitro transcribed RNAs . Next , we employed small-angle X-ray scattering techniques to study solution conformation and low-resolution structures of these RNAs , which suggest that the 3 ' terminal regions are highly extended as compared to the 5 ' terminal regions for both viruses . Using computational modeling tools , we reconstructed 3-dimensional structures of each RNA fragment and compared them with derived small-angle X-ray scattering low-resolution structures . This approach allowed us to reinforce that the 5 ' terminal regions adopt more dynamic structures compared to the mainly double-stranded structures of the 3 ' terminal regions . Supplementary Materials : The following are available online at https://www.mdpi.com/1999-4915/12/2/190/s1 . Figure S1 : Sequence alignment of 5 ' ( top panel , first 95 nucleotides ) and 3 ' ( bottom panel , last 101 nucleotides ) TRs of Powassan , Murray valley encephalitis , dengue , and West Nile viruses ; Figure S2 : The lowest energy structures of MVEV and PowV 5 ' and 3 ' terminal regions are presented in Figure 1 .", "gold_segments": [{"segment_text": "Viral infections are responsible for numerous deaths worldwide .", "label": "background"}, {"segment_text": "Flaviviruses , which contain RNA as their genetic material ,", "label": "background"}, {"segment_text": "are one of the most pathogenic families of viruses .", "label": "background"}, {"segment_text": "There is an increasing amount of evidence suggesting that their 5 ' and 3 ' non-coding terminal regions are critical for their survival .", "label": "background"}, {"segment_text": "Information on their structural features is essential to gain detailed insights into their functions and interactions with host proteins .", "label": "background"}, {"segment_text": "In this study , the 5 ' and 3 ' terminal regions of Murray Valley encephalitis virus and Powassan virus were examined using biophysical and computational modeling methods .", "label": "method"}, {"segment_text": "First , we used size exclusion chromatography and analytical ultracentrifuge methods to investigate the purity of in-vitro transcribed RNAs .", "label": "method"}, {"segment_text": "Next , we employed small-angle X-ray scattering techniques to study solution conformation and low-resolution structures of these RNAs ,", "label": "method"}, {"segment_text": "which suggest that the 3 ' terminal regions are highly extended as compared to the 5 ' terminal regions for both viruses .", "label": "method"}, {"segment_text": "Using computational modeling tools , we reconstructed 3-dimensional structures of each RNA fragment and compared them with derived small-angle X-ray scattering low-resolution structures .", "label": "method"}, {"segment_text": "This approach allowed us to reinforce that the 5 ' terminal regions adopt more dynamic structures compared to the mainly double-stranded structures of the 3 ' terminal regions .", "label": "finding"}, {"segment_text": "Supplementary Materials : The following are available online at https://www.mdpi.com/1999-4915/12/2/190/s1 .", "label": "finding"}, {"segment_text": "Figure S1 : Sequence alignment of 5 ' ( top panel , first 95 nucleotides ) and 3 ' ( bottom panel , last 101 nucleotides ) TRs of Powassan ,", "label": "finding"}, {"segment_text": "Murray valley encephalitis , dengue ,", "label": "finding"}, {"segment_text": "and West Nile viruses ; Figure S2 : The lowest energy structures of MVEV and PowV 5 ' and 3 ' terminal regions are presented in Figure 1 .", "label": "finding"}], "n_segments": 15}
{"paper_id": "d4f9da845a7cd9ffab610124c8609d01e598ce9d", "title": "Isolation of influenza viruses in MDCK 33016PF cells and clearance of contaminating respiratory viruses", "coda_paper_id": 1346, "has_expert_labels": false, "abstract_text": "This paper summarizes results obtained by multiplex PCR screening of human clinical samples for respiratory viruses and corresponding data obtained after passaging of virus-positive samples in MDCK 33016PF cells . Using the ResPlexII v2 .0 ( Qiagen ) multiplex PCR , 393 positive results were obtained in 468 clinical samples collected during an influenza season in Germany . The overall distribution of positive results was influenza A 42.0 % , influenza B 38.7 % , adenovirus 1.5 % , bocavirus 0.5 % , coronavirus 3.3 % , enterovirus 5.6 % , metapneumovirus 1.0 % , parainfluenza virus 0.8 % , rhinovirus 4.1 % , and respiratory syncytial virus ( RSV ) 2.5 % . Double infections of influenza virus together with another virus were found for adenovirus B and E , bocavirus , coronavirus , enterovirus and for rhinovirus . These other viruses were rapidly lost upon passages in MDCK 33016PF cells and under conditions as applied to influenza virus passaging . Clinical samples , in which no influenza virus but other viruses were found , were also subject to passages in MDCK 33016PF cells . Using lower inoculum dilutions than those normally applied for preparations containing influenza virus ( total dilution of the original sample of ∼ 10 4 ) , the positive results for the different viruses turned negative already after 2 or 3 passages in MDCK 33016PF cells . These results demonstrate that , under practical conditions as applied to grow influenza viruses , contaminating viruses can be effectively removed by passages in MDCK cells . In combination with their superior isolation efficiency , MDCK cells appear highly suitable to be used as an alternative to embryonated eggs to isolate and propagate influenza vaccine candidate viruses .", "gold_segments": [{"segment_text": "This paper summarizes results obtained by multiplex PCR screening of human clinical samples for respiratory viruses and corresponding data obtained after passaging of virus-positive samples in MDCK 33016PF cells .", "label": "purpose"}, {"segment_text": "Using the ResPlexII v2 .0 ( Qiagen ) multiplex PCR ,", "label": "method"}, {"segment_text": "393 positive results were obtained in 468 clinical samples collected during an influenza season in Germany .", "label": "method"}, {"segment_text": "The overall distribution of positive results was influenza A 42.0 % ,", "label": "finding"}, {"segment_text": "influenza B 38.7 % , adenovirus 1.5 % ,", "label": "finding"}, {"segment_text": "bocavirus 0.5 % , coronavirus 3.3 % ,", "label": "finding"}, {"segment_text": "enterovirus 5.6 % , metapneumovirus 1.0 % ,", "label": "finding"}, {"segment_text": "parainfluenza virus 0.8 % , rhinovirus 4.1 % ,", "label": "finding"}, {"segment_text": "and respiratory syncytial virus ( RSV ) 2.5 % .", "label": "finding"}, {"segment_text": "Double infections of influenza virus together with another virus were found for adenovirus B and E ,", "label": "finding"}, {"segment_text": "bocavirus , coronavirus , enterovirus and for rhinovirus .", "label": "finding"}, {"segment_text": "These other viruses were rapidly lost upon passages in MDCK 33016PF cells and under conditions as applied to influenza virus passaging .", "label": "finding"}, {"segment_text": "Clinical samples , in which no influenza virus but other viruses were found ,", "label": "finding"}, {"segment_text": "were also subject to passages in MDCK 33016PF cells .", "label": "finding"}, {"segment_text": "Using lower inoculum dilutions than those normally applied for preparations containing influenza virus ( total dilution of the original sample of ∼ 10 4 ) ,", "label": "finding"}, {"segment_text": "the positive results for the different viruses turned negative already after 2 or 3 passages in MDCK 33016PF cells .", "label": "finding"}, {"segment_text": "These results demonstrate that , under practical conditions as applied to grow influenza viruses ,", "label": "finding"}, {"segment_text": "contaminating viruses can be effectively removed by passages in MDCK cells .", "label": "finding"}, {"segment_text": "In combination with their superior isolation efficiency ,", "label": "finding"}, {"segment_text": "MDCK cells appear highly suitable to be used as an alternative to embryonated eggs to isolate and propagate influenza vaccine candidate viruses .", "label": "finding"}], "n_segments": 20}
{"paper_id": "670f2388055a866aa6706a2c1130d68c2f37d15d", "title": "Lysophosphatidic Acid Triggers Apoptosis in HeLa Cells through the Upregulation of Tumor Necrosis Factor Receptor Superfamily Member 21", "coda_paper_id": 1519, "has_expert_labels": false, "abstract_text": "Lysophosphatidic acid ( LPA ) , a naturally occurring bioactive phospholipid , activates G protein-coupled receptors ( GPCRs ) , leading to regulation of diverse cellular events including cell survival and apoptosis . Despite extensive studies of the signaling pathways that mediate LPA-regulated cell growth and survival , the mechanisms underlying the apoptotic effect of LPA remain largely unclear . In this study , we investigated this issue in HeLa cells . Our data demonstrate that LPA induces apoptosis in HeLa cells at pathologic concentrations with a concomitant upregulation of the expression of TNFRSF21 ( tumor necrosis factor receptor superfamily member 21 ) , also known as death receptor number 6 ( DR6 ) involved in inflammation . Moreover , treatment of cells with LPA receptor ( LPAR ) antagonist abolished the DR6 upregulation by LPA . LPA-induced DR6 expression was also abrogated by pertussis toxin ( PTX ) , an inhibitor of GPCRs , and by inhibitors of PI3K , PKC , MEK , and ERK . Intriguingly , LPA-induced DR6 expression was specifically blocked by dominant-negative form of PKC ( PKC - DN ) . LPA-induced DR6 expression was also dramatically inhibited by knockdown of ERK or CREB . These results suggest that activation of the MEK/ERK pathway and the transcription factor CREB mediate LPA-induced DR6 expression . More interestingly , knockdown of DR6 using siRNA approach remarkably attenuated LPA-induced apoptosis . In conclusion , our results suggest that LPA-induced apoptosis in HeLa cells is mediated by the upregulation of DR6 expression .", "gold_segments": [{"segment_text": "Lysophosphatidic acid ( LPA ) ,", "label": "background"}, {"segment_text": "a naturally occurring bioactive phospholipid ,", "label": "background"}, {"segment_text": "activates G protein-coupled receptors ( GPCRs ) ,", "label": "background"}, {"segment_text": "leading to regulation of diverse cellular events including cell survival and apoptosis .", "label": "background"}, {"segment_text": "Despite extensive studies of the signaling pathways that mediate LPA-regulated cell growth and survival ,", "label": "background"}, {"segment_text": "the mechanisms underlying the apoptotic effect of LPA remain largely unclear .", "label": "background"}, {"segment_text": "In this study , we investigated this issue in HeLa cells .", "label": "purpose"}, {"segment_text": "Our data demonstrate that LPA induces apoptosis in HeLa cells at pathologic concentrations with a concomitant upregulation of the expression of TNFRSF21 ( tumor necrosis factor receptor superfamily member 21 ) ,", "label": "finding"}, {"segment_text": "also known as death receptor number 6 ( DR6 ) involved in inflammation .", "label": "finding"}, {"segment_text": "Moreover , treatment of cells with LPA receptor ( LPAR ) antagonist abolished the DR6 upregulation by LPA .", "label": "finding"}, {"segment_text": "LPA-induced DR6 expression was also abrogated by pertussis toxin ( PTX ) ,", "label": "finding"}, {"segment_text": "an inhibitor of GPCRs , and by inhibitors of PI3K ,", "label": "finding"}, {"segment_text": "PKC , MEK , and ERK .", "label": "finding"}, {"segment_text": "Intriguingly , LPA-induced DR6 expression was specifically blocked by dominant-negative form of PKC ( PKC - DN ) .", "label": "finding"}, {"segment_text": "LPA-induced DR6 expression was also dramatically inhibited by knockdown of ERK or CREB .", "label": "finding"}, {"segment_text": "These results suggest that activation of the MEK/ERK pathway and the transcription factor CREB mediate LPA-induced DR6 expression .", "label": "finding"}, {"segment_text": "More interestingly , knockdown of DR6 using siRNA approach remarkably attenuated LPA-induced apoptosis .", "label": "finding"}, {"segment_text": "In conclusion , our results suggest that LPA-induced apoptosis in HeLa cells is mediated by the upregulation of DR6 expression .", "label": "finding"}], "n_segments": 18}
