[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Lupus-prone mice infected with curliproducing bacteria have higher autoantibody titers compared to controls.

Document title: Amyloid-DNA Composites of Bacterial Biofilms Stimulate Autoimmunity.

Abstract sentences:
[0] Research on the human microbiome has established that commensal and pathogenic bacteria can influence obesity, cancer, and autoimmunity through mechanisms mostly unknown.
[1] We found that a component of bacterial biofilms, the amyloid protein curli, irreversibly formed fibers with bacterial DNA during biofilm formation.
[2] This interaction accelerated amyloid polymerization and created potent immunogenic complexes that activated immune cells, including dendritic cells, to produce cytokines such as type I interferons, which are pathogenic in systemic lupus erythematosus (SLE).
[3] When given systemically, curli-DNA composites triggered immune activation and production of autoantibodies in lupus-prone and wild-type mice.
[4] We also found that the infection of lupus-prone mice with curli-producing bacteria triggered higher autoantibody titers compared to curli-deficient bacteria.
[5] These data provide a mechanism by which the microbiome and biofilm-producing enteric infections may contribute to the progression of SLE and point to a potential molecular target for treatment of autoimmunity.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [4]
Explanation: Evidence states: "We also found that the infection of lupus-prone mice with curli-producing bacteria triggered higher autoantibody titers compared to curli-deficient bacteria.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Ly49Q directs the organization of neutrophil migration to inflammation sites by regulating membrane raft functions.

Document title: The Ly49Q receptor plays a crucial role in neutrophil polarization and migration by regulating raft trafficking.

Abstract sentences:
[0] Neutrophils rapidly undergo polarization and directional movement to infiltrate the sites of infection and inflammation.
[1] Here, we show that an inhibitory MHC I receptor, Ly49Q, was crucial for the swift polarization of and tissue infiltration by neutrophils.
[2] During the steady state, Ly49Q inhibited neutrophil adhesion by preventing focal-complex formation, likely by inhibiting Src and PI3 kinases.
[3] However, in the presence of inflammatory stimuli, Ly49Q mediated rapid neutrophil polarization and tissue infiltration in an ITIM-domain-dependent manner.
[4] These opposite functions appeared to be mediated by distinct use of effector phosphatase SHP-1 and SHP-2.
[5] Ly49Q-dependent polarization and migration were affected by Ly49Q regulation of membrane raft functions.
[6] We propose that Ly49Q is pivotal in switching neutrophils to their polarized morphology and rapid migration upon inflammation, through its spatiotemporal regulation of membrane rafts and raft-associated signaling molecules.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [1]
Explanation: Evidence states: "Here, we show that an inhibitory MHC I receptor, Ly49Q, was crucial for the swift polarization of and tissue infiltration by neutrophils.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Ly49Q directs the organization of neutrophil migration to inflammation sites by regulating membrane raft functions.

Document title: The Ly49Q receptor plays a crucial role in neutrophil polarization and migration by regulating raft trafficking.

Abstract sentences:
[0] Neutrophils rapidly undergo polarization and directional movement to infiltrate the sites of infection and inflammation.
[1] Here, we show that an inhibitory MHC I receptor, Ly49Q, was crucial for the swift polarization of and tissue infiltration by neutrophils.
[2] During the steady state, Ly49Q inhibited neutrophil adhesion by preventing focal-complex formation, likely by inhibiting Src and PI3 kinases.
[3] However, in the presence of inflammatory stimuli, Ly49Q mediated rapid neutrophil polarization and tissue infiltration in an ITIM-domain-dependent manner.
[4] These opposite functions appeared to be mediated by distinct use of effector phosphatase SHP-1 and SHP-2.
[5] Ly49Q-dependent polarization and migration were affected by Ly49Q regulation of membrane raft functions.
[6] We propose that Ly49Q is pivotal in switching neutrophils to their polarized morphology and rapid migration upon inflammation, through its spatiotemporal regulation of membrane rafts and raft-associated signaling molecules.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [5]
Explanation: Evidence states: "Ly49Q-dependent polarization and migration were affected by Ly49Q regulation of membrane raft functions.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Ly6C hi monocytes have a lower inflammatory capacity compared to their Ly6C lo counterparts.

Document title: Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis.

Abstract sentences:
[0] Mononuclear phagocytes, including monocytes, macrophages, and dendritic cells, contribute to tissue integrity as well as to innate and adaptive immune defense.
[1] Emerging evidence for labor division indicates that manipulation of these cells could bear therapeutic potential.
[2] However, specific ontogenies of individual populations and the overall functional organization of this cellular network are not well defined.
[3] Here we report a fate-mapping study of the murine monocyte and macrophage compartment taking advantage of constitutive and conditional CX(3)CR1 promoter-driven Cre recombinase expression.
[4] We have demonstrated that major tissue-resident macrophage populations, including liver Kupffer cells and lung alveolar, splenic, and peritoneal macrophages, are established prior to birth and maintain themselves subsequently during adulthood independent of replenishment by blood monocytes.
[5] Furthermore, we have established that short-lived Ly6C(+) monocytes constitute obligatory steady-state precursors of blood-resident Ly6C(-) cells and that the abundance of Ly6C(+) blood monocytes dynamically controls the circulation lifespan of their progeny.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Ly6C hi monocytes have a lower inflammatory capacity than Ly6C lo monocytes.

Document title: Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response.

Abstract sentences:
[0] Blood monocytes are well-characterized precursors for macrophages and dendritic cells.
[1] Subsets of human monocytes with differential representation in various disease states are well known.
[2] In contrast, mouse monocyte subsets have been characterized minimally.
[3] In this study we identify three subpopulations of mouse monocytes that can be distinguished by differential expression of Ly-6C, CD43, CD11c, MBR, and CD62L.
[4] The subsets share the characteristics of extensive phagocytosis, similar expression of M-CSF receptor (CD115), and development into macrophages upon M-CSF stimulation.
[5] By eliminating blood monocytes with dichloromethylene-bisphosphonate-loaded liposomes and monitoring their repopulation, we showed a developmental relationship between the subsets.
[6] Monocytes were maximally depleted 18 h after liposome application and subsequently reappeared in the circulation.
[7] These cells were exclusively of the Ly-6C(high) subset, resembling bone marrow monocytes.
[8] Serial flow cytometric analyses of newly released Ly-6C(high) monocytes showed that Ly-6C expression on these cells was down-regulated while in circulation.
[9] Under inflammatory conditions elicited either by acute infection with Listeria monocytogenes or chronic infection with Leishmania major, there was a significant increase in immature Ly-6C(high) monocytes, resembling the inflammatory left shift of granulocytes.
[10] In addition, acute peritoneal inflammation recruited preferentially Ly-6C(med-high) monocytes.
[11] Taken together, these data identify distinct subpopulations of mouse blood monocytes that differ in maturation stage and capacity to become recruited to inflammatory sites.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [9]
Explanation: Evidence states: "Under inflammatory conditions elicited either by acute infection with Listeria monocytogenes or chronic infection with Leishmania major, there was a significant increase in immature Ly-6C(high) monocytes, resembling the inflammatory left shift of granulocytes.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Ly6C hi monocytes have a lower inflammatory capacity than Ly6C lo monocytes.

