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[ "Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ∼30% of patients with breast cancer.", "However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR.", "We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance.", "Digital transcript counting was used to profile surgically resected breast cancers after NAC.", "Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status.", "BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes.", "DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy.", "Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival.", "Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts.", "Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy." ]

[ 6 ]

[ "Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ∼30% of patients with breast cancer.", "However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR.", "We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance.", "Digital transcript counting was used to profile surgically resected breast cancers after NAC.", "Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status.", "BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes.", "DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy.", "Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival.", "Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts.", "Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy." ]

[ 4, 5, 9 ]

[ "Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ∼30% of patients with breast cancer.", "However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR.", "We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance.", "Digital transcript counting was used to profile surgically resected breast cancers after NAC.", "Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status.", "BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes.", "DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy.", "Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival.", "Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts.", "Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy." ]

[ 6 ]

[ "IMPORTANCE Identification of the bacterium responsible for an outbreak can aid in disease management.", "However, traditional culture-based diagnosis can be difficult, particularly if no specific diagnostic test is available for an outbreak strain.", "OBJECTIVE To explore the potential of metagenomics, which is the direct sequencing of DNA extracted from microbiologically complex samples, as an open-ended clinical discovery platform capable of identifying and characterizing bacterial strains from an outbreak without laboratory culture.", "DESIGN, SETTING, AND PATIENTS In a retrospective investigation, 45 samples were selected from fecal specimens obtained from patients with diarrhea during the 2011 outbreak of Shiga-toxigenic Escherichia coli (STEC) O104:H4 in Germany.", "Samples were subjected to high-throughput sequencing (August-September 2012), followed by a 3-phase analysis (November 2012-February 2013).", "In phase 1, a de novo assembly approach was developed to obtain a draft genome of the outbreak strain.", "In phase 2, the depth of coverage of the outbreak strain genome was determined in each sample.", "In phase 3, sequences from each sample were compared with sequences from known bacteria to identify pathogens other than the outbreak strain.", "MAIN OUTCOMES AND MEASURES The recovery of genome sequence data for the purposes of identification and characterization of the outbreak strain and other pathogens from fecal samples.", "RESULTS During phase 1, a draft genome of the STEC outbreak strain was obtained.", "During phase 2, the outbreak strain genome was recovered from 10 samples at greater than 10-fold coverage and from 26 samples at greater than 1-fold coverage.", "Sequences from the Shiga-toxin genes were detected in 27 of 40 STEC-positive samples (67%).", "In phase 3, sequences from Clostridium difficile, Campylobacter jejuni, Campylobacter concisus, and Salmonella enterica were recovered.", "CONCLUSIONS AND RELEVANCE These results suggest the potential of metagenomics as a culture-independent approach for the identification of bacterial pathogens during an outbreak of diarrheal disease.", "Challenges include improving diagnostic sensitivity, speeding up and simplifying workflows, and reducing costs." ]

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[ "IMPORTANCE Identification of the bacterium responsible for an outbreak can aid in disease management.", "However, traditional culture-based diagnosis can be difficult, particularly if no specific diagnostic test is available for an outbreak strain.", "OBJECTIVE To explore the potential of metagenomics, which is the direct sequencing of DNA extracted from microbiologically complex samples, as an open-ended clinical discovery platform capable of identifying and characterizing bacterial strains from an outbreak without laboratory culture.", "DESIGN, SETTING, AND PATIENTS In a retrospective investigation, 45 samples were selected from fecal specimens obtained from patients with diarrhea during the 2011 outbreak of Shiga-toxigenic Escherichia coli (STEC) O104:H4 in Germany.", "Samples were subjected to high-throughput sequencing (August-September 2012), followed by a 3-phase analysis (November 2012-February 2013).", "In phase 1, a de novo assembly approach was developed to obtain a draft genome of the outbreak strain.", "In phase 2, the depth of coverage of the outbreak strain genome was determined in each sample.", "In phase 3, sequences from each sample were compared with sequences from known bacteria to identify pathogens other than the outbreak strain.", "MAIN OUTCOMES AND MEASURES The recovery of genome sequence data for the purposes of identification and characterization of the outbreak strain and other pathogens from fecal samples.", "RESULTS During phase 1, a draft genome of the STEC outbreak strain was obtained.", "During phase 2, the outbreak strain genome was recovered from 10 samples at greater than 10-fold coverage and from 26 samples at greater than 1-fold coverage.", "Sequences from the Shiga-toxin genes were detected in 27 of 40 STEC-positive samples (67%).", "In phase 3, sequences from Clostridium difficile, Campylobacter jejuni, Campylobacter concisus, and Salmonella enterica were recovered.", "CONCLUSIONS AND RELEVANCE These results suggest the potential of metagenomics as a culture-independent approach for the identification of bacterial pathogens during an outbreak of diarrheal disease.", "Challenges include improving diagnostic sensitivity, speeding up and simplifying workflows, and reducing costs." ]

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[ "Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC).", "Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis.", "We found that p62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associated HSCs, negatively controls HSC activation.", "Total body or HSC-specific p62 ablation potentiates HSCs and enhances inflammation, fibrosis, and HCC progression.", "p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target gene recruitment.", "Loss of p62 in HSCs impairs the repression of fibrosis and inflammation by VDR agonists.", "This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSCs, whose activation supports HCC." ]

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[ "Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport.", "Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance.", "Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression.", "Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)).", "Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity.", "Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention.", "These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice." ]