{"paper_id": "18fce7553c78f84d21e05f8a2e0ea556e60189a3", "title": "Antiparallel Four-Stranded Coiled Coil Specified by a 3-3-1 Hydrophobic Heptad Repeat", "coda_paper_id": 1713, "has_expert_labels": false, "abstract_text": "Coiled-coil sequences in proteins commonly share a seven-amino acid repeat with nonpolar side chains at the first ( a ) and fourth ( d ) positions . We investigate here the role of a 3-3-1 hydrophobic repeat containing nonpolar amino acids at the a , d , and g positions in determining the structures of coiled coils using mutants of the GCN4 leucine zipper dimerization domain . When three charged residues at the g positions in the parental sequence are replaced by nonpolar alanine or valine side chains , stable four-helix structures result . The X-ray crystal structures of the tetramers reveal antiparallel , four-stranded coiled coils in which the a , d , and g side chains interlock in a combination of knobs-into-knobs and knobs-into-holes packing . Interfacial interactions in a coiled coil can therefore be prescribed by hydrophobic-polar patterns beyond the canonical 3-4 heptad repeat . The results suggest that the conserved , charged residues at the g positions in the GCN4 leucine zipper can impart a negative design element to disfavor thermodynamically more stable , antiparallel tetramers .", "gold_segments": [{"segment_text": "Coiled-coil sequences in proteins commonly share a seven-amino acid repeat with nonpolar side chains at the first ( a ) and fourth ( d ) positions .", "label": "background"}, {"segment_text": "We investigate here the role of a 3-3-1 hydrophobic repeat containing nonpolar amino acids at the a ,", "label": "purpose"}, {"segment_text": "d , and g positions in determining the structures of coiled coils using mutants of the GCN4 leucine zipper dimerization domain .", "label": "purpose"}, {"segment_text": "When three charged residues at the g positions in the parental sequence are replaced by nonpolar alanine or valine side chains , stable four-helix structures result .", "label": "method"}, {"segment_text": "The X-ray crystal structures of the tetramers reveal antiparallel ,", "label": "finding"}, {"segment_text": "four-stranded coiled coils in which the a ,", "label": "finding"}, {"segment_text": "d , and g side chains interlock in a combination of knobs-into-knobs and knobs-into-holes packing .", "label": "finding"}, {"segment_text": "Interfacial interactions in a coiled coil can therefore be prescribed by hydrophobic-polar patterns beyond the canonical 3-4 heptad repeat .", "label": "finding"}, {"segment_text": "The results suggest that the conserved ,", "label": "finding"}, {"segment_text": "charged residues at the g positions in the GCN4 leucine zipper can impart a negative design element to disfavor thermodynamically more stable , antiparallel tetramers .", "label": "finding"}], "n_segments": 10}
{"paper_id": "ed53f5474b63bae0932ca91b1770c5b54fbf56da", "title": "Proteomic approaches to uncovering virus-host protein interactions during the progression of viral infection", "coda_paper_id": 1375, "has_expert_labels": false, "abstract_text": "The integration of proteomic methods to virology has facilitated a significant breadth of biological insight into mechanisms of virus replication , antiviral host responses and viral subversion of host defenses . Throughout the course of infection , these cellular mechanisms rely heavily on the formation of temporally and spatially regulated virus-host protein-protein interactions . Reviewed here are proteomic-based approaches that have been used to characterize this dynamic virus-host interplay . Specifically discussed are the contribution of integrative mass spectrometry , antibody-based affinity purification of protein complexes , cross-linking and protein array techniques for elucidating complex networks of virus-host protein associations during infection with a diverse range of RNA and DNA viruses . The benefits and limitations of applying proteomic methods to virology are explored , and the contribution of these approaches to important biological discoveries and to inspiring new tractable avenues for the design of antiviral therapeutics is highlighted . ARTICLE HISTORY", "gold_segments": [{"segment_text": "The integration of proteomic methods to virology has facilitated a significant breadth of biological insight into mechanisms of virus replication ,", "label": "background"}, {"segment_text": "antiviral host responses and viral subversion of host defenses .", "label": "background"}, {"segment_text": "Throughout the course of infection ,", "label": "background"}, {"segment_text": "these cellular mechanisms rely heavily on the formation of temporally and spatially regulated virus-host protein-protein interactions .", "label": "background"}, {"segment_text": "Reviewed here are proteomic-based approaches that have been used to characterize this dynamic virus-host interplay .", "label": "purpose"}, {"segment_text": "Specifically discussed are the contribution of integrative mass spectrometry ,", "label": "purpose"}, {"segment_text": "antibody-based affinity purification of protein complexes ,", "label": "purpose"}, {"segment_text": "cross-linking and protein array techniques for elucidating complex networks of virus-host protein associations during infection with a diverse range of RNA and DNA viruses .", "label": "method"}, {"segment_text": "The benefits and limitations of applying proteomic methods to virology are explored ,", "label": "purpose"}, {"segment_text": "and the contribution of these approaches to important biological discoveries and to inspiring new tractable avenues for the design of antiviral therapeutics is highlighted .", "label": "purpose"}, {"segment_text": "ARTICLE HISTORY", "label": "other"}], "n_segments": 11}
{"paper_id": "7b3eb86651df1d953682383c06c1bcaac104e25e", "title": "Initial performance evaluation of a spotted array Mobile Analysis Platform (MAP) for the detection of influenza A/B, RSV, and MERS coronavirus ☆,☆☆", "coda_paper_id": 1426, "has_expert_labels": false, "abstract_text": "Clinical samples were evaluated with the Mobile Analysis Platform ( MAP ) to determine platform performance for detecting respiratory viruses in samples previously characterized using clinical reverse transcriptase polymerase chain reaction assays . The percent agreement between MAP and clinical results was 97 % for influenza A ( 73/75 ) , 100 % ( 21/21 ) for influenza B , 100 % ( 6/6 ) for respiratory syncytial virus ( RSV ) , and 80 % ( 4/5 ) for negative specimens . The approximate limit of detection of the MAP was 30 copies/assay for RSV and 1500 copies/assay for Middle East respiratory syndrome coronavirus .", "gold_segments": [{"segment_text": "Clinical samples were evaluated with the Mobile Analysis Platform ( MAP ) to determine platform performance for detecting respiratory viruses in samples previously characterized using clinical reverse transcriptase polymerase chain reaction assays .", "label": "method"}, {"segment_text": "The percent agreement between MAP and clinical results was 97 % for influenza A ( 73/75 ) ,", "label": "finding"}, {"segment_text": "100 % ( 21/21 ) for influenza B ,", "label": "finding"}, {"segment_text": "100 % ( 6/6 ) for respiratory syncytial virus ( RSV ) ,", "label": "finding"}, {"segment_text": "and 80 % ( 4/5 ) for negative specimens .", "label": "finding"}, {"segment_text": "The approximate limit of detection of the MAP was 30 copies/assay for RSV and 1500 copies/assay for Middle East respiratory syndrome coronavirus .", "label": "finding"}], "n_segments": 6}
{"paper_id": "3e5ad0064405fe418dd5b81f08259db26b786ef6", "title": "Reasoning within expressive fuzzy rough description logics", "coda_paper_id": 1485, "has_expert_labels": false, "abstract_text": "It is generally accepted that the management of imprecision and vagueness will yield more intelligent and realistic knowledgebased applications . Description Logics ( DLs ) are suitable , well-known logics for managing structured knowledge that have gained considerable attention the last decade . The current research progress and the existing problems of uncertain or imprecise knowledge representation and reasoning in DLs are analyzed in this paper . An integration between the theories of fuzzy DLs and rough DLs has been attempted by providing fuzzy rough DLs based on fuzzy rough set theory . The syntax , semantics and properties of fuzzy rough DLs are given . It is proved that the satisfiability , subsumption , entailment and ABox consistency reasoning in fuzzy rough DLs may be reduced to the ABox consistency reasoning in the corresponding fuzzy DLs .", "gold_segments": [{"segment_text": "It is generally accepted that the management of imprecision and vagueness will yield more intelligent and realistic knowledgebased applications .", "label": "background"}, {"segment_text": "Description Logics ( DLs ) are suitable ,", "label": "background"}, {"segment_text": "well-known logics for managing structured knowledge that have gained considerable attention the last decade .", "label": "background"}, {"segment_text": "The current research progress and the existing problems of uncertain or imprecise knowledge representation and reasoning in DLs are analyzed in this paper .", "label": "background"}, {"segment_text": "An integration between the theories of fuzzy DLs and rough DLs has been attempted by providing fuzzy rough DLs based on fuzzy rough set theory .", "label": "method"}, {"segment_text": "The syntax , semantics and properties of fuzzy rough DLs are given .", "label": "method"}, {"segment_text": "It is proved that the satisfiability ,", "label": "finding"}, {"segment_text": "subsumption , entailment and ABox consistency reasoning in fuzzy rough DLs may be reduced to the ABox consistency reasoning in the corresponding fuzzy DLs .", "label": "finding"}], "n_segments": 8}
{"paper_id": "a5a96f498ddf9c75a82b1a6a4b9324194b37d5f2", "title": "Detection of SARS Coronavirus in Humans and Animals by Conventional and Quantitative (Real Time) Reverse Transcription Polymerase Chain Reactions", "coda_paper_id": 1920, "has_expert_labels": false, "abstract_text": "Severe acute respiratory syndrome is a novel human disease caused by a coronavirus of animal origin . Soon after the discovery SARS-CoV , several molecular assays were described for the detection of this virus . Of these , conventional and quantitative RT-PCR approaches were the primary tools for SARS-CoV RNA detection . In this chapter we describe a two-step conventional RT-PCR and a one-step quantitative RT-PCR that were used routinely in our laboratories during the SARS outbreak .", "gold_segments": [{"segment_text": "Severe acute respiratory syndrome is a novel human disease caused by a coronavirus of animal origin .", "label": "background"}, {"segment_text": "Soon after the discovery SARS-CoV ,", "label": "background"}, {"segment_text": "several molecular assays were described for the detection of this virus .", "label": "background"}, {"segment_text": "Of these , conventional and quantitative RT-PCR approaches were the primary tools for SARS-CoV RNA detection .", "label": "background"}, {"segment_text": "In this chapter we describe a two-step conventional RT-PCR and a one-step quantitative RT-PCR that were used routinely in our laboratories during the SARS outbreak .", "label": "purpose"}], "n_segments": 5}
{"paper_id": "c773008a7d1396060aae0db2d105ea202fcd5bf1", "title": "Characterization of Viral Exposures in United States Occupational Environments", "coda_paper_id": 1560, "has_expert_labels": false, "abstract_text": "Viruses are considered to be the most abundant biological particles and have the capability to infect all forms of life leading to a variety of diseases . American workers in specific occupational environments are threatened by viral exposures , highlighting the importance to recognize the type and risk of exposure , as well as the preventive measures that can be taken to reduce the risk of exposure . For example , healthcare workers can potentially be exposed to air and bloodborne pathogens , such as hepatitis and the human immunodeficiency virus . These types of exposures have led to the development of preventive equipment and regulations intended to reduce viral exposures in occupational settings . This chapter will discuss the characteristics of viruses and the occupationally relevant viruses of which people in varying occupations can potentially encounter . Regulatory guidelines and protective strategies will also be reviewed .", "gold_segments": [{"segment_text": "Viruses are considered to be the most abundant biological particles and have the capability to infect all forms of life leading to a variety of diseases .", "label": "background"}, {"segment_text": "American workers in specific occupational environments are threatened by viral exposures ,", "label": "background"}, {"segment_text": "highlighting the importance to recognize the type and risk of exposure ,", "label": "background"}, {"segment_text": "as well as the preventive measures that can be taken to reduce the risk of exposure .", "label": "background"}, {"segment_text": "For example , healthcare workers can potentially be exposed to air and bloodborne pathogens ,", "label": "background"}, {"segment_text": "such as hepatitis and the human immunodeficiency virus .", "label": "background"}, {"segment_text": "These types of exposures have led to the development of preventive equipment and regulations intended to reduce viral exposures in occupational settings .", "label": "background"}, {"segment_text": "This chapter will discuss the characteristics of viruses and the occupationally relevant viruses of which people in varying occupations can potentially encounter .", "label": "finding"}, {"segment_text": "Regulatory guidelines and protective strategies will also be reviewed .", "label": "finding"}], "n_segments": 9}