Document title: Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response.

Abstract sentences:
[0] Blood monocytes are well-characterized precursors for macrophages and dendritic cells.
[1] Subsets of human monocytes with differential representation in various disease states are well known.
[2] In contrast, mouse monocyte subsets have been characterized minimally.
[3] In this study we identify three subpopulations of mouse monocytes that can be distinguished by differential expression of Ly-6C, CD43, CD11c, MBR, and CD62L.
[4] The subsets share the characteristics of extensive phagocytosis, similar expression of M-CSF receptor (CD115), and development into macrophages upon M-CSF stimulation.
[5] By eliminating blood monocytes with dichloromethylene-bisphosphonate-loaded liposomes and monitoring their repopulation, we showed a developmental relationship between the subsets.
[6] Monocytes were maximally depleted 18 h after liposome application and subsequently reappeared in the circulation.
[7] These cells were exclusively of the Ly-6C(high) subset, resembling bone marrow monocytes.
[8] Serial flow cytometric analyses of newly released Ly-6C(high) monocytes showed that Ly-6C expression on these cells was down-regulated while in circulation.
[9] Under inflammatory conditions elicited either by acute infection with Listeria monocytogenes or chronic infection with Leishmania major, there was a significant increase in immature Ly-6C(high) monocytes, resembling the inflammatory left shift of granulocytes.
[10] In addition, acute peritoneal inflammation recruited preferentially Ly-6C(med-high) monocytes.
[11] Taken together, these data identify distinct subpopulations of mouse blood monocytes that differ in maturation stage and capacity to become recruited to inflammatory sites.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [10]
Explanation: Evidence states: "In addition, acute peritoneal inflammation recruited preferentially Ly-6C(med-high) monocytes.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Lymphadenopathy is observed in knockin mouse lacking the SHP-2 MAPK pathway.

Document title: Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses.

Abstract sentences:
[0] We generated a series of knockin mouse lines, in which the cytokine receptor gp130-dependent STAT3 and/or SHP2 signals were disrupted, by replacing the mouse gp130 gene with human gp130 mutant cDNAs.
[1] The SHP2 signal-deficient mice (gp130F759/F759 were born normal but displayed splenomegaly and lymphadenopathy and an enhanced acute phase reaction.
[2] In contrast, the STAT3 signal-deficient mice (gp130FXQ/FXXQ) died perinatally, like the gp130-deficient mice (gp130D/D).
[3] The gp130F759/F759 mice showed prolonged gp130-induced STAT3 activation, indicating a negative regulatory role for SHP2.
[4] Th1-type cytokine production and IgG2a and IgG2b production were increased in the gp130F759/F759 mice, while they were decreased in the gp130FXXQ/FXXQ immune system.
[5] These results indicate that the balance of positive and negative signals generated through gp130 regulates the immune responses.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [1]
Explanation: Evidence states: "The SHP2 signal-deficient mice (gp130F759/F759 were born normal but displayed splenomegaly and lymphadenopathy and an enhanced acute phase reaction.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Macrolides have no protective effect against myocardial infarction.

Document title: Antibiotics and risk of subsequent first-time acute myocardial infarction.

Abstract sentences:
[0] CONTEXT Increasing evidence supports the hypothesis of a causal association between certain bacterial infections and increased risk of developing acute myocardial infarction.
[1] If such a causal association exists, subjects who used antibiotics active against the bacteria, regardless of indication, might be at lower risk of developing acute myocardial infarction than nonusers.
[2] OBJECTIVE To determine whether previous use of antibiotics decreases the risk of developing a first-time acute myocardial infarction.
[3] DESIGN Population-based case-control analysis.
[4] SETTING The United Kingdom-based General Practice Research Database comprising 350 general practices.
[5] PATIENTS A total of 3315 case patients aged 75 years or younger with a diagnosis of first-time acute myocardial infarction between 1992 and 1997 and 13139 controls without myocardial infarction matched to cases for age, sex, general practice attended, and calendar time.
[6] MAIN OUTCOME MEASURES Use of antibiotics among those who did or did not have a first-time acute myocardial infarction.
[7] RESULTS Cases were significantly less likely to have used tetracycline antibiotics (adjusted odds ratio [OR], 0.70; 95% confidence interval [CI], 0.55-0.90) or quinolones (adjusted OR, 0.45; 95% CI, 0.21-0.95).
[8] No effect was found for previous use of macrolides (primarily erythromycin), sulfonamides, penicillins, or cephalosporins.
[9] CONCLUSIONS The findings from this large case-control analysis provide further, albeit indirect, evidence for an association between bacterial infections with organisms susceptible to tetracycline or quinolone antibiotics and the risk of acute myocardial infarction.
[10] These results of preliminary nature should stimulate more research to further explore the role of infections in the etiology of acute myocardial infarction.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [8]
Explanation: Evidence states: "No effect was found for previous use of macrolides (primarily erythromycin), sulfonamides, penicillins, or cephalosporins.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Macrolides protect against myocardial infarction.

Document title: Antibiotics and risk of subsequent first-time acute myocardial infarction.

Abstract sentences:
[0] CONTEXT Increasing evidence supports the hypothesis of a causal association between certain bacterial infections and increased risk of developing acute myocardial infarction.
[1] If such a causal association exists, subjects who used antibiotics active against the bacteria, regardless of indication, might be at lower risk of developing acute myocardial infarction than nonusers.
[2] OBJECTIVE To determine whether previous use of antibiotics decreases the risk of developing a first-time acute myocardial infarction.
[3] DESIGN Population-based case-control analysis.
[4] SETTING The United Kingdom-based General Practice Research Database comprising 350 general practices.
[5] PATIENTS A total of 3315 case patients aged 75 years or younger with a diagnosis of first-time acute myocardial infarction between 1992 and 1997 and 13139 controls without myocardial infarction matched to cases for age, sex, general practice attended, and calendar time.
[6] MAIN OUTCOME MEASURES Use of antibiotics among those who did or did not have a first-time acute myocardial infarction.
[7] RESULTS Cases were significantly less likely to have used tetracycline antibiotics (adjusted odds ratio [OR], 0.70; 95% confidence interval [CI], 0.55-0.90) or quinolones (adjusted OR, 0.45; 95% CI, 0.21-0.95).
[8] No effect was found for previous use of macrolides (primarily erythromycin), sulfonamides, penicillins, or cephalosporins.
[9] CONCLUSIONS The findings from this large case-control analysis provide further, albeit indirect, evidence for an association between bacterial infections with organisms susceptible to tetracycline or quinolone antibiotics and the risk of acute myocardial infarction.
[10] These results of preliminary nature should stimulate more research to further explore the role of infections in the etiology of acute myocardial infarction.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [8]
Explanation: Evidence states: "No effect was found for previous use of macrolides (primarily erythromycin), sulfonamides, penicillins, or cephalosporins.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Macropinocytosis contributes to a cell's supply of amino acids via the intracellular uptake of protein.