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[ "BACKGROUND The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared.", "In this study, we aimed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease.", "METHODS We used linked electronic health records from 1997 to 2010 in the CALIBER (CArdiovascular research using LInked Bespoke studies and Electronic health Records) programme to assemble a cohort of 1·25 million patients, 30 years of age or older and initially free from cardiovascular disease, a fifth of whom received blood pressure-lowering treatments.", "We studied the heterogeneity in the age-specific associations of clinically measured blood pressure with 12 acute and chronic cardiovascular diseases, and estimated the lifetime risks (up to 95 years of age) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30, 60, and 80 years.", "This study is registered at ClinicalTrials.gov, number NCT01164371.", "FINDINGS During 5·2 years median follow-up, we recorded 83,098 initial cardiovascular disease presentations.", "In each age group, the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90-114 mm Hg and diastolic blood pressure of 60-74 mm Hg, with no evidence of a J-shaped increased risk at lower blood pressures.", "The effect of high blood pressure varied by cardiovascular disease endpoint, from strongly positive to no effect.", "Associations with high systolic blood pressure were strongest for intracerebral haemorrhage (hazard ratio 1·44 [95% CI 1·32-1·58]), subarachnoid haemorrhage (1·43 [1·25-1·63]), and stable angina (1·41 [1·36-1·46]), and weakest for abdominal aortic aneurysm (1·08 [1·00-1·17]).", "Compared with diastolic blood pressure, raised systolic blood pressure had a greater effect on angina, myocardial infarction, and peripheral arterial disease, whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure.", "Pulse pressure associations were inverse for abdominal aortic aneurysm (HR per 10 mm Hg 0·91 [95% CI 0·86-0·98]) and strongest for peripheral arterial disease (1·23 [1·20-1·27]).", "People with hypertension (blood pressure ≥140/90 mm Hg or those receiving blood pressure-lowering drugs) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63·3% (95% CI 62·9-63·8) compared with 46·1% (45·5-46·8) for those with normal blood pressure, and developed cardiovascular disease 5·0 years earlier (95% CI 4·8-5·2).", "Stable and unstable angina accounted for most (43%) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years, whereas heart failure and stable angina accounted for the largest proportion (19% each) of years of life lost from index age 80 years.", "INTERPRETATION The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolic associations are concordant, are not supported by the findings of this high-resolution study.", "Despite modern treatments, the lifetime burden of hypertension is substantial.", "These findings emphasise the need for new blood pressure-lowering strategies, and will help to inform the design of randomised trials to assess them.", "FUNDING Medical Research Council, National Institute for Health Research, and Wellcome Trust." ]

[ 9 ]

[ "Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression.", "MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown.", "Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF.", "Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF.", "Tumour-initiating cells (TICs) exhibit elevated G-CSF.", "MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop.", "Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients.", "These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment." ]

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[ "Developmental abnormalities, cancer, and premature aging each have been linked to defects in the DNA damage response (DDR).", "Mutations in the ATR checkpoint regulator cause developmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome).", "Here we show that eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance of age-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities.", "Histological and genetic analyses indicate that ATR deletion causes acute cellular loss in tissues in which continuous cell proliferation is required for maintenance.", "Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity.", "In aggregate, these studies suggest that reduced regenerative capacity in adults via deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance of age-related phenotypes." ]

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[ "Developmental abnormalities, cancer, and premature aging each have been linked to defects in the DNA damage response (DDR).", "Mutations in the ATR checkpoint regulator cause developmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome).", "Here we show that eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance of age-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities.", "Histological and genetic analyses indicate that ATR deletion causes acute cellular loss in tissues in which continuous cell proliferation is required for maintenance.", "Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity.", "In aggregate, these studies suggest that reduced regenerative capacity in adults via deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance of age-related phenotypes." ]

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[ "Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule.", "The Notch1 receptor was proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine has been localized to its submembrane domain.", "Investigating how this step might be regulated by a deubiquitinase (DUB) activity will provide new insight for understanding Notch receptor activation and downstream signaling.", "An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor.", "We show that eIF3f has an intrinsic DUB activity.", "Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant.", "We also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor.", "Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway.", "Our results support two new and provocative conclusions: (1) The activated form of Notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function.", "(2) The enzyme accounting for this deubiquitinase activity is eIF3f, known so far as a translation initiation factor.", "These data improve our knowledge of Notch signaling but also open new avenues of research on the Zomes family and the translation initiation factors." ]

[ 6 ]

[ "Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule.", "The Notch1 receptor was proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine has been localized to its submembrane domain.", "Investigating how this step might be regulated by a deubiquitinase (DUB) activity will provide new insight for understanding Notch receptor activation and downstream signaling.", "An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor.", "We show that eIF3f has an intrinsic DUB activity.", "Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant.", "We also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor.", "Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway.", "Our results support two new and provocative conclusions: (1) The activated form of Notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function.", "(2) The enzyme accounting for this deubiquitinase activity is eIF3f, known so far as a translation initiation factor.", "These data improve our knowledge of Notch signaling but also open new avenues of research on the Zomes family and the translation initiation factors." ]

[ 6 ]

[ "Salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia.", "Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17 (TH17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S. typhimurium dissemination.", "In SIV-negative macaques, the gene expression profile induced by S. typhimurium in ligated ileal loops was dominated by TH17 responses, including the expression of interleukin-17 (IL-17) and IL-22.", "TH17 cells were markedly depleted in SIV-infected rhesus macaques, resulting in blunted TH17 responses to S. typhimurium infection and increased bacterial dissemination.", "IL-17 receptor–deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function.", "We conclude that SIV infection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbial dissemination from the gastrointestinal tract." ]

[ 1, 3 ]

[ "Salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia.", "Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17 (TH17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S. typhimurium dissemination.", "In SIV-negative macaques, the gene expression profile induced by S. typhimurium in ligated ileal loops was dominated by TH17 responses, including the expression of interleukin-17 (IL-17) and IL-22.", "TH17 cells were markedly depleted in SIV-infected rhesus macaques, resulting in blunted TH17 responses to S. typhimurium infection and increased bacterial dissemination.", "IL-17 receptor–deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function.", "We conclude that SIV infection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbial dissemination from the gastrointestinal tract." ]

[ 1, 3 ]