{"paper_id": "a8dc7f137a340a631699a817a26b4b4d26136e7b", "title": "Article 117 1 B Cell Biology, a section of the journal Frontiers in Immunology", "coda_paper_id": 1175, "has_expert_labels": false, "abstract_text": "Affinity maturation is the process whereby the immune system generates antibodies of higher affinities during a response to antigen . It is unique in being the only evolutionary mechanism known to operate on a molecule in an organism 's own body . Deciphering the structural mechanisms through which somatic mutations in antibody genes increase affinity is critical to understanding the evolution of immune repertoires . Next-generation sequencing ( NGS ) has allowed the reconstruction of antibody clonal lineages in response to viral pathogens , such as HIV-1 , which was not possible in earlier studies of affinity maturation . Crystal structures of antibodies from these lineages bound to their target antigens have revealed , at the atomic level , how antibodies evolve to penetrate the glycan shield of envelope glycoproteins , and how viruses in turn evolve to escape neutralization . Collectively , structural studies of affinity maturation have shown that increased antibody affinity can arise from any one or any combination of multiple diverse mechanisms , including improved shape complementarity at the interface with antigen , increased buried surface area upon complex formation , additional interfacial polar or hydrophobic interactions , and preorganization or rigidification of the antigenbinding site .", "gold_segments": [{"segment_text": "Affinity maturation is the process whereby the immune system generates antibodies of higher affinities during a response to antigen .", "label": "background"}, {"segment_text": "It is unique in being the only evolutionary mechanism known to operate on a molecule in an organism 's own body .", "label": "background"}, {"segment_text": "Deciphering the structural mechanisms through which somatic mutations in antibody genes increase affinity is critical to understanding the evolution of immune repertoires .", "label": "background"}, {"segment_text": "Next-generation sequencing ( NGS ) has allowed the reconstruction of antibody clonal lineages in response to viral pathogens ,", "label": "background"}, {"segment_text": "such as HIV-1 , which was not possible in earlier studies of affinity maturation .", "label": "background"}, {"segment_text": "Crystal structures of antibodies from these lineages bound to their target antigens have revealed ,", "label": "background"}, {"segment_text": "at the atomic level , how antibodies evolve to penetrate the glycan shield of envelope glycoproteins ,", "label": "background"}, {"segment_text": "and how viruses in turn evolve to escape neutralization .", "label": "background"}, {"segment_text": "Collectively , structural studies of affinity maturation have shown that increased antibody affinity can arise from any one or any combination of multiple diverse mechanisms ,", "label": "finding"}, {"segment_text": "including improved shape complementarity at the interface with antigen ,", "label": "finding"}, {"segment_text": "increased buried surface area upon complex formation ,", "label": "finding"}, {"segment_text": "additional interfacial polar or hydrophobic interactions ,", "label": "finding"}, {"segment_text": "and preorganization or rigidification of the antigenbinding site .", "label": "finding"}], "n_segments": 13}
{"paper_id": "2237eb30aefa0342e61144f790fd8a521e521908", "title": "Basic Shock Physiology and Critical Care", "coda_paper_id": 1024, "has_expert_labels": false, "abstract_text": "1 . Shock is the clinical expression of dysoxia . Dysoxia is lack of oxygen supply to , or use by , the cells , limiting energy production . 1 Poor perfusion and diminished oxygen delivery to the tissues with resulting signs of pallor , tachycardia , tachypnea , and altered pulse quality is another way to describe shock . 2 . Oxygen delivery ( DO 2 ) is the amount of oxygen delivered to tissues as determined by cardiac output and oxygen carrying capacity . 2 It is described best by the equation CO Â CaO 2 , in which CO is cardiac output ( the heart rate multiplied by stroke Disclosure : The author has nothing to disclose . Shock Physiology Critical care Exotic animals Most of the literature discussing shock , systemic inflammation , and sepsis relates to experimental studies using small mammals such as rodents and rabbits ; there is a paucity of research of these syndromes in other species , such as ferrets , birds , and reptiles . Although small mammals , experimentally , have a similar autonomic response to dogs during induced hemorrhage and shock states , this response is not noted in the clinical setting , in which decompensated shock is more commonly reported . Poor perfusion affects every major organ system , but particular attention should be given to the immune system , coagulation system , cardiovascular system , gastrointestinal tract , and kidneys . Knowing how these systems are affected helps explain to clinicians why patients with shock can later become septic or coagulopathic . To ensure the best outcomes in patients who have shock or systemic inflammatory response syndrome , early recognition and intervention by provision of supplemental oxygen and fluid resuscitation is essential .", "gold_segments": [{"segment_text": "1 .", "label": "background"}, {"segment_text": "Shock is the clinical expression of dysoxia .", "label": "background"}, {"segment_text": "Dysoxia is lack of oxygen supply to ,", "label": "background"}, {"segment_text": "or use by , the cells , limiting energy production .", "label": "background"}, {"segment_text": "1 Poor perfusion and diminished oxygen delivery to the tissues with resulting signs of pallor ,", "label": "background"}, {"segment_text": "tachycardia , tachypnea , and altered pulse quality is another way to describe shock .", "label": "background"}, {"segment_text": "2 .", "label": "other"}, {"segment_text": "Oxygen delivery ( DO 2 ) is the amount of oxygen delivered to tissues as determined by cardiac output and oxygen carrying capacity .", "label": "background"}, {"segment_text": "2 It is described best by the equation CO Â CaO 2 ,", "label": "background"}, {"segment_text": "in which CO is cardiac output ( the heart rate multiplied by stroke Disclosure : The author has nothing to disclose .", "label": "background"}, {"segment_text": "Shock Physiology Critical care Exotic animals", "label": "background"}, {"segment_text": "Most of the literature discussing shock ,", "label": "background"}, {"segment_text": "systemic inflammation , and sepsis relates to experimental studies using small mammals such as rodents and rabbits ; there is a paucity of research of these syndromes in other species ,", "label": "background"}, {"segment_text": "such as ferrets , birds , and reptiles .", "label": "background"}, {"segment_text": "Although small mammals , experimentally ,", "label": "background"}, {"segment_text": "have a similar autonomic response to dogs during induced hemorrhage and shock states ,", "label": "background"}, {"segment_text": "this response is not noted in the clinical setting ,", "label": "background"}, {"segment_text": "in which decompensated shock is more commonly reported .", "label": "background"}, {"segment_text": "Poor perfusion affects every major organ system ,", "label": "background"}, {"segment_text": "but particular attention should be given to the immune system ,", "label": "background"}, {"segment_text": "coagulation system , cardiovascular system ,", "label": "background"}, {"segment_text": "gastrointestinal tract , and kidneys .", "label": "background"}, {"segment_text": "Knowing how these systems are affected helps explain to clinicians why patients with shock can later become septic or coagulopathic .", "label": "background"}, {"segment_text": "To ensure the best outcomes in patients who have shock or systemic inflammatory response syndrome ,", "label": "finding"}, {"segment_text": "early recognition and intervention by provision of supplemental oxygen and fluid resuscitation is essential .", "label": "finding"}], "n_segments": 25}
{"paper_id": "a23739aba0ae99bdf7e687731f4c61770cb6569d", "title": "Virus detection and its association with symptoms during influenza-like illness in a sample of healthy adults enrolled in a randomised controlled vaccine trial", "coda_paper_id": 1370, "has_expert_labels": false, "abstract_text": "Background Viral respiratory infections are associated with significant morbidity and mortality . Many new aetiological agents have been described recently . Objectives We looked for respiratory viruses in a populationbased sample of healthy adults with influenza-like illness ( ILI ) . We investigated host and spatio-temporal associations with virus isolation and host , spatio-temporal and virus associations with self-reported symptoms . Patients ⁄ Methods We recruited 586 participants experiencing 651 illness episodes from a population of healthy adults enrolled in an influenza vaccine effectiveness trial . At ILI assessment visits , a respiratory swab was collected and tested for viruses using a combination of polymerase chain reaction ( PCR ) assays . Participants also completed a questionnaire detailing their clinical course in 336 episodes . Of 643 samples analysed , a virus was identified in 44 % . Half were picornaviruses , with influenza and coronaviruses the Conclusions Our findings indicate that a greater number of symptoms are displayed by individuals presenting with influenza confirmed ILI compared with other agents that cause ILI . While influenza vaccination reduced the probability of influenza virus detection , symptom score for influenza-positive ILI was not attenuated . Please cite this paper as : Howard et al. ( 2013 ) Virus detection and its association with symptoms during influenza-like illness in a sample of healthy adults enrolled in a randomised controlled vaccine trial . Influenza and Other Respiratory Viruses 7 ( 3 ) , 330-339 .", "gold_segments": [{"segment_text": "Background Viral respiratory infections are associated with significant morbidity and mortality .", "label": "background"}, {"segment_text": "Many new aetiological agents have been described recently .", "label": "background"}, {"segment_text": "Objectives We looked for respiratory viruses in a populationbased sample of healthy adults with influenza-like illness ( ILI ) .", "label": "purpose"}, {"segment_text": "We investigated host and spatio-temporal associations with virus isolation and host ,", "label": "purpose"}, {"segment_text": "spatio-temporal and virus associations with self-reported symptoms .", "label": "purpose"}, {"segment_text": "Patients ⁄ Methods We recruited 586 participants experiencing 651 illness episodes from a population of healthy adults enrolled in an influenza vaccine effectiveness trial .", "label": "method"}, {"segment_text": "At ILI assessment visits , a respiratory swab was collected and tested for viruses using a combination of polymerase chain reaction ( PCR ) assays .", "label": "method"}, {"segment_text": "Participants also completed a questionnaire detailing their clinical course in 336 episodes .", "label": "method"}, {"segment_text": "Of 643 samples analysed , a virus was identified in 44 % .", "label": "finding"}, {"segment_text": "Half were picornaviruses , with influenza and coronaviruses the Conclusions Our findings indicate that a greater number of symptoms are displayed by individuals presenting with influenza confirmed ILI compared with other agents that cause ILI .", "label": "finding"}, {"segment_text": "While influenza vaccination reduced the probability of influenza virus detection ,", "label": "finding"}, {"segment_text": "symptom score for influenza-positive ILI was not attenuated .", "label": "finding"}, {"segment_text": "Please cite this paper as : Howard et al. ( 2013 ) Virus detection and its association with symptoms during influenza-like illness in a sample of healthy adults enrolled in a randomised controlled vaccine trial .", "label": "other"}, {"segment_text": "Influenza and Other Respiratory Viruses 7 ( 3 ) , 330-339 .", "label": "other"}], "n_segments": 14}