Document title: The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1

Abstract sentences:
[0] Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids.
[1] Recently, Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell's dependence on extracellular glutamine.
[2] Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source.
[3] Lysosomal degradation of extracellular proteins can sustain cell survival and induce activation of mTORC1 but fails to elicit significant cell accumulation.
[4] Unlike its growth-promoting activity under amino-acid-replete conditions, we discovered that mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source.
[5] Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo.
[6] Thus, by preventing nutritional consumption of extracellular proteins, mTORC1 couples growth to availability of free amino acids.
[7] These results may have important implications for the use of mTOR inhibitors as therapeutics.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [2]
Explanation: Evidence states: "Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Many proteins in human cells can be post-translationally modified at lysine residues via acetylation.

Document title: Protein Lysine Acetylated/Deacetylated Enzymes and the Metabolism-Related Diseases

Abstract sentences:
[0] Lysine acetylation is a reversible posttranslational modifcation, an epigenetic phenomenon, referred to as transfer of an acetyl group from acetyl CoA to lysine e- amino group of targeted protein, which is modulated by acetyltransferases (histone/ lysine (K) acetyltransferases, HATs/KATs) and deacetylases (histone/lysine (K) deacetylases, HDACs/KDACs).
[1] Lysine acetylation regulates various metabolic processes, such as fatty acid oxidation, Krebs cycle, oxidative phosphorylation, angiogenesis and so on.
[2] Thus disorders of lysine acetylation may be correlated with obesity, diabetes and cardiovascular disease, which are termed as the metabolic complication.
[3] With accumulating studies on proteomic acetylation, lysine acetylation also involves in cell immune status and degenerative diseases, for example, Alzheimer’s disease and Huntington’s disease.
[4] This review primarily summarizes the current studies of lysine acetylation in metabolism modulation and in metabolism-related diseases, such as cardiovascular disease and fat metabolism disorder.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [0]
Explanation: Evidence states: "Lysine acetylation is a reversible posttranslational modifcation, an epigenetic phenomenon, referred to as transfer of an acetyl group from acetyl CoA to lysine e- amino group of targeted protein, which is modulated by acetyltransferases (histone/ lysine (K) acetyltransferases, HATs/KATs) and deacetylases (histone/lysine (K) deacetylases, HDACs/KDACs).". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mathematical models predict that using Artemisinin-based combination therapy over nongametocytocidal drugs have a dramatic impact in reducing malaria transmission.

Document title: Modelling the Impact of Artemisinin Combination Therapy and Long-Acting Treatments on Malaria Transmission Intensity

Abstract sentences:
[0] BACKGROUND Artemisinin derivatives used in recently introduced combination therapies (ACTs) for Plasmodium falciparum malaria significantly lower patient infectiousness and have the potential to reduce population-level transmission of the parasite.
[1] With the increased interest in malaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs with different pharmacodynamics becomes a key issue.
[2] This study estimates the reduction in transmission that may be achieved by introducing different types of treatment for symptomatic P. falciparum malaria in endemic areas.
[3] METHODS AND FINDINGS We developed a mathematical model to predict the potential impact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania.
[4] We also estimated the impact that could be achieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects.
[5] Rates of treatment, asymptomatic infection, and symptomatic infection in the six study areas were estimated using the model together with data from a cross-sectional survey of 5,667 individuals conducted prior to policy change from sulfadoxine-pyrimethamine to ACT.
[6] The effects of ACT and other drug types on gametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data.
[7] Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved by ACT were highest in the areas with low initial transmission.
[8] A 53% reduction in prevalence of infection was seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalence of parasitaemia was lowest (3.7%), compared to an 11% reduction in the highest-transmission setting (baseline slide prevalence = 57.1%).
[9] Estimated percentage reductions in incidence of clinical episodes were similar.
[10] The absolute size of the public health impact, however, was greater in the highest-transmission area, with 54 clinical episodes per 100 persons per year averted compared to five per 100 persons per year in the lowest-transmission area.
[11] High coverage was important.
[12] Reducing presumptive treatment through improved diagnosis substantially reduced the number of treatment courses required per clinical episode averted in the lower-transmission settings although there was some loss of overall impact on transmission.
[13] An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest-transmission setting.
[14] CONCLUSIONS Our results suggest that ACTs have the potential for transmission reductions approaching those achieved by insecticide-treated nets in lower-transmission settings.
[15] ACT partner drugs and nonartemisinin regimens with longer prophylactic times could result in a larger impact in higher-transmission settings, although their long term benefit must be evaluated in relation to the risk of development of parasite resistance.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [13]
Explanation: Evidence states: "An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest-transmission setting.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mercaptopurine is anabolized into the inactive methylmercaptopurine by thiopurine methyltrasnferase (TPMT).

Document title: Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

Abstract sentences:
[0] Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors.
[1] Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease.
[2] Using whole-exome sequencing, we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs.
[3] NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts.
[4] These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Metastatic colorectal cancer treated with a single agent fluoropyrimidines resulted in reduced efficacy and lower quality of life when compared with oxaliplatin-based chemotherapy in elderly patients.

Document title: Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial

Abstract sentences:
[0] BACKGROUND Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials.
[1] We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer.
[2] METHODS We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy.
[3] After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D).
[4] Treatment allocation was not masked.
[5] Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks.
[6] The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL).
[7] Analysis was by intention to treat.
[8] Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU).
[9] This study is registered, number ISRCTN21221452.
[10] FINDINGS 459 patients were randomly assigned (115 to each of groups A-C, 114 to group D).
[11] Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3-7·5] vs 4·5 months [2·8-6·4]; hazard ratio 0·84, 95% CI 0·69-1·01, p=0·07).
[12] Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine.
[13] The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03).
[14] In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14-1·52), less widespread disease (1·51, 1·05-2·19), and use of oxaliplatin (0·57, 0·39-0·82) were predictive of better OTU.
[15] INTERPRETATION FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial.
[16] On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met.
[17] Capecitabine did not improve QoL compared with fluorouracil.
[18] Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit.
[19] FUNDING Cancer Research UK and the Medical Research Council.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [16]
Explanation: Evidence states: "On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mice defective for deoxyribonucleic acid (DNA) polymerase I (polI) reveal increased sensitivity to ionizing radiation (IR).