[ "CONTEXT Delayed cerebral vasospasm causes permanent neurological deficits or death in at least 15% of patients following otherwise successful treatment for ruptured intracranial aneurysm.", "Decreased bioavailability of nitric oxide has been associated with the development of cerebral vasospasm.", "OBJECTIVE To determine whether infusions of nitrite will prevent delayed cerebral vasospasm.", "DESIGN, SETTING, AND SUBJECTS A total of 14 anesthetized cynomolgus monkeys had an autologous blood clot placed around the right middle cerebral artery.", "Cerebral arteriography was performed before clot placement and on days 7 and 14 to assess vasospasm.", "The study was conducted from August 2003 to February 2004.", "INTERVENTIONS A 90-mg sodium nitrite intravenous solution infused over 24 hours plus a 45-mg sodium nitrite bolus daily (n = 3); a 180-mg sodium nitrite intravenous solution infused over 24 hours (n = 3); or a control saline solution infusion (n = 8).", "Each was infused continuously for 14 days.", "MAIN OUTCOME MEASURES Nitrite, S-nitrosothiol, and methemoglobin levels in blood and cerebrospinal fluid and degree of arteriographic vasospasm.", "RESULTS In control monkeys, mean (SD) cerebrospinal fluid nitrite levels decreased from 3.1 (1.5) micromol/L to 0.4 (0.1) micromol/L at day 7 and to 0.4 (0.4) micromol/L at day 14 (P = .03).", "All 8 control monkeys developed significant vasospasm of the right middle cerebral artery, which was complicated by stroke and death in 1 animal.", "Sodium nitrite infusions increased the nitrite and methemoglobin levels (<2.1% of total hemoglobin) in the blood and cerebrospinal fluid without evoking systemic hypotension.", "Nitrite infusion prevented development of vasospasm (no animals developed significant vasospasm; mean [SD] reduction in right middle cerebral artery area on day 7 after subarachnoid hemorrhage of 8% [9%] in nitrite-treated monkeys vs 47% [5%] in saline-treated controls; P<.001).", "There was a negative correlation between the concentration of nitrite in cerebrospinal fluid and the degree of cerebral vasospasm (P<.001).", "Pharmacological effects of nitrite infusion were also associated with the formation of S-nitrosothiol in cerebrospinal fluid.", "There was no clinical or pathological evidence of nitrite toxicity.", "CONCLUSION Subacute sodium nitrite infusions prevented delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage." ]

[ 1, 10, 12 ]

[ "BACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics.", "Much of the risk for endometrial cancer development is influenced by the environment and lifestyle.", "Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer.", "The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development.", "METHODS AND FINDINGS Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer.", "A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer.", "These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women.", "Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels.", "Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment.", "HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A).", "Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression.", "CONCLUSIONS HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response.", "The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies.", "Please see later in the article for the Editors' Summary." ]

[ 10 ]

[ "BACKGROUND Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas.", "We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk.", "METHODS AND FINDINGS We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013).", "We applied space-time scan statistics and mathematical models to confirm the findings.", "We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks.", "In the study area, this population density was typical of villages and some peri-urban areas.", "Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks.", "The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range.", "Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks.", "CONCLUSIONS Rural areas may contribute at least as much to the dissemination of dengue fever as cities.", "Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts.", "Please see later in the article for the Editors' Summary." ]

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[ "BACKGROUND Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas.", "We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk.", "METHODS AND FINDINGS We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013).", "We applied space-time scan statistics and mathematical models to confirm the findings.", "We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks.", "In the study area, this population density was typical of villages and some peri-urban areas.", "Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks.", "The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range.", "Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks.", "CONCLUSIONS Rural areas may contribute at least as much to the dissemination of dengue fever as cities.", "Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts.", "Please see later in the article for the Editors' Summary." ]

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[ "CONTEXT Dexamethasone is widely used to prevent postoperative nausea and vomiting (PONV) in pediatric tonsillectomy.", "OBJECTIVE To assess whether dexamethasone dose-dependently reduces the risk of PONV at 24 hours after tonsillectomy.", "DESIGN, SETTING, AND PATIENTS Randomized placebo-controlled trial conducted among 215 children undergoing elective tonsillectomy at a major public teaching hospital in Switzerland from February 2005 to December 2007.", "INTERVENTIONS Children were randomly assigned to receive dexamethasone (0.05, 0.15, or 0.5 mg/kg) or placebo intravenously after induction of anesthesia.", "Acetaminophen-codeine and ibuprofen were given as postoperative analgesia.", "Follow-up continued until the 10th postoperative day.", "MAIN OUTCOME MEASURES The primary end point was prevention of PONV at 24 hours; secondary end points were decrease in the need for ibuprofen at 24 hours and evaluation of adverse effects.", "RESULTS At 24 hours, 24 of 54 participants who received placebo (44%; 95% confidence interval [CI], 31%-59%) had experienced PONV compared with 20 of 53 (38%; 95% CI, 25%-52%), 13 of 54 (24%; 95% CI, 13%-38%), and 6 of 52 (12%; 95% CI, 4%-23%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P<.001 for linear trend).", "Children who received dexamethasone received significantly less ibuprofen.", "There were 26 postoperative bleeding episodes in 22 children.", "Two of 53 (4%; 95% CI, 0.5%-13%)", "children who received placebo had bleeding compared with 6 of 53 (11%; 95% CI, 4%-23%), 2 of 51 (4%; 95% CI, 0.5%-13%), and 12 of 50 (24%; 95% CI, 13%-38%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P = .003).", "Dexamethasone, 0.5 mg/kg, was associated with the highest bleeding risk (adjusted relative risk, 6.80; 95% CI, 1.77-16.5).", "Eight children had to undergo emergency reoperation because of bleeding, all of whom had received dexamethasone.", "The trial was stopped early for safety reasons.", "CONCLUSION In this study of children undergoing tonsillectomy, dexamethasone decreased the risk of PONV dose dependently but was associated with an increased risk of postoperative bleeding.", "TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00403806." ]