{"paper_id": "ff00ce9f9d007f4c0f424208d1540e64ace3e57f", "title": "DIFFERENTIATED CULTURES OF PRIMARY HAMSTER TRACHEAL AIRWAY EPITHELIAL CELLS", "coda_paper_id": 1289, "has_expert_labels": false, "abstract_text": "Primary airway epithelial cell cultures can provide a faithful representation of the in vivo airway while allowing for a controlled nutrient source and isolation from other tissues or immune cells . The methods used have significant differences based on tissue source , cell isolation , culture conditions , and assessment of culture purity . We modified and optimized a method for generating tracheal epithelial cultures from Syrian golden hamsters and characterized the cultures for cell composition and function . Soon after initial plating , the epithelial ceils reached a high transepithelial resistance and formed tight junctions . The cells differentiated into a heterogeneous , nlulticellnlar culture containing ciliated , secretory , and basal ceils after culture at an air-liquid interface ( ALI ) . The secretory cell populations initially consisted of MUC5ACpositive goblet cells and MUC5ACICCSP double-positive ceils , but the makeup changed to predominantly Clara cell secretory protein ( CCSP ) - positive Clara cells after 14 d . The ciliated cell populations differentiated rapidly after ALl , as judged by the appearance of 6 tubulin IV-positive cells . The cultures produced mucus , CCSP , and trypsin-like proteases and were capable of wound repair as judged by increased expression of matrilysin . Our method provides an efficient , high-yield protocol for producing differentiated hamster tracheal epithelial cells that can be used for a variety of in vitro studies including tracheal cell differentiation , airway disease mechanisms , and pathogen-host interactions .", "gold_segments": [{"segment_text": "Primary airway epithelial cell cultures can provide a faithful representation of the in vivo airway while allowing for a controlled nutrient source and isolation from other tissues or immune cells .", "label": "background"}, {"segment_text": "The methods used have significant differences based on tissue source ,", "label": "background"}, {"segment_text": "cell isolation , culture conditions ,", "label": "background"}, {"segment_text": "and assessment of culture purity .", "label": "background"}, {"segment_text": "We modified and optimized a method for generating tracheal epithelial cultures from Syrian golden hamsters and characterized the cultures for cell composition and function .", "label": "method"}, {"segment_text": "Soon after initial plating , the epithelial ceils reached a high transepithelial resistance and formed tight junctions .", "label": "finding"}, {"segment_text": "The cells differentiated into a heterogeneous ,", "label": "finding"}, {"segment_text": "nlulticellnlar culture containing ciliated , secretory ,", "label": "finding"}, {"segment_text": "and basal ceils after culture at an air-liquid interface ( ALI ) .", "label": "finding"}, {"segment_text": "The secretory cell populations initially consisted of MUC5ACpositive goblet cells and MUC5ACICCSP double-positive ceils ,", "label": "finding"}, {"segment_text": "but the makeup changed to predominantly Clara cell secretory protein ( CCSP ) - positive Clara cells after 14 d .", "label": "finding"}, {"segment_text": "The ciliated cell populations differentiated rapidly after ALl ,", "label": "finding"}, {"segment_text": "as judged by the appearance of 6 tubulin IV-positive cells .", "label": "finding"}, {"segment_text": "The cultures produced mucus , CCSP ,", "label": "finding"}, {"segment_text": "and trypsin-like proteases and were capable of wound repair as judged by increased expression of matrilysin .", "label": "finding"}, {"segment_text": "Our method provides an efficient ,", "label": "finding"}, {"segment_text": "high-yield protocol for producing differentiated hamster tracheal epithelial cells that can be used for a variety of in vitro studies including tracheal cell differentiation ,", "label": "finding"}, {"segment_text": "airway disease mechanisms , and pathogen-host interactions .", "label": "finding"}], "n_segments": 18}
{"paper_id": "589bb887a113e04b714724a7ec3589037449dc39", "title": "RNase L Mediated Protection from Virus Induced Demyelination", "coda_paper_id": 1901, "has_expert_labels": false, "abstract_text": "IFN-a/b plays a critical role in limiting viral spread , restricting viral tropism and protecting mice from neurotropic coronavirus infection . However , the IFN-a/b dependent mechanisms underlying innate anti-viral functions within the CNS are poorly understood . The role of RNase L in viral encephalomyelitis was explored based on its functions in inhibiting translation , inducing apoptosis , and propagating the IFN-a/b pathway through RNA degradation intermediates . Infection of RNase L deficient ( RL 2/2 ) mice with a sub-lethal , demyelinating mouse hepatitis virus variant revealed that the majority of mice succumbed to infection by day 12 p.i. However , RNase L deficiency did not affect overall control of infectious virus , or diminish IFN-a/b expression in the CNS . Furthermore , increased morbidity and mortality could not be attributed to altered proinflammatory signals or composition of cells infiltrating the CNS . The unique phenotype of infected RL 2/2 mice was rather manifested in earlier onset and increased severity of demyelination and axonal damage in brain stem and spinal cord without evidence for enhanced neuronal infection . Increased tissue damage coincided with sustained brain stem infection , foci of microglia infection in grey matter , and increased apoptotic cells . These data demonstrate a novel protective role for RNase L in viral induced CNS encephalomyelitis , which is not reflected in overall viral control or propagation of IFN-a/b mediated signals . Protective function is rather associated with cell type specific and regional restriction of viral replication in grey matter and ameliorated neurodegeneration and demyelination .", "gold_segments": [{"segment_text": "IFN-a/b plays a critical role in limiting viral spread ,", "label": "background"}, {"segment_text": "restricting viral tropism and protecting mice from neurotropic coronavirus infection .", "label": "background"}, {"segment_text": "However , the IFN-a/b dependent mechanisms underlying innate anti-viral functions within the CNS are poorly understood .", "label": "background"}, {"segment_text": "The role of RNase L in viral encephalomyelitis was explored based on its functions in inhibiting translation ,", "label": "background"}, {"segment_text": "inducing apoptosis , and propagating the IFN-a/b pathway through RNA degradation intermediates .", "label": "background"}, {"segment_text": "Infection of RNase L deficient ( RL 2/2 ) mice with a sub-lethal ,", "label": "background"}, {"segment_text": "demyelinating mouse hepatitis virus variant revealed that the majority of mice succumbed to infection by day 12 p.i. However ,", "label": "background"}, {"segment_text": "RNase L deficiency did not affect overall control of infectious virus ,", "label": "finding"}, {"segment_text": "or diminish IFN-a/b expression in the CNS .", "label": "finding"}, {"segment_text": "Furthermore , increased morbidity and mortality could not be attributed to altered proinflammatory signals or composition of cells infiltrating the CNS .", "label": "finding"}, {"segment_text": "The unique phenotype of infected RL 2/2 mice was rather manifested in earlier onset and increased severity of demyelination and axonal damage in brain stem and spinal cord without evidence for enhanced neuronal infection .", "label": "finding"}, {"segment_text": "Increased tissue damage coincided with sustained brain stem infection ,", "label": "finding"}, {"segment_text": "foci of microglia infection in grey matter , and increased apoptotic cells .", "label": "finding"}, {"segment_text": "These data demonstrate a novel protective role for RNase L in viral induced CNS encephalomyelitis ,", "label": "finding"}, {"segment_text": "which is not reflected in overall viral control or propagation of IFN-a/b mediated signals .", "label": "finding"}, {"segment_text": "Protective function is rather associated with cell type specific and regional restriction of viral replication in grey matter and ameliorated neurodegeneration and demyelination .", "label": "finding"}], "n_segments": 16}
{"paper_id": "4eea4c989b10f3f5a235693877b8df2aa4c72522", "title": "A placebo-controlled trial of two intranasal vaccines to prevent tracheobronchitis (kennel cough) in dogs entering a humane shelter", "coda_paper_id": 1471, "has_expert_labels": false, "abstract_text": "A placebo-controlled field trial was conducted to compare the effectiveness of intranasal ( IN ) vaccines containing Bordetella bronchiseptica and canine-parainfluenza virus , with ( IN-BPA ) or without ( IN-BP ) canine-adenovirus type 2 , for prevention of kennel cough at a humane shelter . Dogs were examined on admission to the shelter and those without respiratory signs of disease were assigned daily , on a rotating basis , to receive one of three vaccines . We enrolled 972 healthy dogs . Dogs were monitored for up to 30 days post-vaccination for coughing and other clinical signs of respiratory disease . Thirty-three ( 10.7 % ; 95 % confidence interval ( CI ) : 7.2 , 14.2 ) dogs in the IN-BP group , 36 ( 10.2 % ; 95 % CI : 7.0 , 13.4 ) dogs in the IN-BPA group , and 42 ( 13.5 % ; 95 % CI : 9.7 , 17.3 ) dogs in the IN-P group coughed spontaneously for ≥ 1 day within 30 days of vaccination ( P = 0.37 ) . The IN-BP and IN-BPA vaccines were 20.7 and 24.4 % effective , respectively , in reducing coughing compared with a placebo vaccine . The strongest prognostic factor for coughing ( regardless of vaccine group ) was the number of days spent at the shelter , with each additional day increasing the risk of coughing by 3 % ( 95 % CI : 0.5 , 6.3 ) . The low incidence of coughing in the shelter during this study precluded observation of differences in vaccine effectiveness . No differences in vaccine-associated adverse events ( coughing , sneezing , nasal or ocular discharge ) were noted during the first 3 days post-administration or thereafter .", "gold_segments": [{"segment_text": "A placebo-controlled field trial was conducted to compare the effectiveness of intranasal ( IN ) vaccines containing Bordetella bronchiseptica and canine-parainfluenza virus ,", "label": "method"}, {"segment_text": "with ( IN-BPA ) or without ( IN-BP ) canine-adenovirus type 2 ,", "label": "method"}, {"segment_text": "for prevention of kennel cough at a humane shelter .", "label": "method"}, {"segment_text": "Dogs were examined on admission to the shelter and those without respiratory signs of disease were assigned daily ,", "label": "method"}, {"segment_text": "on a rotating basis , to receive one of three vaccines .", "label": "method"}, {"segment_text": "We enrolled 972 healthy dogs .", "label": "method"}, {"segment_text": "Dogs were monitored for up to 30 days post-vaccination for coughing and other clinical signs of respiratory disease .", "label": "method"}, {"segment_text": "Thirty-three ( 10.7 % ; 95 % confidence interval ( CI ) : 7.2 ,", "label": "finding"}, {"segment_text": "14.2 ) dogs in the IN-BP group ,", "label": "finding"}, {"segment_text": "36 ( 10.2 % ; 95 % CI : 7.0 , 13.4 ) dogs in the IN-BPA group ,", "label": "finding"}, {"segment_text": "and 42 ( 13.5 % ; 95 % CI : 9.7 , 17.3 ) dogs in the IN-P group coughed spontaneously for ≥ 1 day within 30 days of vaccination ( P = 0.37 ) .", "label": "finding"}, {"segment_text": "The IN-BP and IN-BPA vaccines were 20.7 and 24.4 % effective ,", "label": "finding"}, {"segment_text": "respectively , in reducing coughing compared with a placebo vaccine .", "label": "finding"}, {"segment_text": "The strongest prognostic factor for coughing ( regardless of vaccine group ) was the number of days spent at the shelter ,", "label": "finding"}, {"segment_text": "with each additional day increasing the risk of coughing by 3 % ( 95 % CI : 0.5 , 6.3 ) .", "label": "finding"}, {"segment_text": "The low incidence of coughing in the shelter during this study precluded observation of differences in vaccine effectiveness .", "label": "finding"}, {"segment_text": "No differences in vaccine-associated adverse events ( coughing , sneezing , nasal or ocular discharge ) were noted during the first 3 days post-administration or thereafter .", "label": "finding"}], "n_segments": 17}