Document title: Nonoverlapping functions of DNA polymerases mu, lambda, and terminal deoxynucleotidyltransferase during immunoglobulin V(D)J recombination in vivo.

Abstract sentences:
[0] DNA polymerases mu (pol mu), lambda (pol lambda), and terminal deoxynucleotidyltransferase (TdT) are enzymes of the pol X family that share homology in sequence and functional domain organization.
[1] We showed previously that pol mu participates in light chain but surprisingly not heavy chain gene rearrangement.
[2] We show here that immunoglobulin heavy chain junctions from pol lambda-deficient animals have shorter length with normal N-additions, thus indicating that pol lambda is recruited during heavy chain rearrangement at a step that precedes the action of TdT. In contrast to previous in vitro studies, analysis of animals with combined inactivation of these enzymes revealed no overlapping or compensatory activities for V(D)J recombination between pol mu, pol lambda, and TdT. This complex usage of polymerases with distinct catalytic specificities may correspond to the specific function that the third hypervariable region assumes for each immunoglobulin chain, with pol lambda maintaining a large heavy chain junctional heterogeneity and pol mu ensuring a restricted light chain junctional variability.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mice that lack Interferon-γ or its receptor exhibit high resistance to experimental autoimmune myocarditis.

Document title: Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice: enhanced disease severity by impaired inducible nitric oxide synthase induction.

Abstract sentences:
[0] BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases.
[1] Little is known about its role in inflammatory heart disease.
[2] METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality.
[3] Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease.
[4] The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts.
[5] Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis.
[6] CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [2]
Explanation: Evidence states: "METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mice that lack Interferon-γ or its receptor exhibit high resistance to experimental autoimmune myocarditis.

Document title: Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice: enhanced disease severity by impaired inducible nitric oxide synthase induction.

Abstract sentences:
[0] BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases.
[1] Little is known about its role in inflammatory heart disease.
[2] METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality.
[3] Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease.
[4] The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts.
[5] Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis.
[6] CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [3]
Explanation: Evidence states: "Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mice that lack Interferon-γ or its receptor exhibit high resistance to experimental autoimmune myocarditis.

Document title: Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice: enhanced disease severity by impaired inducible nitric oxide synthase induction.

Abstract sentences:
[0] BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases.
[1] Little is known about its role in inflammatory heart disease.
[2] METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality.
[3] Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease.
[4] The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts.
[5] Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis.
[6] CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [6]
Explanation: Evidence states: "CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mice without IFN-γ or its receptor are resistant to EAM induced with α-MyHC/CFA.

Document title: Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: induction by IL-12 and protection by IFN-gamma.

Abstract sentences:
[0] IL-12 and IFN-gamma positively regulate each other and type 1 inflammatory responses, which are believed to cause tissue damage in autoimmune diseases.
[1] We investigated the role of the IL-12/IFN-gamma (Th1) axis in the development of autoimmune myocarditis.
[2] IL-12p40-deficient mice on a susceptible background resisted myocarditis.
[3] In the absence of IL-12, autospecific CD4(+) T cells proliferated poorly and showed increased Th2 cytokine responses.
[4] However, IFN-gamma-deficient mice developed fatal autoimmune disease, and blockade of IL-4R signaling did not confer susceptibility to myocarditis in IL-12p40-deficient mice, demonstrating that IL-12 triggers autoimmunity by a mechanism independent of the effector cytokines IFN-gamma and IL-4.
[5] In conclusion, our results suggest that the IL-12/IFN-gamma axis is a double-edged sword for the development of autoimmune myocarditis.
[6] Although IL-12 mediates disease by induction/expansion of Th1-type cells, IFN-gamma production from these cells limits disease progression.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: MicroRNA is involved in the regulation of Neural Stem Cell (NSC) differentiation and proliferation dynamic homeostasis

Document title: Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation.

Abstract sentences:
[0] Methyl-CpG binding protein 1 (MBD1) regulates gene expression via a DNA methylation-mediated epigenetic mechanism.
[1] We have previously demonstrated that MBD1 deficiency impairs adult neural stem/progenitor cell (aNSC) differentiation and neurogenesis, but the underlying mechanism was unclear.
[2] Here, we show that MBD1 regulates the expression of several microRNAs in aNSCs and, specifically, that miR-184 is directly repressed by MBD1.
[3] High levels of miR-184 promoted proliferation but inhibited differentiation of aNSCs, whereas inhibition of miR-184 rescued the phenotypes associated with MBD1 deficiency.
[4] We further found that miR-184 regulates the expression of Numblike (Numbl), a known regulator of brain development, by binding to the 3'-UTR of Numbl mRNA and affecting its translation.
[5] Expression of exogenous Numbl could rescue the aNSC defects that result from either miR-184 overexpression or MBD1 deficiency.
[6] Therefore, MBD1, miR-184, and Numbl form a regulatory network that helps control the balance between proliferation and differentiation of aNSCs.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [3]
Explanation: Evidence states: "High levels of miR-184 promoted proliferation but inhibited differentiation of aNSCs, whereas inhibition of miR-184 rescued the phenotypes associated with MBD1 deficiency.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Microarray results from culture-amplified mixtures of serotypes correlate poorly with microarray results from uncultured mixtures.

Document title: The PneuCarriage Project: A Multi-Centre Comparative Study to Identify the Best Serotyping Methods for Examining Pneumococcal Carriage in Vaccine Evaluation Studies