[ 10, 11, 12, 15 ]

[ "CONTEXT Observational studies suggest that surgically induced loss of weight may be effective therapy for type 2 diabetes.", "OBJECTIVE To determine if surgically induced weight loss results in better glycemic control and less need for diabetes medications than conventional approaches to weight loss and diabetes control.", "DESIGN, SETTING, AND PARTICIPANTS Unblinded randomized controlled trial conducted from December 2002 through December 2006 at the University Obesity Research Center in Australia, with general community recruitment to established treatment programs.", "Participants were 60 obese patients (BMI >30 and <40) with recently diagnosed (<2 years) type 2 diabetes.", "INTERVENTIONS Conventional diabetes therapy with a focus on weight loss by lifestyle change vs laparoscopic adjustable gastric banding with conventional diabetes care.", "MAIN OUTCOME MEASURES Remission of type 2 diabetes (fasting glucose level <126 mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA1c] value <6.2% while taking no glycemic therapy).", "Secondary measures included weight and components of the metabolic syndrome.", "Analysis was by intention-to-treat.", "RESULTS Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up.", "Remission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%) in the conventional-therapy group.", "Relative risk of remission for the surgical group was 5.5 (95% confidence interval, 2.2-14.0).", "Surgical and conventional-therapy groups lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001).", "Remission of type 2 diabetes was related to weight loss (R2 = 0.46, P < .001) and lower baseline HbA1c levels (combined R2 = 0.52, P < .001).", "There were no serious complications in either group.", "CONCLUSIONS Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss.", "These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed.", "TRIAL REGISTRATION actr.org Identifier: ACTRN012605000159651." ]

[ 9, 10, 14 ]

[ "CONTEXT Observational studies suggest that surgically induced loss of weight may be effective therapy for type 2 diabetes.", "OBJECTIVE To determine if surgically induced weight loss results in better glycemic control and less need for diabetes medications than conventional approaches to weight loss and diabetes control.", "DESIGN, SETTING, AND PARTICIPANTS Unblinded randomized controlled trial conducted from December 2002 through December 2006 at the University Obesity Research Center in Australia, with general community recruitment to established treatment programs.", "Participants were 60 obese patients (BMI >30 and <40) with recently diagnosed (<2 years) type 2 diabetes.", "INTERVENTIONS Conventional diabetes therapy with a focus on weight loss by lifestyle change vs laparoscopic adjustable gastric banding with conventional diabetes care.", "MAIN OUTCOME MEASURES Remission of type 2 diabetes (fasting glucose level <126 mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA1c] value <6.2% while taking no glycemic therapy).", "Secondary measures included weight and components of the metabolic syndrome.", "Analysis was by intention-to-treat.", "RESULTS Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up.", "Remission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%) in the conventional-therapy group.", "Relative risk of remission for the surgical group was 5.5 (95% confidence interval, 2.2-14.0).", "Surgical and conventional-therapy groups lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001).", "Remission of type 2 diabetes was related to weight loss (R2 = 0.46, P < .001) and lower baseline HbA1c levels (combined R2 = 0.52, P < .001).", "There were no serious complications in either group.", "CONCLUSIONS Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss.", "These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed.", "TRIAL REGISTRATION actr.org Identifier: ACTRN012605000159651." ]

[ 9, 10, 14 ]

[ "BACKGROUND Diabetes mellitus is a major risk factor for adverse outcomes after acute coronary syndromes (ACS).", "Because this disease may be associated with increased platelet aggregation, we investigated whether diabetic patients with ACS derive particular benefit from platelet glycoprotein (GP) IIb/IIIa receptor inhibition.", "METHODS AND RESULTS We performed a meta-analysis of the diabetic populations enrolled in the 6 large-scale platelet GP IIb/IIIa inhibitor ACS trials: PRISM, PRISM-PLUS, PARAGON A, PARAGON B, PURSUIT, and GUSTO IV.", "Among 6458 diabetic patients, platelet GP IIb/IIIa inhibition was associated with a significant mortality reduction at 30 days, from 6.2% to 4.6% (OR 0.74; 95% CI 0.59 to 0.92; P=0.007).", "Conversely, 23 072 nondiabetic patients had no survival benefit (3.0% versus 3.0%).", "The interaction between platelet GP IIb/IIIa inhibition and diabetic status was statistically significant (P=0.036).", "Among 1279 diabetic patients undergoing percutaneous coronary intervention (PCI) during index hospitalization, the use of these agents was associated with a mortality reduction at 30 days from 4.0% to 1.2% (OR 0.30; 95% CI 0.14 to 0.69; P=0.002).", "CONCLUSIONS This meta-analysis, including the entire large-scale trial experience of intravenous platelet GP IIb/IIIa inhibitors for the medical management of non-ST-segment-elevation ACS, shows that these agents may significantly reduce mortality at 30 days in diabetic patients.", "Although not based on a randomized assessment, the survival benefit appears to be of greater magnitude in patients undergoing PCI.", "Therefore, the use of platelet GP IIb/IIIa inhibitors should be strongly considered in diabetic patients with ACS." ]

[]