{"paper_id": "239f21cba5b6c2861ef65214421a5b333576b8c8", "title": "Immunohistochemical and molecular detection of natural cases of bovine rotavirus and coronavirus infection causing enteritis in dairy calves", "coda_paper_id": 1123, "has_expert_labels": false, "abstract_text": "Bovine rotavirus ( BRoV ) and bovine coronavirus ( BCoV ) are major enteric viral pathogens responsible for calve diarrhoea . They are widespread both in dairy and beef cattle throughout the world and causing huge economic losses . The diagnosis of these agents is very difficult due to non-specific nature of lesions and the involvement of some intrinsic and extrinsic risk factors . We performed postmortem of 45 calves , which was below three months of age . Out of 45 necropscid calves , three ( 6.66 % ) cases were positive for BRoV and four ( 8.88 % ) cases were found positive for BCoV , screened by reverse transcriptase polymerase chain reaction ( RT-PCR ) . Further RT-PCR positive cases were confirmed by immunohistochemistry ( IHC ) in paraffin-embedded intestinal tissue sections . Three cases of enteritis caused by BRoV showed the hallmark lesions of the shortening and fusion of villi , denudation and infiltration of mononuclear cells in the lamina propria . The BRoV antigen distribution was prominent within the lining epithelium of the villi , peyer 's patches in the ileum and strong immunoreactions in the lymphocytes and some macrophages of the mesenteric lymph nodes . Four cases in which BCoV was detected , grossly lesions characterized by colonic mucosa covered with thick , fibrinous and diphtheritic membrane . Histopathologically , jejunum showed skipping lesion of micro-abscesses in crypts . The BCoV antigen distribution was prominent within the necrotic crypts in the jejunum and cryptic micro-abscesses in the colon and ileum . It is the first report of BRoV and BCoV antigen demonstration in the jejunum , colon , ileum , Peyer 's patches and mesenteric lymph nodes of naturally infected calves from India by using IHC .", "gold_segments": [{"segment_text": "Bovine rotavirus ( BRoV ) and bovine coronavirus ( BCoV ) are major enteric viral pathogens responsible for calve diarrhoea .", "label": "background"}, {"segment_text": "They are widespread both in dairy and beef cattle throughout the world and causing huge economic losses .", "label": "background"}, {"segment_text": "The diagnosis of these agents is very difficult due to non-specific nature of lesions and the involvement of some intrinsic and extrinsic risk factors .", "label": "background"}, {"segment_text": "We performed postmortem of 45 calves ,", "label": "method"}, {"segment_text": "which was below three months of age .", "label": "method"}, {"segment_text": "Out of 45 necropscid calves ,", "label": "finding"}, {"segment_text": "three ( 6.66 % ) cases were positive for BRoV and four ( 8.88 % ) cases were found positive for BCoV ,", "label": "finding"}, {"segment_text": "screened by reverse transcriptase polymerase chain reaction ( RT-PCR ) .", "label": "finding"}, {"segment_text": "Further RT-PCR positive cases were confirmed by immunohistochemistry ( IHC ) in paraffin-embedded intestinal tissue sections .", "label": "finding"}, {"segment_text": "Three cases of enteritis caused by BRoV showed the hallmark lesions of the shortening and fusion of villi ,", "label": "finding"}, {"segment_text": "denudation and infiltration of mononuclear cells in the lamina propria .", "label": "finding"}, {"segment_text": "The BRoV antigen distribution was prominent within the lining epithelium of the villi ,", "label": "finding"}, {"segment_text": "peyer 's patches in the ileum and strong immunoreactions in the lymphocytes and some macrophages of the mesenteric lymph nodes .", "label": "finding"}, {"segment_text": "Four cases in which BCoV was detected ,", "label": "finding"}, {"segment_text": "grossly lesions characterized by colonic mucosa covered with thick , fibrinous and diphtheritic membrane .", "label": "finding"}, {"segment_text": "Histopathologically , jejunum showed skipping lesion of micro-abscesses in crypts .", "label": "finding"}, {"segment_text": "The BCoV antigen distribution was prominent within the necrotic crypts in the jejunum and cryptic micro-abscesses in the colon and ileum .", "label": "finding"}, {"segment_text": "It is the first report of BRoV and BCoV antigen demonstration in the jejunum ,", "label": "finding"}, {"segment_text": "colon , ileum , Peyer 's patches and mesenteric lymph nodes of naturally infected calves from India by using IHC .", "label": "finding"}], "n_segments": 19}
{"paper_id": "54e82ae1126dc9eed820d7a255cb4edca68a9f82", "title": "Development of rapid immunochromatographic strip test for the detection of porcine epidemic diarrhoea virus", "coda_paper_id": 1339, "has_expert_labels": false, "abstract_text": "Porcine epidemic diarrhoea virus ( PEDV ) causes acute and severe watery diarrhoea and dehydration , as well as 50-100 per cent mortality in piglets . For the PEDV diagnosis , a rapid test kit that is specific and sensitive to PEDV is critical to monitor this disease at pig farms . The present study aimed to develop an immunochromatographic assay ( ICA ) strip test for detecting PEDV in faecal swabs . The newly developed diagnostic test showed a detection limit of 10 4.0 TCID 50 / ml of PEDV . Using faecal swab samples , the relative sensitivity and specificity of the ICA kit were 95.0 per cent and 98.6 per cent , respectively , compared with those of real-time RT-PCR . In samples from piglets experimentally infected with PEDV , the results showed 100 per cent agreement with those found by real-time RT-PCR . Our developed test strip will be useful for rapid diagnosis and can be used for epidemiological surveillance of PEDV infection .", "gold_segments": [{"segment_text": "Porcine epidemic diarrhoea virus ( PEDV ) causes acute and severe watery diarrhoea and dehydration ,", "label": "background"}, {"segment_text": "as well as 50-100 per cent mortality in piglets .", "label": "background"}, {"segment_text": "For the PEDV diagnosis , a rapid test kit that is specific and sensitive to PEDV is critical to monitor this disease at pig farms .", "label": "background"}, {"segment_text": "The present study aimed to develop an immunochromatographic assay ( ICA ) strip test for detecting PEDV in faecal swabs .", "label": "purpose"}, {"segment_text": "The newly developed diagnostic test showed a detection limit of 10 4.0 TCID 50 / ml of PEDV .", "label": "finding"}, {"segment_text": "Using faecal swab samples , the relative sensitivity and specificity of the ICA kit were 95.0 per cent and 98.6 per cent ,", "label": "finding"}, {"segment_text": "respectively , compared with those of real-time RT-PCR .", "label": "finding"}, {"segment_text": "In samples from piglets experimentally infected with PEDV ,", "label": "finding"}, {"segment_text": "the results showed 100 per cent agreement with those found by real-time RT-PCR .", "label": "finding"}, {"segment_text": "Our developed test strip will be useful for rapid diagnosis and can be used for epidemiological surveillance of PEDV infection .", "label": "finding"}], "n_segments": 10}
{"paper_id": "7684764a3cffa417816fe0249e426116eabe2b6a", "title": "Epidemiology and Infection Seeking out SARI: an automated search of electronic health records", "coda_paper_id": 1552, "has_expert_labels": false, "abstract_text": "The definition of severe acute respiratory infection ( SARI ) a respiratory illness with fever and cough , occurring within the past 10 days and requiring hospital admissionhas not been evaluated for critically ill patients . Using integrated electronic health records data , we developed an automated search algorithm to identify SARI cases in a large cohort of critical care patients and evaluate patient outcomes . We conducted a retrospective cohort study of all admissions to a medical intensive care unit from August 2009 through March 2016 . Subsets were randomly selected for deriving and validating a search algorithm , which was compared with temporal trends in laboratory-confirmed influenza to ensure that SARI was correlated with influenza . The algorithm was applied to the cohort to identify clinical differences for patients with and without SARI . For identifying SARI , the algorithm ( sensitivity , 86.9 % ; specificity , 95.6 % ) outperformed billing-based searching ( sensitivity , 73.8 % ; specificity , 78.8 % ) . Automated searching correlated with peaks in laboratory-confirmed influenza . Adjusted for severity of illness , SARI was associated with more hospital , intensive care unit and ventilator days but not with death or dismissal to home . The search algorithm accurately identified SARI for epidemiologic study and surveillance . • SARI is a public health concept being adopted worldwide . • We made a search algorithm that correctly identified large SARI patient cohorts . • The algorithm is useful for epidemiologic research in intensive care settings . • Outcomes between SARI and non-SARI patients were different . • Further differentiation among critically ill patients may be feasible . https://www.cambridge.org/core/terms . https://doi .", "gold_segments": [{"segment_text": "The definition of severe acute respiratory infection ( SARI ) a respiratory illness with fever and cough ,", "label": "background"}, {"segment_text": "occurring within the past 10 days and requiring hospital admissionhas not been evaluated for critically ill patients .", "label": "background"}, {"segment_text": "Using integrated electronic health records data ,", "label": "background"}, {"segment_text": "we developed an automated search algorithm to identify SARI cases in a large cohort of critical care patients and evaluate patient outcomes .", "label": "purpose"}, {"segment_text": "We conducted a retrospective cohort study of all admissions to a medical intensive care unit from August 2009 through March 2016 .", "label": "method"}, {"segment_text": "Subsets were randomly selected for deriving and validating a search algorithm ,", "label": "method"}, {"segment_text": "which was compared with temporal trends in laboratory-confirmed influenza to ensure that SARI was correlated with influenza .", "label": "method"}, {"segment_text": "The algorithm was applied to the cohort to identify clinical differences for patients with and without SARI .", "label": "method"}, {"segment_text": "For identifying SARI , the algorithm ( sensitivity , 86.9 % ; specificity , 95.6 % ) outperformed billing-based searching ( sensitivity , 73.8 % ; specificity , 78.8 % ) .", "label": "method"}, {"segment_text": "Automated searching correlated with peaks in laboratory-confirmed influenza .", "label": "method"}, {"segment_text": "Adjusted for severity of illness ,", "label": "finding"}, {"segment_text": "SARI was associated with more hospital ,", "label": "finding"}, {"segment_text": "intensive care unit and ventilator days but not with death or dismissal to home .", "label": "finding"}, {"segment_text": "The search algorithm accurately identified SARI for epidemiologic study and surveillance .", "label": "finding"}, {"segment_text": "• SARI is a public health concept being adopted worldwide .", "label": "finding"}, {"segment_text": "• We made a search algorithm that correctly identified large SARI patient cohorts .", "label": "finding"}, {"segment_text": "• The algorithm is useful for epidemiologic research in intensive care settings .", "label": "finding"}, {"segment_text": "• Outcomes between SARI and non-SARI patients were different .", "label": "finding"}, {"segment_text": "• Further differentiation among critically ill patients may be feasible .", "label": "finding"}, {"segment_text": "https://www.cambridge.org/core/terms .", "label": "other"}, {"segment_text": "https://doi .", "label": "other"}], "n_segments": 21}
{"paper_id": "fc5352a50f90e04d8c5ed64243f863417133e4dc", "title": "Main factors influencing recovery in MERS Co-V patients using machine learning", "coda_paper_id": 1902, "has_expert_labels": false, "abstract_text": "Background : Middle East Respiratory Syndrome ( MERS ) is a major infectious disease which has affected the Middle Eastern countries , especially the Kingdom of Saudi Arabia ( KSA ) since 2012 . The high mortality rate associated with this disease has been a major cause of concern . This paper aims at identifying the major factors influencing MERS recovery in KSA . Methods : The data used for analysis was collected from the Ministry of Health website , KSA . The important factors impelling the recovery are found using machine learning . Machine learning models such as support vector machine , conditional inference tree , naïve Bayes and J48 are modelled to identify the important factors . Univariate and multivariate logistic regression analysis is also carried out to identify the significant factors statistically . Result : The main factors influencing MERS recovery rate are identified as age , pre-existing diseases , severity of disease and whether the patient is a healthcare worker or not . In spite of MERS being a zoonotic disease , contact with camels is not a major factor influencing recovery . Conclusion : The methods used were able to determine the prime factors influencing MERS recovery . It can be comprehended that awareness about symptoms and seeking medical intervention at the onset of development of symptoms will make a long way in reducing the mortality rate .", "gold_segments": [{"segment_text": "Background : Middle East Respiratory Syndrome ( MERS ) is a major infectious disease which has affected the Middle Eastern countries ,", "label": "background"}, {"segment_text": "especially the Kingdom of Saudi Arabia ( KSA ) since 2012 .", "label": "background"}, {"segment_text": "The high mortality rate associated with this disease has been a major cause of concern .", "label": "background"}, {"segment_text": "This paper aims at identifying the major factors influencing MERS recovery in KSA .", "label": "purpose"}, {"segment_text": "Methods : The data used for analysis was collected from the Ministry of Health website , KSA .", "label": "method"}, {"segment_text": "The important factors impelling the recovery are found using machine learning .", "label": "method"}, {"segment_text": "Machine learning models such as support vector machine ,", "label": "method"}, {"segment_text": "conditional inference tree , naïve Bayes and J48 are modelled to identify the important factors .", "label": "method"}, {"segment_text": "Univariate and multivariate logistic regression analysis is also carried out to identify the significant factors statistically .", "label": "method"}, {"segment_text": "Result : The main factors influencing MERS recovery rate are identified as age ,", "label": "finding"}, {"segment_text": "pre-existing diseases , severity of disease and whether the patient is a healthcare worker or not .", "label": "finding"}, {"segment_text": "In spite of MERS being a zoonotic disease ,", "label": "finding"}, {"segment_text": "contact with camels is not a major factor influencing recovery .", "label": "finding"}, {"segment_text": "Conclusion : The methods used were able to determine the prime factors influencing MERS recovery .", "label": "finding"}, {"segment_text": "It can be comprehended that awareness about symptoms and seeking medical intervention at the onset of development of symptoms will make a long way in reducing the mortality rate .", "label": "finding"}], "n_segments": 15}