Abstract sentences:
[0] BACKGROUND The pneumococcus is a diverse pathogen whose primary niche is the nasopharynx.
[1] Over 90 different serotypes exist, and nasopharyngeal carriage of multiple serotypes is common.
[2] Understanding pneumococcal carriage is essential for evaluating the impact of pneumococcal vaccines.
[3] Traditional serotyping methods are cumbersome and insufficient for detecting multiple serotype carriage, and there are few data comparing the new methods that have been developed over the past decade.
[4] We established the PneuCarriage project, a large, international multi-centre study dedicated to the identification of the best pneumococcal serotyping methods for carriage studies.
[5] METHODS AND FINDINGS Reference sample sets were distributed to 15 research groups for blinded testing.
[6] Twenty pneumococcal serotyping methods were used to test 81 laboratory-prepared (spiked) samples.
[7] The five top-performing methods were used to test 260 nasopharyngeal (field) samples collected from children in six high-burden countries.
[8] Sensitivity and positive predictive value (PPV) were determined for the test methods and the reference method (traditional serotyping of >100 colonies from each sample).
[9] For the alternate serotyping methods, the overall sensitivity ranged from 1% to 99% (reference method 98%), and PPV from 8% to 100% (reference method 100%), when testing the spiked samples.
[10] Fifteen methods had ≥70% sensitivity to detect the dominant (major) serotype, whilst only eight methods had ≥70% sensitivity to detect minor serotypes.
[11] For the field samples, the overall sensitivity ranged from 74.2% to 95.8% (reference method 93.8%), and PPV from 82.2% to 96.4% (reference method 99.6%).
[12] The microarray had the highest sensitivity (95.8%) and high PPV (93.7%).
[13] The major limitation of this study is that not all of the available alternative serotyping methods were included.
[14] CONCLUSIONS Most methods were able to detect the dominant serotype in a sample, but many performed poorly in detecting the minor serotype populations.
[15] Microarray with a culture amplification step was the top-performing method.
[16] Results from this comprehensive evaluation will inform future vaccine evaluation and impact studies, particularly in low-income settings, where pneumococcal disease burden remains high.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mitochondria are uninvolved in apoptosis.

Document title: Mitochondria: Dynamic Organelles in Disease, Aging, and Development

Abstract sentences:
[0] Mitochondria are the primary energy-generating system in most eukaryotic cells.
[1] Additionally, they participate in intermediary metabolism, calcium signaling, and apoptosis.
[2] Given these well-established functions, it might be expected that mitochondrial dysfunction would give rise to a simple and predictable set of defects in all tissues.
[3] However, mitochondrial dysfunction has pleiotropic effects in multicellular organisms.
[4] Clearly, much about the basic biology of mitochondria remains to be understood.
[5] Here we discuss recent work that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [1]
Explanation: Evidence states: "Additionally, they participate in intermediary metabolism, calcium signaling, and apoptosis.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Modifying the epigenome in the brain affects the normal human aging process by affecting certain genes related to neurogenesis.

Document title: Epigenetic mechanisms in neurological disease

Abstract sentences:
[0] The exploration of brain epigenomes, which consist of various types of DNA methylation and covalent histone modifications, is providing new and unprecedented insights into the mechanisms of neural development, neurological disease and aging.
[1] Traditionally, chromatin defects in the brain were considered static lesions of early development that occurred in the context of rare genetic syndromes, but it is now clear that mutations and maladaptations of the epigenetic machinery cover a much wider continuum that includes adult-onset neurodegenerative disease.
[2] Here, we describe how recent advances in neuroepigenetics have contributed to an improved mechanistic understanding of developmental and degenerative brain disorders, and we discuss how they could influence the development of future therapies for these conditions.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Monoclonal antibody targeting of N-cadherin inhibits metastasis.

Document title: Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance

Abstract sentences:
[0] The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology.
[1] Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC.
[2] Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis.
[3] Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro.
[4] In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression.
[5] N-cadherin–specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion.
[6] These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance.
[7] Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [4]
Explanation: Evidence states: "In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Monoclonal antibody targeting of N-cadherin inhibits metastasis.

Document title: Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance

Abstract sentences:
[0] The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology.
[1] Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC.
[2] Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis.
[3] Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro.
[4] In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression.
[5] N-cadherin–specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion.
[6] These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance.
[7] Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [7]
Explanation: Evidence states: "Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Most termination events in Okazaki fragments are sequence specific.

Document title: Quantitative, genome-wide analysis of eukaryotic replication initiation and termination.

Abstract sentences:
[0] Many fundamental aspects of DNA replication, such as the exact locations where DNA synthesis is initiated and terminated, how frequently origins are used, and how fork progression is influenced by transcription, are poorly understood.
[1] Via the deep sequencing of Okazaki fragments, we comprehensively document replication fork directionality throughout the S. cerevisiae genome, which permits the systematic analysis of initiation, origin efficiency, fork progression, and termination.
[2] We show that leading-strand initiation preferentially occurs within a nucleosome-free region at replication origins.
[3] Using a strain in which late origins can be induced to fire early, we show that replication termination is a largely passive phenomenon that does not rely on cis-acting sequences or replication fork pausing.
[4] The replication profile is predominantly determined by the kinetics of origin firing, allowing us to reconstruct chromosome-wide timing profiles from an asynchronous culture.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [1]
Explanation: Evidence states: "Via the deep sequencing of Okazaki fragments, we comprehensively document replication fork directionality throughout the S. cerevisiae genome, which permits the systematic analysis of initiation, origin efficiency, fork progression, and termination.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mutant mice lacking SVCT2 have greatly increased ascorbic acid levels in both brain and adrenals.

Document title: Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival

Abstract sentences:
[0] The only proven requirement for ascorbic acid (vitamin C) is in preventing scurvy, presumably because it is a cofactor for hydroxylases required for post-translational modifications that stabilize collagen.
[1] We have created mice deficient in the mouse ortholog (solute carrier family 23 member 1 or Slc23a1) of a rat ascorbic-acid transporter, Svct2 (ref.
[2] 4).
[3] Cultured embryonic fibroblasts from homozygous Slc23a1−/− mice had less than 5% of normal ascorbic-acid uptake.
[4] Ascorbic-acid levels were undetectable or markedly reduced in the blood and tissues of Slc23a1−/− mice.
[5] Prenatal supplementation of pregnant females did not elevate blood ascorbic acid in Slc23a1−/− fetuses, suggesting Slc23a1 is important in placental ascorbic-acid transport.
[6] Slc23a1−/− mice died within a few minutes of birth with respiratory failure and intraparenchymal brain hemorrhage.
[7] Lungs showed no postnatal expansion but had normal surfactant protein B levels.
[8] Brain hemorrhage was unlikely to be simply a form of scurvy since Slc23a1−/− mice showed no hemorrhage in any other tissues and their skin had normal skin 4-hydroxyproline levels despite low ascorbic-acid content.
[9] We conclude that Slc23a1 is required for transport of ascorbic acid into many tissues and across the placenta.
[10] Deficiency of the transporter is lethal in newborn mice, thereby revealing a previously unrecognized requirement for ascorbic acid in the perinatal period.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [4]
Explanation: Evidence states: "Ascorbic-acid levels were undetectable or markedly reduced in the blood and tissues of Slc23a1−/− mice.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mutant mice lacking SVCT2 have greatly increased ascorbic acid levels in both brain and adrenals.