[ "BACKGROUND Although unstable coronary artery disease is the most common reason for admission to a coronary care unit, the long-term prognosis of patients with this diagnosis is unknown.", "This is particularly true for patients with diabetes mellitus, who are known to have a high morbidity and mortality after an acute myocardial infarction.", "METHODS AND RESULTS Prospectively collected data from 6 different countries in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry were analyzed to determine the 2-year prognosis of diabetic and nondiabetic patients who were hospitalized with unstable angina or non-Q-wave myocardial infarction.", "Overall, 1718 of 8013 registry patients (21%) had diabetes.", "Diabetic patients had a higher rate of coronary bypass surgery than nondiabetic patients (23% versus 20%, P:<0.001) but had similar rates of catheterization and angioplasty.", "Diabetes independently predicted mortality (relative risk [RR], 1.57; 95% CI, 1.38 to 1.81; P:<0.001), as well as cardiovascular death, new myocardial infarction, stroke, and new congestive heart failure.", "Moreover, compared with their nondiabetic counterparts, women had a significantly higher risk than men (RR, 1.98; 95% CI, 1.60 to 2.44; and RR, 1.28; 95% CI, 1.06 to 1.56, respectively).", "Interestingly, diabetic patients without prior cardiovascular disease had the same event rates for all outcomes as nondiabetic patients with previous vascular disease.", "CONCLUSIONS Hospitalization for unstable angina or non-Q-wave myocardial infarction predicts a high 2-year morbidity and mortality; this is especially evident for patients with diabetes.", "Diabetic patients with no previous cardiovascular disease have the same long-term morbidity and mortality as nondiabetic patients with established cardiovascular disease after hospitalization for unstable coronary artery disease." ]

[ 5 ]

[ "In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase.", "Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines.", "We show that in normal dividing progenitor cells E2f1-3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival.", "In differentiating cells E2f1-3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle.", "The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions.", "Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency.", "This work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles." ]

[]

[ "The Drosophila lymph gland is a haematopoietic organ in which progenitor cells, which are most akin to the common myeloid progenitor in mammals, proliferate and differentiate into three types of mature cell--plasmatocytes, crystal cells and lamellocytes--the functions of which are reminiscent of mammalian myeloid cells.", "During the first and early second instars of larval development, the lymph gland contains only progenitors, whereas in the third instar, a medial region of the primary lobe of the lymph gland called the medullary zone contains these progenitors, and maturing blood cells are found juxtaposed in a peripheral region designated the cortical zone.", "A third group of cells referred to as the posterior signalling centre functions as a haematopoietic niche.", "Similarly to mammalian myeloid cells, Drosophila blood cells respond to multiple stresses including hypoxia, infection and oxidative stress.", "However, how systemic signals are sensed by myeloid progenitors to regulate cell-fate determination has not been well described.", "Here, we show that the haematopoietic progenitors of Drosophila are direct targets of systemic (insulin) and nutritional (essential amino acid) signals, and that these systemic signals maintain the progenitors by promoting Wingless (WNT in mammals) signalling.", "We expect that this study will promote investigation of such possible direct signal sensing mechanisms by mammalian myeloid progenitors." ]

[ 5 ]

[ "The Drosophila lymph gland is a haematopoietic organ in which progenitor cells, which are most akin to the common myeloid progenitor in mammals, proliferate and differentiate into three types of mature cell--plasmatocytes, crystal cells and lamellocytes--the functions of which are reminiscent of mammalian myeloid cells.", "During the first and early second instars of larval development, the lymph gland contains only progenitors, whereas in the third instar, a medial region of the primary lobe of the lymph gland called the medullary zone contains these progenitors, and maturing blood cells are found juxtaposed in a peripheral region designated the cortical zone.", "A third group of cells referred to as the posterior signalling centre functions as a haematopoietic niche.", "Similarly to mammalian myeloid cells, Drosophila blood cells respond to multiple stresses including hypoxia, infection and oxidative stress.", "However, how systemic signals are sensed by myeloid progenitors to regulate cell-fate determination has not been well described.", "Here, we show that the haematopoietic progenitors of Drosophila are direct targets of systemic (insulin) and nutritional (essential amino acid) signals, and that these systemic signals maintain the progenitors by promoting Wingless (WNT in mammals) signalling.", "We expect that this study will promote investigation of such possible direct signal sensing mechanisms by mammalian myeloid progenitors." ]

[ 5 ]

[ "Importance Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential.", "Objective To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age.", "Design, Setting, and Participants Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area.", "Exposures Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH.", "Main Outcomes and Measures The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle).", "Conception was defined as a positive pregnancy test result.", "Results A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis.", "After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively).", "Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively).", "Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively).", "Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001).", "Conclusions and Relevance Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility.", "These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics." ]

[ 7, 8, 9, 11 ]

[ "The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals.", "Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation.", "We report that rapid evolution of enhancers is a universal feature of mammalian genomes.", "Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements.", "In contrast, almost all liver promoters are partially or fully conserved across these species.", "Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences.", "These results provide important insight into the functional genetics underpinning mammalian regulatory evolution." ]

[]

[ "The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals.", "Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation.", "We report that rapid evolution of enhancers is a universal feature of mammalian genomes.", "Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements.", "In contrast, almost all liver promoters are partially or fully conserved across these species.", "Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences.", "These results provide important insight into the functional genetics underpinning mammalian regulatory evolution." ]

[]

[ "Subdividing proliferating tissues into compartments is an evolutionarily conserved strategy of animal development [1-6].", "Signals across boundaries between compartments can result in local expression of secreted proteins organizing growth and patterning of tissues [1-6].", "Sharp and straight interfaces between compartments are crucial for stabilizing the position of such organizers and therefore for precise implementation of body plans.", "Maintaining boundaries in proliferating tissues requires mechanisms to counteract cell rearrangements caused by cell division; however, the nature of such mechanisms remains unclear.", "Here we quantitatively analyzed cell morphology and the response to the laser ablation of cell bonds in the vicinity of the anteroposterior compartment boundary in developing Drosophila wings.", "We found that mechanical tension is approximately 2.5-fold increased on cell bonds along this compartment boundary as compared to the remaining tissue.", "Cell bond tension is decreased in the presence of Y-27632 [7], an inhibitor of Rho-kinase whose main effector is Myosin II [8].", "Simulations using a vertex model [9] demonstrate that a 2.5-fold increase in local cell bond tension suffices to guide the rearrangement of cells after cell division to maintain compartment boundaries.", "Our results provide a physical mechanism in which the local increase in Myosin II-dependent cell bond tension directs cell sorting at compartment boundaries." ]