{"paper_id": "df1ac404fb17ee52dac2e055ac1f7dd91e9c8f10", "title": "Inhibitory Antibodies Targeting Emerging Viruses: Advancements and Mechanisms RECENT EMERGING VIRUS THREATS DEMONSTRATE A NEED FOR NOVEL RESPONSES", "coda_paper_id": 1540, "has_expert_labels": false, "abstract_text": "From Ebola virus outbreaks in Western Africa to the introduction of chikungunya and Zika viruses in the Americas , new and neglected viruses continue to emerge and spread around the world . Due to a lack of existing vaccines or specific therapeutics , little other than supportive care and attempts to interrupt transmission can be provided during initial outbreaks . This has prompted a shift in vaccine design and development to identify novel epitopes and mechanisms of protection that may offer a broader range of protection against groups or whole families of viruses . Receptor-binding domains and other motifs within viral envelope proteins represent one excellent opportunity to target communal epitopes shared by related viruses . Similarly , for viruses where envelope participates in driving viral egress from infected cells , shared epitopes need to be identified to guide the development of broadly protective antibodies and vaccines . Here , we discuss recent advances in our understanding of broadly protective humoral responses for emerging viruses .", "gold_segments": [{"segment_text": "From Ebola virus outbreaks in Western Africa to the introduction of chikungunya and Zika viruses in the Americas ,", "label": "background"}, {"segment_text": "new and neglected viruses continue to emerge and spread around the world .", "label": "background"}, {"segment_text": "Due to a lack of existing vaccines or specific therapeutics ,", "label": "background"}, {"segment_text": "little other than supportive care and attempts to interrupt transmission can be provided during initial outbreaks .", "label": "background"}, {"segment_text": "This has prompted a shift in vaccine design and development to identify novel epitopes and mechanisms of protection that may offer a broader range of protection against groups or whole families of viruses .", "label": "background"}, {"segment_text": "Receptor-binding domains and other motifs within viral envelope proteins represent one excellent opportunity to target communal epitopes shared by related viruses .", "label": "background"}, {"segment_text": "Similarly , for viruses where envelope participates in driving viral egress from infected cells ,", "label": "background"}, {"segment_text": "shared epitopes need to be identified to guide the development of broadly protective antibodies and vaccines .", "label": "background"}, {"segment_text": "Here , we discuss recent advances in our understanding of broadly protective humoral responses for emerging viruses .", "label": "purpose"}], "n_segments": 9}
{"paper_id": "e7e044d8d6e74a821be3aa346e5c3a0e9b648bb8", "title": "Cutaneous Phaeohyphomycosis Caused by Exophiala attenuata in a Domestic Cat", "coda_paper_id": 1797, "has_expert_labels": false, "abstract_text": "A 7-year-old female-spayed , domestic short-haired cat was presented to her veterinarian with a mass on the hind paw . Histopathologic examination of a tissue biopsy revealed nodular pyogranulomatous panniculitis with intralesional pigmented fungal hyphae . A dematiaceous fungal isolate was isolated with a micromorphological phenotype consistent with the anamorphic genus Exophiala : budding cells , torulose mycelium and annellidic conidiogenesis from simple conidiophores consisting of terminal and lateral cells that tapered to a short beak at the apex . Sequence homology of the internal transcribed spacer region of the rDNA gene confirmed the identification of the isolate as Exophiala attenuata . Reported here is the first confirmed case of feline phaeohyphomycosis caused by E. attenuata in North America . Similar to historical cases of feline phaeohyphomycosis caused by Exophiala spp. , there was no history or postmortem evidence to suggest the patient was in an immunocompromised state ( e.g. , suffering from FeLV or FIV ) . Although aggressive surgical excision of local lesions is recommended prior to drug treatment when dealing with subcutaneous phaeohyphomycosis , surgery followed by itraconazole treatment did not resolve the E. attenuata infection in this cat .", "gold_segments": [{"segment_text": "A 7-year-old female-spayed , domestic short-haired cat was presented to her veterinarian with a mass on the hind paw .", "label": "background"}, {"segment_text": "Histopathologic examination of a tissue biopsy revealed nodular pyogranulomatous panniculitis with intralesional pigmented fungal hyphae .", "label": "finding"}, {"segment_text": "A dematiaceous fungal isolate was isolated with a micromorphological phenotype consistent with the anamorphic genus Exophiala : budding cells ,", "label": "method"}, {"segment_text": "torulose mycelium and annellidic conidiogenesis from simple conidiophores consisting of terminal and lateral cells that tapered to a short beak at the apex .", "label": "method"}, {"segment_text": "Sequence homology of the internal transcribed spacer region of the rDNA gene confirmed the identification of the isolate as Exophiala attenuata .", "label": "finding"}, {"segment_text": "Reported here is the first confirmed case of feline phaeohyphomycosis caused by E. attenuata in North America .", "label": "finding"}, {"segment_text": "Similar to historical cases of feline phaeohyphomycosis caused by Exophiala spp. ,", "label": "finding"}, {"segment_text": "there was no history or postmortem evidence to suggest the patient was in an immunocompromised state ( e.g. , suffering from FeLV or FIV ) .", "label": "finding"}, {"segment_text": "Although aggressive surgical excision of local lesions is recommended prior to drug treatment when dealing with subcutaneous phaeohyphomycosis ,", "label": "finding"}, {"segment_text": "surgery followed by itraconazole treatment did not resolve the E. attenuata infection in this cat .", "label": "finding"}], "n_segments": 10}
{"paper_id": "5eb9dfd35738c13f2a7c3cceebb39ba6b9939fb2", "title": "Comparison of the inhibitory effects of interferon alfacon-1 and ribavirin on yellow fever virus infection in a hamster model NIH Public Access", "coda_paper_id": 1656, "has_expert_labels": false, "abstract_text": "Antiviral compounds were evaluated for efficacy against yellow fever virus ( YFV ) in a hamster model of YFV-induced liver disease . Challenge with a 10 2 50 % cell culture infectious doses of YFV resulted in a 50-80 % mortality rate in female hamsters . Virus was detected by QRT-PCR in liver , kidney , spleen , and serum with peak titers on 4-6 days post-viral challenge ( dpi ) . Serum levels of alkaline phosphatase , alanine aminotransferase ( ALT ) , bilirubin , blood urea nitrogen , potassium , and creatinine were significantly elevated , while serum levels of albumin , amylase , glucose , calcium , globulin , phosphorus , sodium , and total protein were significantly reduced . Packed cell volume and white blood cell count were significantly elevated during the course of the infection . Intraperitoneal treatment of hamsters with 0.5-5 μg/kg/d interferon ( IFN ) alfacon-1 , 100 mg/kg/d viramidine , or 50 mg/kg/d ribavirin , initiated 4 h prior to YFV challenge , resulted in significant improvement in survival and serum ALT levels . Treatment with IFN alfacon-1 or ribavirin starting 2 dpi , also significantly improved survival and serum ALT levels in hamsters challenged with YFV . Pre-and post-virus exposure treatment with IFN alfacon-1 was efficacious in improving disease in YFVinfected hamsters .", "gold_segments": [{"segment_text": "Antiviral compounds were evaluated for efficacy against yellow fever virus ( YFV ) in a hamster model of YFV-induced liver disease .", "label": "background"}, {"segment_text": "Challenge with a 10 2 50 % cell culture infectious doses of YFV resulted in a 50-80 % mortality rate in female hamsters .", "label": "finding"}, {"segment_text": "Virus was detected by QRT-PCR in liver ,", "label": "finding"}, {"segment_text": "kidney , spleen , and serum with peak titers on 4-6 days post-viral challenge ( dpi ) .", "label": "finding"}, {"segment_text": "Serum levels of alkaline phosphatase ,", "label": "finding"}, {"segment_text": "alanine aminotransferase ( ALT ) ,", "label": "finding"}, {"segment_text": "bilirubin , blood urea nitrogen ,", "label": "finding"}, {"segment_text": "potassium , and creatinine were significantly elevated ,", "label": "finding"}, {"segment_text": "while serum levels of albumin ,", "label": "finding"}, {"segment_text": "amylase , glucose , calcium ,", "label": "finding"}, {"segment_text": "globulin , phosphorus , sodium ,", "label": "finding"}, {"segment_text": "and total protein were significantly reduced .", "label": "finding"}, {"segment_text": "Packed cell volume and white blood cell count were significantly elevated during the course of the infection .", "label": "finding"}, {"segment_text": "Intraperitoneal treatment of hamsters with 0.5-5 μg/kg/d interferon ( IFN ) alfacon-1 ,", "label": "finding"}, {"segment_text": "100 mg/kg/d viramidine , or 50 mg/kg/d ribavirin ,", "label": "finding"}, {"segment_text": "initiated 4 h prior to YFV challenge ,", "label": "finding"}, {"segment_text": "resulted in significant improvement in survival and serum ALT levels .", "label": "finding"}, {"segment_text": "Treatment with IFN alfacon-1 or ribavirin starting 2 dpi ,", "label": "finding"}, {"segment_text": "also significantly improved survival and serum ALT levels in hamsters challenged with YFV .", "label": "finding"}, {"segment_text": "Pre-and post-virus exposure treatment with IFN alfacon-1 was efficacious in improving disease in YFVinfected hamsters .", "label": "finding"}], "n_segments": 20}
{"paper_id": "2d35471f0c80b4aef72a56d08bca7c063346160e", "title": "FebriDx®: A Rapid Diagnostic Test for Differentiating Bacterial and Viral Aetiologies in Acute Respiratory Infections", "coda_paper_id": 1781, "has_expert_labels": false, "abstract_text": "FebriDx ® is a rapid , point-of-care diagnostic test that is designed to aid in the differentiation of bacterial and viral acute respiratory infections ( ARIs ) , thus helping to guide decisions regarding the prescription of antibiotics in the outpatient setting . FebriDx carries a CE mark for use in the EU and is also approved in several other countries , including Canada , Saudi Arabia and Singapore . It is indicated for use in patients > 2 years old with symptoms consistent with a community-acquired ARI . The test involves the use of an immunoassay on a fingerstick blood sample to provide simultaneous , qualitative measurement of elevated levels of C-reactive protein ( CRP ) and myxovirus resistance protein A ( MxA ) . In two prospective , multicentre studies in patients with acute upper respiratory tract infections , FebriDx was shown to be both sensitive and specific in identifying patients with a clinically significant infection and in differentiating between infections of bacterial and viral aetiology . The test is simple , requires no additional equipment and produces actionable results in ~ 10 min . As was demonstrated in a small , retrospective analysis , FebriDx results can help guide ( improve ) antibiotic prescribing decisions . Reducing the unnecessary or inappropriate prescription of antibiotics for ARIs of probable viral aetiology is important for antibiotic stewardship and can also reduce the unnecessary exposure of patients to the risk of antibiotic-related adverse events . FebriDx thus represents a useful diagnostic tool in the outpatient setting . A simple , all-in-one , diagnostic test to assist in the diagnosis of bacterial or viral ARIs by measuring the host response to infection Based on a rapid immunoassay that provides simultaneous , qualitative measurement of elevated levels of CRP and MxA Sensitive and specific in identifying patients with a clinically significant infection and in differentiating between infections of bacterial and viral