Document title: Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival

Abstract sentences:
[0] The only proven requirement for ascorbic acid (vitamin C) is in preventing scurvy, presumably because it is a cofactor for hydroxylases required for post-translational modifications that stabilize collagen.
[1] We have created mice deficient in the mouse ortholog (solute carrier family 23 member 1 or Slc23a1) of a rat ascorbic-acid transporter, Svct2 (ref.
[2] 4).
[3] Cultured embryonic fibroblasts from homozygous Slc23a1−/− mice had less than 5% of normal ascorbic-acid uptake.
[4] Ascorbic-acid levels were undetectable or markedly reduced in the blood and tissues of Slc23a1−/− mice.
[5] Prenatal supplementation of pregnant females did not elevate blood ascorbic acid in Slc23a1−/− fetuses, suggesting Slc23a1 is important in placental ascorbic-acid transport.
[6] Slc23a1−/− mice died within a few minutes of birth with respiratory failure and intraparenchymal brain hemorrhage.
[7] Lungs showed no postnatal expansion but had normal surfactant protein B levels.
[8] Brain hemorrhage was unlikely to be simply a form of scurvy since Slc23a1−/− mice showed no hemorrhage in any other tissues and their skin had normal skin 4-hydroxyproline levels despite low ascorbic-acid content.
[9] We conclude that Slc23a1 is required for transport of ascorbic acid into many tissues and across the placenta.
[10] Deficiency of the transporter is lethal in newborn mice, thereby revealing a previously unrecognized requirement for ascorbic acid in the perinatal period.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [8]
Explanation: Evidence states: "Brain hemorrhage was unlikely to be simply a form of scurvy since Slc23a1−/− mice showed no hemorrhage in any other tissues and their skin had normal skin 4-hydroxyproline levels despite low ascorbic-acid content.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Mutations in G-Beta protein GNB2 are present in many cancers, resulting in loss of interaction with G-alpha subunits and concomitant activation of AKT pathway.

Document title: Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance

Abstract sentences:
[0] Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined.
[1] Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling.
[2] Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer.
[3] Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms.
[4] Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies.
[5] In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival.
[6] In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF.
[7] Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context.
[8] Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: N-terminal cleavage increases success identifying transcription start sites.

Document title: Identification and Functional Characterization of N-Terminally Acetylated Proteins in Drosophila melanogaster

Abstract sentences:
[0] Protein modifications play a major role for most biological processes in living organisms.
[1] Amino-terminal acetylation of proteins is a common modification found throughout the tree of life: the N-terminus of a nascent polypeptide chain becomes co-translationally acetylated, often after the removal of the initiating methionine residue.
[2] While the enzymes and protein complexes involved in these processes have been extensively studied, only little is known about the biological function of such N-terminal modification events.
[3] To identify common principles of N-terminal acetylation, we analyzed the amino-terminal peptides from proteins extracted from Drosophila Kc167 cells.
[4] We detected more than 1,200 mature protein N-termini and could show that N-terminal acetylation occurs in insects with a similar frequency as in humans.
[5] As the sole true determinant for N-terminal acetylation we could extract the (X)PX rule that indicates the prevention of acetylation under all circumstances.
[6] We could show that this rule can be used to genetically engineer a protein to study the biological relevance of the presence or absence of an acetyl group, thereby generating a generic assay to probe the functional importance of N-terminal acetylation.
[7] We applied the assay by expressing mutated proteins as transgenes in cell lines and in flies.
[8] Here, we present a straightforward strategy to systematically study the functional relevance of N-terminal acetylations in cells and whole organisms.
[9] Since the (X)PX rule seems to be of general validity in lower as well as higher eukaryotes, we propose that it can be used to study the function of N-terminal acetylation in all species.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: N-terminal cleavage reduces success identifying transcription start sites.

Document title: Identification and Functional Characterization of N-Terminally Acetylated Proteins in Drosophila melanogaster

Abstract sentences:
[0] Protein modifications play a major role for most biological processes in living organisms.
[1] Amino-terminal acetylation of proteins is a common modification found throughout the tree of life: the N-terminus of a nascent polypeptide chain becomes co-translationally acetylated, often after the removal of the initiating methionine residue.
[2] While the enzymes and protein complexes involved in these processes have been extensively studied, only little is known about the biological function of such N-terminal modification events.
[3] To identify common principles of N-terminal acetylation, we analyzed the amino-terminal peptides from proteins extracted from Drosophila Kc167 cells.
[4] We detected more than 1,200 mature protein N-termini and could show that N-terminal acetylation occurs in insects with a similar frequency as in humans.
[5] As the sole true determinant for N-terminal acetylation we could extract the (X)PX rule that indicates the prevention of acetylation under all circumstances.
[6] We could show that this rule can be used to genetically engineer a protein to study the biological relevance of the presence or absence of an acetyl group, thereby generating a generic assay to probe the functional importance of N-terminal acetylation.
[7] We applied the assay by expressing mutated proteins as transgenes in cell lines and in flies.
[8] Here, we present a straightforward strategy to systematically study the functional relevance of N-terminal acetylations in cells and whole organisms.
[9] Since the (X)PX rule seems to be of general validity in lower as well as higher eukaryotes, we propose that it can be used to study the function of N-terminal acetylation in all species.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: N348I mutations cause resistance to zidovudine (AZT).

Document title: N348I in the Connection Domain of HIV-1 Reverse Transcriptase Confers Zidovudine and Nevirapine Resistance

Abstract sentences:
[0] Background The catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) consists of DNA polymerase, connection, and ribonuclease H (RNase H) domains.
[1] Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme.
[2] However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region.
[3] The British Columbia Centre for Excellence in HIV/AIDS (the Centre) genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre’s database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals.
[4] The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance.
[5] Methods and Findings The prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre’s database.
[6] N348I increased in prevalence from below 1% in 368 treatmentnao ¨ve individuals to 12.1% in 1,009 treatment-experienced patients (p ¼ 7.7 3 10 � 12 ).
[7] N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs) M41L and T215Y/F (p , 0.001), the lamivudine resistance mutations M184V/I (p , 0.001), and non-nucleoside RTI (NNRTI) resistance mutations K103N and Y181C/I (p , 0.001).
[8] The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43–4.81).
[9] The appearance of N348I was associated with a significant increase in viral load (p , 0.001), which was as large as the viral load increases observed for any of the TAMs.
[10] However, this analysis did not account for the simultaneous selection of other RT or protease inhibitor resistance mutations on viral load.
[11] To delineate the role of this mutation in RT inhibitor resistance, N348I was introduced into HIV-1 molecular clones containing different genetic backbones.
[12] N348I decreased zidovudine susceptibility 2- to 4-fold in the context of wildtype HIV-1 or when combined with TAMs.
[13] N348I also decreased susceptibility to nevirapine (7.4fold) and efavirenz (2.5-fold) and significantly potentiated resistance to these drugs when combined with K103N.
[14] Biochemical analyses of recombinant RT containing N348I provide supporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give some insight into the molecular mechanism of resistance.
[15] Conclusions

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [14]
Explanation: Evidence states: "Biochemical analyses of recombinant RT containing N348I provide supporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give some insight into the molecular mechanism of resistance.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: NF2 (Merlin) causes phosphorylation and subsequent cytoplasmic sequestration of YAP in Drosophila by activating LATS1/2 kinases.