[ 8 ]

[ "As organisms develop, their tissues can become separated into distinct cell populations through the establishment of compartment boundaries.", "Compartment boundaries have been discovered in a wide variety of tissues, but in many cases the molecular mechanisms that separate cells remain poorly understood.", "In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventral compartment boundary, through a process that depends on the actin cytoskeleton.", "Here, we show that the dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation is regulated downstream of Notch signaling.", "Conversely, the dorsal-ventral boundary is depleted for the Par-3 homologue Bazooka.", "We further show that mutations in the Myosin heavy chain subunit encoded by zipper can impair dorsal-ventral compartmentalization without affecting anterior-posterior compartmentalization.", "These observations identify a distinct accumulation and requirement for Myosin activity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractile tension along an F-actin cable at the compartment boundary contributes to compartmentalization." ]

[ 3 ]

[ "Activation of the insect innate immune system is dependent on a limited number of pattern recognition receptors (PRRs) capable of interacting with pathogen-associated molecular pattern.", "Here we report a novel role of an alternatively spliced hypervariable immunoglobulin domain-encoding gene, Dscam, in generating a broad range of PRRs implicated in immune defense in the malaria vector Anopheles gambiae.", "The mosquito Down syndrome cell adhesion molecule gene, AgDscam, has a complex genome organization with 101 exons that can produce over 31,000 potential alternative splice forms with different combinations of adhesive domains and interaction specificities.", "AgDscam responds to infection by producing pathogen challenge-specific splice form repertoires.", "Transient silencing of AgDscam compromises the mosquito's resistance to infections with bacteria and the malaria parasite Plasmodium.", "AgDscam is mediating phagocytosis of bacteria with which it can associate and defend against in a splice form–specific manner.", "AgDscam is a hypervariable PRR of the A. gambiae innate immune system." ]

[ 1, 3, 5, 6 ]

[ "Nonhomologous end joining (NHEJ) can effectively resolve chromosome breaks despite diverse end structures; however, it is unclear how the steps employed for resolution are determined.", "We sought to address this question by analysing cellular NHEJ of ends with systematically mispaired and damaged termini.", "We show NHEJ is uniquely proficient at bypassing subtle terminal mispairs and radiomimetic damage by direct ligation.", "Nevertheless, bypass ability varies widely, with increases in mispair severity gradually reducing bypass products from 85 to 6%.", "End-processing by nucleases and polymerases is increased to compensate, although paths with the fewest number of steps to generate a substrate suitable for ligation are favoured.", "Thus, both the frequency and nature of end processing are tailored to meet the needs of the ligation step.", "We propose a model where the ligase organizes all steps during NHEJ within the stable paired-end complex to limit end processing and associated errors." ]

[]

[ "Nonhomologous end joining (NHEJ) can effectively resolve chromosome breaks despite diverse end structures; however, it is unclear how the steps employed for resolution are determined.", "We sought to address this question by analysing cellular NHEJ of ends with systematically mispaired and damaged termini.", "We show NHEJ is uniquely proficient at bypassing subtle terminal mispairs and radiomimetic damage by direct ligation.", "Nevertheless, bypass ability varies widely, with increases in mispair severity gradually reducing bypass products from 85 to 6%.", "End-processing by nucleases and polymerases is increased to compensate, although paths with the fewest number of steps to generate a substrate suitable for ligation are favoured.", "Thus, both the frequency and nature of end processing are tailored to meet the needs of the ligation step.", "We propose a model where the ligase organizes all steps during NHEJ within the stable paired-end complex to limit end processing and associated errors." ]

[]

[ "Humoral immune responses depend on B cells encountering antigen, interacting with helper T cells, proliferating and differentiating into low-affinity plasma cells or, after organizing into a germinal center (GC), high-affinity plasma cells and memory B cells.", "Remarkably, each of these events occurs in association with distinct stromal cells in separate subcompartments of the lymphoid tissue.", "B cells must migrate from niche to niche in a rapid and highly regulated manner to successfully mount a response.", "The chemokine, CXCL13, plays a central role in guiding B cells to follicles whereas T-zone chemokines guide activated B cells to the T zone.", "Sphingosine-1-phosphate (S1P) promotes cell egress from the tissue, as well as marginal-zone B-cell positioning in the spleen.", "Recent studies have identified a role for the orphan receptor, EBV-induced molecule 2 (EBI2; GPR183), in guiding activated B cells to inter and outer follicular niche(s) and down-regulation of this receptor is essential for organizing cells into GCs.", "In this review, we discuss current understanding of the roles played by chemokines, S1P and EBI2 in the migration events that underlie humoral immune responses." ]

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[ "The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-γ (IFN-γ)–producing T lymphocytes.", "Here we show that dying tumor cells release ATP, which then acts on P2X7 purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1β (IL-1β).", "The priming of IFN-γ–producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3−/−) or caspase-1–deficient (Casp-1−/−) mice unless exogenous IL-1β is provided.", "Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7−/− or Nlrp3−/− or Casp1−/− hosts.", "Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele.", "These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells." ]

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[ "Lymphocytes provide optimal responses against pathogens with minimal inflammatory pathology.", "However, the intrinsic mechanisms regulating these responses are unknown.", "Here, we report that deletion of both transcription factors Egr2 and Egr3 in lymphocytes resulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but also impaired antigen receptor-induced proliferation of B and T cells.", "Egr2- and Egr3-defective B and T cells had hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigen receptor-induced activation of transcription factor AP-1 was severely impaired.", "We discovered that Egr2 and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3, inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells.", "Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis by promoting antigen receptor signaling and controlling inflammation." ]

[]