aetiology Produces actionable results in ~ 10 min which can be used to help guide antibiotic prescribing decisions turer of FebriDx was also offered an opportunity to review this article . Changes resulting from comments received were made on the basis of scientific and editorial merit .", "gold_segments": [{"segment_text": "FebriDx ® is a rapid ,", "label": "background"}, {"segment_text": "point-of-care diagnostic test that is designed to aid in the differentiation of bacterial and viral acute respiratory infections ( ARIs ) ,", "label": "background"}, {"segment_text": "thus helping to guide decisions regarding the prescription of antibiotics in the outpatient setting .", "label": "background"}, {"segment_text": "FebriDx carries a CE mark for use in the EU and is also approved in several other countries ,", "label": "background"}, {"segment_text": "including Canada , Saudi Arabia and Singapore .", "label": "background"}, {"segment_text": "It is indicated for use in patients > 2 years old with symptoms consistent with a community-acquired ARI .", "label": "background"}, {"segment_text": "The test involves the use of an immunoassay on a fingerstick blood sample to provide simultaneous ,", "label": "background"}, {"segment_text": "qualitative measurement of elevated levels of C-reactive protein ( CRP ) and myxovirus resistance protein A ( MxA ) .", "label": "background"}, {"segment_text": "In two prospective , multicentre studies in patients with acute upper respiratory tract infections ,", "label": "method"}, {"segment_text": "FebriDx was shown to be both sensitive and specific in identifying patients with a clinically significant infection and in differentiating between infections of bacterial and viral aetiology .", "label": "finding"}, {"segment_text": "The test is simple , requires no additional equipment and produces actionable results in ~ 10 min .", "label": "background"}, {"segment_text": "As was demonstrated in a small ,", "label": "finding"}, {"segment_text": "retrospective analysis , FebriDx results can help guide ( improve ) antibiotic prescribing decisions .", "label": "finding"}, {"segment_text": "Reducing the unnecessary or inappropriate prescription of antibiotics for ARIs of probable viral aetiology is important for antibiotic stewardship and can also reduce the unnecessary exposure of patients to the risk of antibiotic-related adverse events .", "label": "finding"}, {"segment_text": "FebriDx thus represents a useful diagnostic tool in the outpatient setting .", "label": "finding"}, {"segment_text": "A simple , all-in-one , diagnostic test to assist in the diagnosis of bacterial or viral ARIs by measuring the host response to infection Based on a rapid immunoassay that provides simultaneous ,", "label": "finding"}, {"segment_text": "qualitative measurement of elevated levels of CRP and MxA Sensitive and specific in identifying patients with a clinically significant infection and in differentiating between infections of bacterial and viral aetiology Produces actionable results in ~ 10 min which can be used to help guide antibiotic prescribing decisions turer of FebriDx was also offered an opportunity to review this article .", "label": "finding"}, {"segment_text": "Changes resulting from comments received were made on the basis of scientific and editorial merit .", "label": "finding"}], "n_segments": 18}
{"paper_id": "07396bda4a37d13aaf15fdf67d61971549f4162c", "title": "Viral Etiology of Acute Respiratory Infection in Gansu Province", "coda_paper_id": 1841, "has_expert_labels": false, "abstract_text": "Background : Acute respiratory infections ( ARIs ) are the leading cause of children and their leading killer . ARIs are responsible for at least six percent of the world 's disability and death . Viruses are one of the most common agents causing ARIs . Few studies on the viral etiology and clinical characteristics of ARIs have been performed in the northwest region of China , including Gansu Province . Methods : Clinical and demographic information and throat swabs were collected from 279 patients from January 1st to December 30st , 2011 . Multiplex RT-PCR was performed to detect 16 respiratory viral pathogens . Results : 279 patients were admitted for ARIs . The patients aged from 1 month to 12 years , with the median age of 2 years . Of which , 105 ( 37.6 % ) were positive for at least one pathogen . A total of 136 respiratory viral pathogens were identified from the 105 patients . Respiratory syncytial virus ( RSV ) was the most frequently detected pathogen ( 26.5 % , 36/136 ) , followed by parainfluenza virus ( PIV ) 1-3 ( 22.1 % , 30/136 ) , human rhinovirus ( HRV ) ( 21.3 % , 29/136 ) , human coronavirus ( CoV ) ( 10.3 % , 14/136 ) and human adenovirus ( HAdV ) ( 9.6 % , 13/136 ) . Influenza A ( Flu A ) , human metapneumovirus ( hMPV ) and human bocavirus ( BoCA ) were found 4.4 % , 3.7 % and 2.2 % , respectively . Influenza B ( Flu B ) and seasonal influenza A H1N1 ( sH1N1 ) were not detected . Single-infections were detected in 30.5 % ( 85/279 ) of cases . RSV was the most common pathogens in patients under 1 year and showed seasonal variation with peaks during winter and spring . Conclusions : This paper presents data on the epidemiology of viral pathogens associated with ARIs among children in Gansu Province , China . RSV is most frequently detected in our study . The findings could serve as a reference for local CDC in drawing up further plans to prevent and control ARIs .", "gold_segments": [{"segment_text": "Background : Acute respiratory infections ( ARIs ) are the leading cause of children and their leading killer .", "label": "background"}, {"segment_text": "ARIs are responsible for at least six percent of the world 's disability and death .", "label": "background"}, {"segment_text": "Viruses are one of the most common agents causing ARIs .", "label": "background"}, {"segment_text": "Few studies on the viral etiology and clinical characteristics of ARIs have been performed in the northwest region of China , including Gansu Province .", "label": "background"}, {"segment_text": "Methods : Clinical and demographic information and throat swabs were collected from 279 patients from January 1st to December 30st , 2011 .", "label": "method"}, {"segment_text": "Multiplex RT-PCR was performed to detect 16 respiratory viral pathogens .", "label": "method"}, {"segment_text": "Results : 279 patients were admitted for ARIs .", "label": "finding"}, {"segment_text": "The patients aged from 1 month to 12 years ,", "label": "finding"}, {"segment_text": "with the median age of 2 years .", "label": "finding"}, {"segment_text": "Of which , 105 ( 37.6 % ) were positive for at least one pathogen .", "label": "finding"}, {"segment_text": "A total of 136 respiratory viral pathogens were identified from the 105 patients .", "label": "finding"}, {"segment_text": "Respiratory syncytial virus ( RSV ) was the most frequently detected pathogen ( 26.5 % , 36/136 ) ,", "label": "finding"}, {"segment_text": "followed by parainfluenza virus ( PIV ) 1-3 ( 22.1 % , 30/136 ) ,", "label": "finding"}, {"segment_text": "human rhinovirus ( HRV ) ( 21.3 % , 29/136 ) ,", "label": "finding"}, {"segment_text": "human coronavirus ( CoV ) ( 10.3 % , 14/136 ) and human adenovirus ( HAdV ) ( 9.6 % , 13/136 ) .", "label": "finding"}, {"segment_text": "Influenza A ( Flu A ) ,", "label": "finding"}, {"segment_text": "human metapneumovirus ( hMPV ) and human bocavirus ( BoCA ) were found 4.4 % ,", "label": "finding"}, {"segment_text": "3.7 % and 2.2 % , respectively .", "label": "finding"}, {"segment_text": "Influenza B ( Flu B ) and seasonal influenza A H1N1 ( sH1N1 ) were not detected .", "label": "finding"}, {"segment_text": "Single-infections were detected in 30.5 % ( 85/279 ) of cases .", "label": "finding"}, {"segment_text": "RSV was the most common pathogens in patients under 1 year and showed seasonal variation with peaks during winter and spring .", "label": "finding"}, {"segment_text": "Conclusions : This paper presents data on the epidemiology of viral pathogens associated with ARIs among children in Gansu Province , China .", "label": "finding"}, {"segment_text": "RSV is most frequently detected in our study .", "label": "finding"}, {"segment_text": "The findings could serve as a reference for local CDC in drawing up further plans to prevent and control ARIs .", "label": "finding"}], "n_segments": 24}
{"paper_id": "59d3750e2fc06cf47e64fbe18dd09649750e05cf", "title": "molecules Current Understanding of Molecular Pathology and Treatment of Cardiomyopathy in Duchenne Muscular Dystrophy", "coda_paper_id": 1888, "has_expert_labels": false, "abstract_text": "Duchenne muscular dystrophy ( DMD ) is a genetic muscle disorder caused by mutations in the Dmd gene resulting in the loss of the protein dystrophin . Patients do not only experience skeletal muscle degeneration , but also develop severe cardiomyopathy by their second decade , one of the main causes of death . The absence of dystrophin in the heart renders cardiomyocytes more sensitive to stretch-induced damage . Moreover , it pathologically alters intracellular calcium ( Ca 2 + ) concentration , neuronal nitric oxide synthase ( nNOS ) localization and mitochondrial function and leads to inflammation and necrosis , all contributing to the development of cardiomyopathy . Current therapies only treat symptoms and therefore the need for targeting the genetic defect is immense . Several preclinical therapies are undergoing development , including utrophin up-regulation , stop codon read-through therapy , viral gene therapy , cell-based therapy and exon skipping . Some of these therapies are undergoing clinical trials , but these have predominantly focused on skeletal muscle correction . However , improving skeletal muscle function without addressing cardiac aspects of the disease may aggravate cardiomyopathy and therefore it is essential that preclinical and clinical focus include improving heart function . This review consolidates what is known regarding molecular pathology of the DMD heart , specifically focusing on intracellular Ca 2 + , nNOS and mitochondrial dysregulation . It briefly discusses the current treatment options and then elaborates on the preclinical therapeutic approaches currently under development to restore dystrophin thereby improving pathology , with a focus on the heart .", "gold_segments": [{"segment_text": "Duchenne muscular dystrophy ( DMD ) is a genetic muscle disorder caused by mutations in the Dmd gene resulting in the loss of the protein dystrophin .", "label": "background"}, {"segment_text": "Patients do not only experience skeletal muscle degeneration ,", "label": "background"}, {"segment_text": "but also develop severe cardiomyopathy by their second decade ,", "label": "background"}, {"segment_text": "one of the main causes of death .", "label": "background"}, {"segment_text": "The absence of dystrophin in the heart renders cardiomyocytes more sensitive to stretch-induced damage .", "label": "background"}, {"segment_text": "Moreover , it pathologically alters intracellular calcium ( Ca 2 + ) concentration ,", "label": "background"}, {"segment_text": "neuronal nitric oxide synthase ( nNOS ) localization and mitochondrial function and leads to inflammation and necrosis ,", "label": "background"}, {"segment_text": "all contributing to the development of cardiomyopathy .", "label": "background"}, {"segment_text": "Current therapies only treat symptoms and therefore the need for targeting the genetic defect is immense .", "label": "background"}, {"segment_text": "Several preclinical therapies are undergoing development ,", "label": "background"}, {"segment_text": "including utrophin up-regulation , stop codon read-through therapy ,", "label": "background"}, {"segment_text": "viral gene therapy , cell-based therapy and exon skipping .", "label": "background"}, {"segment_text": "Some of these therapies are undergoing clinical trials ,", "label": "background"}, {"segment_text": "but these have predominantly focused on skeletal muscle correction .", "label": "background"}, {"segment_text": "However , improving skeletal muscle function without addressing cardiac aspects of the disease may aggravate cardiomyopathy and therefore it is essential that preclinical and clinical focus include improving heart function .", "label": "background"}, {"segment_text": "This review consolidates what is known regarding molecular pathology of the DMD heart ,", "label": "purpose"}, {"segment_text": "specifically focusing on intracellular Ca 2 + , nNOS and mitochondrial dysregulation .", "label": "purpose"}, {"segment_text": "It briefly discusses the current treatment options and then elaborates on the preclinical therapeutic approaches currently under development to restore dystrophin thereby improving pathology ,", "label": "purpose"}, {"segment_text": "with a focus on the heart .", "label": "purpose"}], "n_segments": 19}