Document title: A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway

Abstract sentences:
[0] The Hippo–YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size.
[1] To identify components of this pathway, we performed an RNAi-based kinome screen in human cells.
[2] Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes.
[3] One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood.
[4] We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases.
[5] Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1.
[6] Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies.
[7] In addition, our findings provide insight into upstream signals of the Hippo–YAP signalling cascade.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: NF2 (Merlin) prevents phosphorylation and subsequent cytoplasmic sequestration of YAP in Drosophila.

Document title: A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway

Abstract sentences:
[0] The Hippo–YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size.
[1] To identify components of this pathway, we performed an RNAi-based kinome screen in human cells.
[2] Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes.
[3] One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood.
[4] We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases.
[5] Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1.
[6] Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies.
[7] In addition, our findings provide insight into upstream signals of the Hippo–YAP signalling cascade.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: NFAT4 activation requires IP3R-mediated Ca2+ mobilization.

Document title: Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca2+ Signals

Abstract sentences:
[0] Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes.
[1] How closely related coexpressed transcription factors are differentially activated remains unclear.
[2] Here, we show that two Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3 and Ca2+ signals for physiologically sustained activation.
[3] NFAT1 is stimulated by sub-plasmalemmal Ca2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclear envelope by nuclear InsP3 receptors.
[4] NFAT1 is rephosphorylated (deactivated) more slowly than NFAT4 in both cytoplasm and nucleus, enabling a more prolonged activation phase.
[5] Oscillations in cytoplasmic Ca2+, long considered the physiological form of Ca2+ signaling, play no role in activating either NFAT protein.
[6] Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca2+.
[7] Our results show how gene expression can be controlled by coincident yet geographically distinct Ca2+ signals, generated by a freely diffusible InsP3 message.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [2]
Explanation: Evidence states: "Here, we show that two Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3 and Ca2+ signals for physiologically sustained activation.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: NFAT4 activation requires IP3R-mediated Ca2+ mobilization.

Document title: Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca2+ Signals

Abstract sentences:
[0] Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes.
[1] How closely related coexpressed transcription factors are differentially activated remains unclear.
[2] Here, we show that two Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3 and Ca2+ signals for physiologically sustained activation.
[3] NFAT1 is stimulated by sub-plasmalemmal Ca2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclear envelope by nuclear InsP3 receptors.
[4] NFAT1 is rephosphorylated (deactivated) more slowly than NFAT4 in both cytoplasm and nucleus, enabling a more prolonged activation phase.
[5] Oscillations in cytoplasmic Ca2+, long considered the physiological form of Ca2+ signaling, play no role in activating either NFAT protein.
[6] Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca2+.
[7] Our results show how gene expression can be controlled by coincident yet geographically distinct Ca2+ signals, generated by a freely diffusible InsP3 message.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [3]
Explanation: Evidence states: "NFAT1 is stimulated by sub-plasmalemmal Ca2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclear envelope by nuclear InsP3 receptors.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: NFAT4 activation requires IP3R-mediated Ca2+ mobilization.

Document title: Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca2+ Signals

Abstract sentences:
[0] Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes.
[1] How closely related coexpressed transcription factors are differentially activated remains unclear.
[2] Here, we show that two Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3 and Ca2+ signals for physiologically sustained activation.
[3] NFAT1 is stimulated by sub-plasmalemmal Ca2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclear envelope by nuclear InsP3 receptors.
[4] NFAT1 is rephosphorylated (deactivated) more slowly than NFAT4 in both cytoplasm and nucleus, enabling a more prolonged activation phase.
[5] Oscillations in cytoplasmic Ca2+, long considered the physiological form of Ca2+ signaling, play no role in activating either NFAT protein.
[6] Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca2+.
[7] Our results show how gene expression can be controlled by coincident yet geographically distinct Ca2+ signals, generated by a freely diffusible InsP3 message.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [6, 7]
Explanation: Evidence states: "Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca2+. Our results show how gene expression can be controlled by coincident yet geographically distinct Ca2+ signals, generated by a freely diffusible InsP3 message.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: NOX2-independent pathways can generate peroxynitrite by reacting with nitrogen intermediates.

Document title: Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer

Abstract sentences:
[0] Antigen-specific CD8+ T-cell tolerance, induced by myeloid-derived suppressor cells (MDSCs), is one of the main mechanisms of tumor escape.
[1] Using in vivo models, we show here that MDSCs directly disrupt the binding of specific peptide–major histocompatibility complex (pMHC) dimers to CD8-expressing T cells through nitration of tyrosines in a T-cell receptor (TCR)-CD8 complex.
[2] This process makes CD8-expressing T cells unable to bind pMHC and to respond to the specific peptide, although they retain their ability to respond to nonspecific stimulation.
[3] Nitration of TCR-CD8 is induced by MDSCs through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact.
[4] Molecular modeling suggests specific sites of nitration that might affect the conformational flexibility of TCR-CD8 and its interaction with pMHC.
[5] These data identify a previously unknown mechanism of T-cell tolerance in cancer that is also pertinent to many pathological conditions associated with accumulation of MDSCs.

[Assistant]
Label: NOT ENOUGH INFORMATION
Rationale sentence ids: []
Explanation: The provided abstract does not contain direct evidence to support or contradict the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: NR5A2 is important in development of endometrial tissues.

Document title: Liver receptor homolog-1 is essential for pregnancy

Abstract sentences:
[0] Successful pregnancy requires coordination of an array of signals and factors from multiple tissues.
[1] One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis.
[2] It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans.
[3] Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation.
[4] Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation.
[5] To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency.
[6] Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death.
[7] Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization.
[8] These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta.
[9] It therefore has multiple, indispensible roles in establishing and sustaining pregnancy.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [7]
Explanation: Evidence states: "Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: NR5A2 is important in development of endometrial tissues.

Document title: Liver receptor homolog-1 is essential for pregnancy

Abstract sentences:
[0] Successful pregnancy requires coordination of an array of signals and factors from multiple tissues.
[1] One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis.
[2] It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans.
[3] Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation.
[4] Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation.
[5] To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency.
[6] Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death.
[7] Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization.
[8] These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta.
[9] It therefore has multiple, indispensible roles in establishing and sustaining pregnancy.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [8]
Explanation: Evidence states: "These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Nanoparticles can be targeted against specific cell types by incorporating aptamers into lipid nanoparticles.