[ "VAP (VAPA and VAPB) is an evolutionarily conserved endoplasmic reticulum (ER)-anchored protein that helps generate tethers between the ER and other membranes through which lipids are exchanged across adjacent bilayers.", "Here, we report that by regulating PI4P levels on endosomes, VAP affects WASH-dependent actin nucleation on these organelles and the function of the retromer, a protein coat responsible for endosome-to-Golgi traffic.", "VAP is recruited to retromer budding sites on endosomes via an interaction with the retromer SNX2 subunit.", "Cells lacking VAP accumulate high levels of PI4P, actin comets, and trans-Golgi proteins on endosomes.", "Such defects are mimicked by downregulation of OSBP, a VAP interactor and PI4P transporter that participates in VAP-dependent ER-endosomes tethers.", "These results reveal a role of PI4P in retromer-/WASH-dependent budding from endosomes.", "Collectively, our data show how the ER can control budding dynamics and association with the cytoskeleton of another membrane by direct contacts leading to bilayer lipid modifications." ]

[]

[ "Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive.", "To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent.", "We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status.", "Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility.", "After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci.", "We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype." ]

[ 5 ]

[ "IMPORTANCE There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants.", "Less pharmacological closure and more supportive management have been observed without evidence to support these changes.", "OBJECTIVE To evaluate the association between early screening echocardiography for PDA and in-hospital mortality.", "DESIGN, SETTING, AND PARTICIPANTS Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011.", "Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable.", "EXPOSURES Early screening echocardiography before day 3 of life.", "MAIN OUTCOMES AND MEASURES The primary outcome was death between day 3 and discharge.", "The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis).", "RESULTS Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired.", "Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7).", "Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]).", "No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed.", "In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04].", "CONCLUSIONS AND RELEVANCE In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions.", "However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity." ]

[ 10, 13 ]

[ "IMPORTANCE There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants.", "Less pharmacological closure and more supportive management have been observed without evidence to support these changes.", "OBJECTIVE To evaluate the association between early screening echocardiography for PDA and in-hospital mortality.", "DESIGN, SETTING, AND PARTICIPANTS Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011.", "Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable.", "EXPOSURES Early screening echocardiography before day 3 of life.", "MAIN OUTCOMES AND MEASURES The primary outcome was death between day 3 and discharge.", "The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis).", "RESULTS Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired.", "Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7).", "Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]).", "No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed.", "In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04].", "CONCLUSIONS AND RELEVANCE In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions.", "However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity." ]

[ 10, 13 ]

[ "Induced pluripotent stem cells (iPSCs) are commonly generated by transduction of Oct4, Sox2, Klf4, and Myc (OSKM) into cells.", "Although iPSCs are pluripotent, they frequently exhibit high variation in terms of quality, as measured in mice by chimera contribution and tetraploid complementation.", "Reliably high-quality iPSCs will be needed for future therapeutic applications.", "Here, we show that one major determinant of iPSC quality is the combination of reprogramming factors used.", "Based on tetraploid complementation, we found that ectopic expression of Sall4, Nanog, Esrrb, and Lin28 (SNEL) in mouse embryonic fibroblasts (MEFs) generated high-quality iPSCs more efficiently than other combinations of factors including OSKM.", "Although differentially methylated regions, transcript number of master regulators, establishment of specific superenhancers, and global aneuploidy were comparable between high- and low-quality lines, aberrant gene expression, trisomy of chromosome 8, and abnormal H2A.X deposition were distinguishing features that could potentially also be applicable to human." ]

[ 4 ]

[ "Lymphocytes provide optimal responses against pathogens with minimal inflammatory pathology.", "However, the intrinsic mechanisms regulating these responses are unknown.", "Here, we report that deletion of both transcription factors Egr2 and Egr3 in lymphocytes resulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but also impaired antigen receptor-induced proliferation of B and T cells.", "Egr2- and Egr3-defective B and T cells had hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigen receptor-induced activation of transcription factor AP-1 was severely impaired.", "We discovered that Egr2 and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3, inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells.", "Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis by promoting antigen receptor signaling and controlling inflammation." ]

[ 2, 3, 4, 5 ]

[ "Lymphocytes provide optimal responses against pathogens with minimal inflammatory pathology.", "However, the intrinsic mechanisms regulating these responses are unknown.", "Here, we report that deletion of both transcription factors Egr2 and Egr3 in lymphocytes resulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but also impaired antigen receptor-induced proliferation of B and T cells.", "Egr2- and Egr3-defective B and T cells had hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigen receptor-induced activation of transcription factor AP-1 was severely impaired.", "We discovered that Egr2 and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3, inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells.", "Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis by promoting antigen receptor signaling and controlling inflammation." ]

[ 2, 3, 4, 5 ]

[ "Traditionally, vaccine development involves tradeoffs between immunogenicity and safety.", "Live-attenuated vaccines typically offer rapid and durable immunity but have reduced safety when compared to inactivated vaccines.", "In contrast, the inability of inactivated vaccines to replicate enhances safety at the expense of immunogenicity, often necessitating multiple doses and boosters.", "To overcome these tradeoffs, we developed the insect-specific alphavirus, Eilat virus (EILV), as a vaccine platform.", "To address the chikungunya fever (CHIKF) pandemic, we used an EILV cDNA clone to design a chimeric virus containing the chikungunya virus (CHIKV) structural proteins.", "The recombinant EILV/CHIKV was structurally identical at 10 Å to wild-type CHIKV, as determined by single-particle cryo-electron microscopy, and it mimicked the early stages of CHIKV replication in vertebrate cells from attachment and entry to viral RNA delivery.", "Yet the recombinant virus remained completely defective for productive replication, providing a high degree of safety.", "A single dose of EILV/CHIKV produced in mosquito cells elicited rapid (within 4 d) and long-lasting (>290 d) neutralizing antibodies that provided complete protection in two different mouse models.", "In nonhuman primates, EILV/CHIKV elicited rapid and robust immunity that protected against viremia and telemetrically monitored fever.", "Our EILV platform represents the first structurally native application of an insect-specific virus in preclinical vaccine development and highlights the potential application of such viruses in vaccinology." ]