{"paper_id": "76787d76b67af412075bcb38ec51f6057f61cd19", "title": "SHORT COMMUNICATION Tandem Placement of a Coronavirus Promoter Results in Enhanced mRNA Synthesis from the Downstream-Most Initiation Site", "coda_paper_id": 1341, "has_expert_labels": false, "abstract_text": "Insertion of the 17-nucleotide promoter region for the bovine coronavirus N gene as part of a 27-nucleotide cassette into the open reading frame of a cloned synthetic defective-interfering ( DI ) RNA resulted in synthesis of subDI RNA transcripts from the replicating DI RNA genome . Duplicating and triplicating the promoter sequence in tandem caused a progressive increase in the efficiency of subgenomic mRNA synthesis despite a concurrent decrease in the rate of DI RNA accumulation that was not specific to the promoter sequences being added . Although initiation of transcription ( leader fusion ) occurred at each of the three promoter sites in the tandem construct , almost all of the transcripts were found as a product of the most downstream ( 3-most on the genome ) promoter . These results show that enhancement of subgenomic mRNA synthesis is a property that can reside within sequence situated near the promoter . A possible role for the plus strand in the downstream promoter choice is suggested .", "gold_segments": [{"segment_text": "Insertion of the 17-nucleotide promoter region for the bovine coronavirus N gene as part of a 27-nucleotide cassette into the open reading frame of a cloned synthetic defective-interfering ( DI ) RNA resulted in synthesis of subDI RNA transcripts from the replicating DI RNA genome .", "label": "finding"}, {"segment_text": "Duplicating and triplicating the promoter sequence in tandem caused a progressive increase in the efficiency of subgenomic mRNA synthesis despite a concurrent decrease in the rate of DI RNA accumulation that was not specific to the promoter sequences being added .", "label": "finding"}, {"segment_text": "Although initiation of transcription ( leader fusion ) occurred at each of the three promoter sites in the tandem construct ,", "label": "finding"}, {"segment_text": "almost all of the transcripts were found as a product of the most downstream ( 3-most on the genome ) promoter .", "label": "finding"}, {"segment_text": "These results show that enhancement of subgenomic mRNA synthesis is a property that can reside within sequence situated near the promoter .", "label": "finding"}, {"segment_text": "A possible role for the plus strand in the downstream promoter choice is suggested .", "label": "finding"}], "n_segments": 6}
{"paper_id": "9c6df064dc7aedea41eca964a69131e37f330f6b", "title": "Enterovirus D-68 Infection, Prophylaxis, and Vaccination in a Novel Permissive Animal Model, the Cotton Rat (Sigmodon hispidus)", "coda_paper_id": 1287, "has_expert_labels": false, "abstract_text": "In recent years , there has been a significant increase in detection of Enterovirus D-68 ( EV-D68 ) among patients with severe respiratory infections worldwide . EV-D68 is now recognized as a re-emerging pathogen ; however , due to lack of a permissive animal model for EV-D68 , a comprehensive understanding of the pathogenesis and immune response against EV-D68 has been hampered . Recently , it was shown that EV-D68 has a strong affinity for α2,6-linked sialic acids ( SAs ) and we have shown previously that α2,6-linked SAs are abundantly present in the respiratory tract of cotton rats ( Sigmodon hispidus ) . Thus , we hypothesized that cotton rats could be a potential model for EV-D68 infection . Here , we evaluated the ability of two recently isolated EV-D68 strains ( VANBT/1 and MO / 14/49 ) , along with the historical prototype Fermon strain ( ATCC ) , to infect cotton rats . We found that cotton rats are permissive to EV-D68 infection without virus adaptation . The different strains of EV-D68 showed variable infection profiles and the ability to produce neutralizing antibody ( NA ) upon intranasal infection or intramuscular immunization . Infection with the VANBT/1 resulted in significant induction of pulmonary cytokine gene expression and lung pathology . Intramuscular immunization with live VANBT/1 or MO/14/49 induced strong homologous antibody responses , but a moderate heterologous NA response . We showed that passive prophylactic administration of serum with high content of NA against VANBT/1 resulted in an efficient antiviral therapy . VANBT/1-immunized animals showed complete protection from VANBT/1 challenge , but induced strong pulmonary Th1 and Th2 cytokine responses and enhanced lung pathology , indicating the generation of exacerbated immune response by immunization . In conclusion , our data illustrate that the cotton rat is a powerful animal model that provides an experimental platform to investigate pathogenesis , immune response , anti-viral therapies and vaccines against EV-D68 infection .", "gold_segments": [{"segment_text": "In recent years , there has been a significant increase in detection of Enterovirus D-68 ( EV-D68 ) among patients with severe respiratory infections worldwide .", "label": "background"}, {"segment_text": "EV-D68 is now recognized as a re-emerging pathogen ; however ,", "label": "background"}, {"segment_text": "due to lack of a permissive animal model for EV-D68 ,", "label": "background"}, {"segment_text": "a comprehensive understanding of the pathogenesis and immune response against EV-D68 has been hampered .", "label": "background"}, {"segment_text": "Recently , it was shown that EV-D68 has a strong affinity for α2,6-linked sialic acids ( SAs ) and we have shown previously that α2,6-linked SAs are abundantly present in the respiratory tract of cotton rats ( Sigmodon hispidus ) .", "label": "background"}, {"segment_text": "Thus , we hypothesized that cotton rats could be a potential model for EV-D68 infection .", "label": "purpose"}, {"segment_text": "Here , we evaluated the ability of two recently isolated EV-D68 strains ( VANBT/1 and MO / 14/49 ) ,", "label": "method"}, {"segment_text": "along with the historical prototype Fermon strain ( ATCC ) , to infect cotton rats .", "label": "method"}, {"segment_text": "We found that cotton rats are permissive to EV-D68 infection without virus adaptation .", "label": "finding"}, {"segment_text": "The different strains of EV-D68 showed variable infection profiles and the ability to produce neutralizing antibody ( NA ) upon intranasal infection or intramuscular immunization .", "label": "finding"}, {"segment_text": "Infection with the VANBT/1 resulted in significant induction of pulmonary cytokine gene expression and lung pathology .", "label": "finding"}, {"segment_text": "Intramuscular immunization with live VANBT/1 or MO/14/49 induced strong homologous antibody responses ,", "label": "finding"}, {"segment_text": "but a moderate heterologous NA response .", "label": "finding"}, {"segment_text": "We showed that passive prophylactic administration of serum with high content of NA against VANBT/1 resulted in an efficient antiviral therapy .", "label": "finding"}, {"segment_text": "VANBT/1-immunized animals showed complete protection from VANBT/1 challenge ,", "label": "finding"}, {"segment_text": "but induced strong pulmonary Th1 and Th2 cytokine responses and enhanced lung pathology ,", "label": "finding"}, {"segment_text": "indicating the generation of exacerbated immune response by immunization .", "label": "finding"}, {"segment_text": "In conclusion , our data illustrate that the cotton rat is a powerful animal model that provides an experimental platform to investigate pathogenesis ,", "label": "finding"}, {"segment_text": "immune response , anti-viral therapies and vaccines against EV-D68 infection .", "label": "finding"}], "n_segments": 19}
{"paper_id": "b298992d7feb9dd3d23192572f975abdf2cebc0a", "title": "Treatment with proteasome inhibitor bortezomib decreases organic anion transporting polypeptide (OATP) 1B3- mediated transport in a substrate-dependent manner", "coda_paper_id": 1503, "has_expert_labels": false, "abstract_text": "OATP1B1 and OATP1B3 mediate hepatic uptake of many drugs ( e.g. , statins ) and can mediate transporter-mediated drug-drug-interactions ( DDIs ) . Bortezomib is the first-in-class proteasome inhibitor drug approved by the U. S. Food and Drug Administration for the treatment of multiple myeloma . The potential of bortezomib to cause OATP-mediated DDIs has not been assessed . The current study investigated the involvement of the ubiquitin-proteasome system ( UPS ) in OATP1B1 and OATP1B3 degradation and determined the effects of proteasome inhibitors on OATP1B1-and OATP1B3-mediated transport . Co-immunoprecipitation of FLAG-OATP1B1 / 1B3 and HA-ubiquitin was observed in human embryonic kidney ( HEK ) 293 cells co-transfected with FLAG-tagged OATP1B1/OATP1B3 and hemagglutinin ( HA ) - tagged ubiquitin , suggesting that OATP1B1 and OATP1B3 can be ubiquitin-modified . Although blocking proteasome activity by bortezomib treatment ( 50 nM , 7 h ) increased the endogenous ubiquitin-conjugated FLAG-OATP1B1 and FLAG-OATP1B3 in HEK293-FLAG-OATP1B1 and-OATP1B3 cells , such treatment did not affect the total protein levels of OATP1B1 and OATP1B3 , suggesting that the UPS plays a minor role in degradation of OATP1B1 and OATP1B3 under current constitutive conditions . Pretreatment with bortezomib ( 50-250 nM , 2-7 h ) significantly decreased transport of ( 3 H ) CCK-8 , a specific OATP1B3 substrate , in HEK293-OATP1B3 and human sandwich-cultured hepatocytes ( SCH ) . However , bortezomib pretreatment had negligible effects on the transport of ( 3 H ) E 2 17βG and ( 3 H ) pitavastatin , dual substrates of OATP1B1 and OATP1B3 , in HEK293-OATP1B1 / 1B3 cells and/or human SCH . Compared with vehicle control treatment , bortezomib pretreatment significantly decreased the maximal transport velocity ( V max ) of OATP1B3-mediated transport of CCK-8 ( 92.25 ± 14.2 vs. 133.95 ± 15.5 pmol/mg protein / min ) without affecting the affinity constant ( K m ) values . Treatment with other proteasome inhibitors MG132 , epoxomicin , and carfilzomib also significantly decreased OATP1B3mediated ( 3 H ) CCK-8 transport . In summary , the current studies for the first time report PLOS ONE | https://doi .", "gold_segments": [{"segment_text": "OATP1B1 and OATP1B3 mediate hepatic uptake of many drugs ( e.g. , statins ) and can mediate transporter-mediated drug-drug-interactions ( DDIs ) .", "label": "background"}, {"segment_text": "Bortezomib is the first-in-class proteasome inhibitor drug approved by the U. S. Food and Drug Administration for the treatment of multiple myeloma .", "label": "background"}, {"segment_text": "The potential of bortezomib to cause OATP-mediated DDIs has not been assessed .", "label": "background"}, {"segment_text": "The current study investigated the involvement of the ubiquitin-proteasome system ( UPS ) in OATP1B1 and OATP1B3 degradation and determined the effects of proteasome inhibitors on OATP1B1-and OATP1B3-mediated transport .", "label": "purpose"}, {"segment_text": "Co-immunoprecipitation of FLAG-OATP1B1 / 1B3 and HA-ubiquitin was observed in human embryonic kidney ( HEK ) 293 cells co-transfected with FLAG-tagged OATP1B1/OATP1B3 and hemagglutinin ( HA ) - tagged ubiquitin ,", "label": "method"}, {"segment_text": "suggesting that OATP1B1 and OATP1B3 can be ubiquitin-modified .", "label": "method"}, {"segment_text": "Although blocking proteasome activity by bortezomib treatment ( 50 nM , 7 h ) increased the endogenous ubiquitin-conjugated FLAG-OATP1B1 and FLAG-OATP1B3 in HEK293-FLAG-OATP1B1 and-OATP1B3 cells ,", "label": "finding"}, {"segment_text": "such treatment did not affect the total protein levels of OATP1B1 and OATP1B3 ,", "label": "finding"}, {"segment_text": "suggesting that the UPS plays a minor role in degradation of OATP1B1 and OATP1B3 under current constitutive conditions .", "label": "finding"}, {"segment_text": "Pretreatment with bortezomib ( 50-250 nM , 2-7 h ) significantly decreased transport of ( 3 H ) CCK-8 ,", "label": "finding"}, {"segment_text": "a specific OATP1B3 substrate , in HEK293-OATP1B3 and human sandwich-cultured hepatocytes ( SCH ) .", "label": "finding"}, {"segment_text": "However , bortezomib pretreatment had negligible effects on the transport of ( 3 H ) E 2 17βG and ( 3 H ) pitavastatin ,", "label": "finding"}, {"segment_text": "dual substrates of OATP1B1 and OATP1B3 ,", "label": "finding"}, {"segment_text": "in HEK293-OATP1B1 / 1B3 cells and/or human SCH .", "label": "finding"}, {"segment_text": "Compared with vehicle control treatment ,", "label": "finding"}, {"segment_text": "bortezomib pretreatment significantly decreased the maximal transport velocity ( V max ) of OATP1B3-mediated transport of CCK-8 ( 92.25 ± 14.2 vs. 133.95 ± 15.5 pmol/mg protein / min ) without affecting the affinity constant ( K m ) values .", "label": "finding"}, {"segment_text": "Treatment with other proteasome inhibitors MG132 ,", "label": "finding"}, {"segment_text": "epoxomicin , and carfilzomib also significantly decreased OATP1B3mediated ( 3 H ) CCK-8 transport .", "label": "finding"}, {"segment_text": "In summary , the current studies for the first time report PLOS ONE | https://doi .", "label": "finding"}], "n_segments": 19}