Document title: Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference–based bone anabolic strategy

Abstract sentences:
[0] Currently, major concerns about the safety and efficacy of RNA interference (RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for osteogenic siRNAs.
[1] Here we screened the aptamer CH6 by cell-SELEX, specifically targeting both rat and human osteoblasts, and then we developed CH6 aptamer–functionalized lipid nanoparticles (LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA).
[2] Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents.
[3] These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [2]
Explanation: Evidence states: "Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Nanoparticles can be targeted against specific cell types by incorporating aptamers into lipid nanoparticles.

Document title: Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference–based bone anabolic strategy

Abstract sentences:
[0] Currently, major concerns about the safety and efficacy of RNA interference (RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for osteogenic siRNAs.
[1] Here we screened the aptamer CH6 by cell-SELEX, specifically targeting both rat and human osteoblasts, and then we developed CH6 aptamer–functionalized lipid nanoparticles (LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA).
[2] Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents.
[3] These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [3]
Explanation: Evidence states: "These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Neutrophil extracellular traps (NETs) are released by ANCA-stimulated neutrophils.

Document title: Netting neutrophils in autoimmune small-vessel vasculitis

Abstract sentences:
[0] Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs).
[1] Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO).
[2] Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.

[Assistant]
Label: SUPPORTS
Rationale sentence ids: [1]
Explanation: Evidence states: "Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO).". This supports the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: New drugs for tuberculosis often do not penetrate the necrotic portion of a tuberculosis lesion in high concentrations.

Document title: The association between sterilizing activity and drug distribution into tuberculosis lesions

Abstract sentences:
[0] Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development.
[1] Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions.
[2] Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside.
[3] In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials.
[4] We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB.
[5] We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs.
[6] The finding that lesion penetration may contribute to treatment outcome has wide implications for TB.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [2]
Explanation: Evidence states: "Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Non-invasive ventilation use should be decreased if there is inadequate response to conventional treatment.

Document title: Cost effectiveness of ward based non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease: economic analysis of randomised controlled trial.

Abstract sentences:
[0] OBJECTIVE To evaluate the cost effectiveness of standard treatment with and without the addition of ward based non-invasive ventilation in patients admitted to hospital with an acute exacerbation of chronic obstructive pulmonary disease.
[1] DESIGN Incremental cost effectiveness analysis of a randomised controlled trial.
[2] SETTING Medical wards in 14 hospitals in the United Kingdom.
[3] PARTICIPANTS The trial comprised 236 patients admitted to hospital with an acute exacerbation of chronic obstructive pulmonary disease and mild to moderate acidosis (pH 7.25-7.35) secondary to respiratory failure.
[4] The economic analysis compared the costs of treatment that these patients received after randomisation.
[5] MAIN OUTCOME MEASURE Incremental cost per in-hospital death.
[6] RESULTS 24/118 died in the group receiving standard treatment and 12/118 in the group receiving non-invasive ventilation (P=0.05).
[7] Allocation to the group receiving non-invasive ventilation was associated with a reduction in costs of 49362 pounds sterling (78741 dollars; 73109 euros), mainly through reduced use of intensive care units.
[8] The incremental cost effectiveness ratio was -645 pounds sterling per death avoided (95% confidence interval -2310 pounds sterling to 386 pounds sterling), indicating a dominant (more effective and less costly) strategy.
[9] Modelling of these data indicates that a typical UK hospital providing a non-invasive ventilation service will avoid six deaths and three to nine admissions to intensive care units per year, with an associated cost reduction of 12000-53000 pounds sterling per year.
[10] CONCLUSIONS Non-invasive ventilation is a highly cost effective treatment that both reduced total costs and improved mortality in hospital.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [9]
Explanation: Evidence states: "Modelling of these data indicates that a typical UK hospital providing a non-invasive ventilation service will avoid six deaths and three to nine admissions to intensive care units per year, with an associated cost reduction of 12000-53000 pounds sterling per year.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Non-invasive ventilation use should be decreased if there is inadequate response to conventional treatment.

Document title: Cost effectiveness of ward based non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease: economic analysis of randomised controlled trial.

Abstract sentences:
[0] OBJECTIVE To evaluate the cost effectiveness of standard treatment with and without the addition of ward based non-invasive ventilation in patients admitted to hospital with an acute exacerbation of chronic obstructive pulmonary disease.
[1] DESIGN Incremental cost effectiveness analysis of a randomised controlled trial.
[2] SETTING Medical wards in 14 hospitals in the United Kingdom.
[3] PARTICIPANTS The trial comprised 236 patients admitted to hospital with an acute exacerbation of chronic obstructive pulmonary disease and mild to moderate acidosis (pH 7.25-7.35) secondary to respiratory failure.
[4] The economic analysis compared the costs of treatment that these patients received after randomisation.
[5] MAIN OUTCOME MEASURE Incremental cost per in-hospital death.
[6] RESULTS 24/118 died in the group receiving standard treatment and 12/118 in the group receiving non-invasive ventilation (P=0.05).
[7] Allocation to the group receiving non-invasive ventilation was associated with a reduction in costs of 49362 pounds sterling (78741 dollars; 73109 euros), mainly through reduced use of intensive care units.
[8] The incremental cost effectiveness ratio was -645 pounds sterling per death avoided (95% confidence interval -2310 pounds sterling to 386 pounds sterling), indicating a dominant (more effective and less costly) strategy.
[9] Modelling of these data indicates that a typical UK hospital providing a non-invasive ventilation service will avoid six deaths and three to nine admissions to intensive care units per year, with an associated cost reduction of 12000-53000 pounds sterling per year.
[10] CONCLUSIONS Non-invasive ventilation is a highly cost effective treatment that both reduced total costs and improved mortality in hospital.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [10]
Explanation: Evidence states: "CONCLUSIONS Non-invasive ventilation is a highly cost effective treatment that both reduced total costs and improved mortality in hospital.". This contradicts the claim.


[User]
Determine whether the claim is SUPPORTS, CONTRADICTS, or NOT ENOUGH INFORMATION based only on the provided abstract. Use sentence indices as rationale evidence.

Claim: Normal expression of RUNX1 has tumor-promoting effects.

Document title: Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL

Abstract sentences:
[0] The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL).
[1] Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3.
[2] This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL.
[3] Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation.
[4] Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL.
[5] Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL.

[Assistant]
Label: CONTRADICTS
Rationale sentence ids: [3]
Explanation: Evidence states: "Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation.". This contradicts the claim.