[ 7, 8 ]

[ "BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system.", "However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU).", "We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.", "METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]).", "mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR.", "Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients.", "The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts.", "In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome.", "Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.", "CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients.", "Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients." ]

[ 5, 7, 9 ]

[ "The marginal costs and benefits of converting malaria programmes from a control to an elimination goal are central to strategic decisions, but empirical evidence is scarce.", "We present a conceptual framework to assess the economics of elimination and analyse a central component of that framework-potential short-term to medium-term financial savings.", "After a review that showed a dearth of existing evidence, the net present value of elimination in five sites was calculated and compared with effective control.", "The probability that elimination would be cost-saving over 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case.", "These findings show that financial savings should not be a primary rationale for elimination, but that elimination might still be a worthy investment if total benefits are sufficient to outweigh marginal costs.", "Robust research into these elimination benefits is urgently needed." ]

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[ "How oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells remains unclear.", "We recently reported that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate.", "Here we report a novel mechanism in which Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation.", "We also report the crystal structure of H11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promoting substrate 3-phosphoglycerate binding.", "Moreover, Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting cancer cell proliferation and tumour growth.", "As PGAM1 is a negative transcriptional target of TP53, and is therefore commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1 upregulation." ]

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[ "The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis.", "However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway.", "Single-minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action.", "We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice.", "The restoration dramatically reduced obesity in Mc4r-null mice.", "The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons.", "The reversal was caused by lower energy expenditure and hyperphagia.", "Corroboratively, selective disruption of glutamate release from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia.", "Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation." ]

[ 5, 7, 8 ]

[ "AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite.", "However, the role of excitatory glutamatergic input in controlling these neurons is unknown.", "To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons.", "Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect.", "Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs.", "Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis.", "Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting." ]

[ 3, 4, 5, 6 ]

[ "The importance of neuropeptides in the hypothalamus has been experimentally established.", "Due to difficulties in assessing function in vivo, the roles of the fast-acting neurotransmitters glutamate and GABA are largely unknown.", "Synaptic vesicular transporters (VGLUTs for glutamate and VGAT for GABA) are required for vesicular uptake and, consequently, synaptic release of neurotransmitters.", "Ventromedial hypothalamic (VMH) neurons are predominantly glutamatergic and express VGLUT2.", "To evaluate the role of glutamate release from VMH neurons, we generated mice lacking VGLUT2 selectively in SF1 neurons (a major subset of VMH neurons).", "These mice have hypoglycemia during fasting secondary to impaired fasting-induced increases in the glucose-raising pancreatic hormone glucagon and impaired induction in liver of mRNAs encoding PGC-1alpha and the gluconeogenic enzymes PEPCK and G6Pase.", "Similarly, these mice have defective counterregulatory responses to insulin-induced hypoglycemia and 2-deoxyglucose (an antimetabolite).", "Thus, glutamate release from VMH neurons is an important component of the neurocircuitry that functions to prevent hypoglycemia." ]

[ 7 ]

[ "In the hypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding and neuropeptide-Y (NPY) neurons stimulate feeding.", "We tested whether neurons in the ventromedial hypothalamic nucleus (VMH), a known satiety center, activate anorexigenic neuronal pathways in the ARC by projecting either excitatory synaptic inputs to POMC neurons and/or inhibitory inputs to NPY neurons.", "Using laser scanning photostimulation in brain slices from transgenic mice, we found that POMC and NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinct synaptic inputs.", "POMC neurons received strong excitatory input from the medial VMH (mVMH), whereas NPY neurons did not and, instead, received weak inhibitory input only from within the ARC.", "The strength of the excitatory input from the mVMH to POMC neurons was diminished by fasting.", "These data identify a new molecularly defined circuit that is dynamically regulated by nutritional state in a manner consistent with the known role of the VMH as a satiety center." ]

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[ "Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance.", "Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology.", "Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function.", "We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet.", "In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters.", "These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity." ]

[ 2, 3, 4 ]

[ "Inflammation induced by recognition of pathogen-associated molecular patterns markedly affects subsequent adaptive responses.", "We asked whether the adaptive immune system can also affect the character and magnitude of innate inflammatory responses.", "We found that the response of memory, but not naive, CD4+ T cells enhances production of multiple innate inflammatory cytokines and chemokines (IICs) in the lung and that, during influenza infection, this leads to early control of virus.", "Memory CD4+ T cell–induced IICs and viral control require cognate antigen recognition and are optimal when memory cells are either T helper type 1 (TH1) or TH17 polarized but are independent of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production and do not require activation of conserved pathogen recognition pathways.", "This represents a previously undescribed mechanism by which memory CD4+ T cells induce an early innate response that enhances immune protection against pathogens." ]

[ 2 ]

[ "BACKGROUND Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer).", "To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study.", "METHODS We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption).", "FINDINGS After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction.", "By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease.", "Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing).", "INTERPRETATION Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors.", "FUNDING Cancer Research UK and the UK Medical Research Council." ]

[ 2, 6 ]

[ "Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) resets their identity back to an embryonic age and, thus, presents a significant hurdle for modeling late-onset disorders.", "In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson's disease (PD).", "Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging.", "We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation.", "Induced aging in PD iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlarged mitochondria or Lewy-body-precursor inclusions.", "Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models." ]

[ 1, 2, 4, 5 ]

[ "BACKGROUND The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease.", "By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context.", "METHODS We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015.", "This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence.", "We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources.", "We used statistical models to pool data, adjust for bias, and incorporate covariates.", "We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value.", "Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk.", "We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates.", "We characterised risk exposure in relation to a Socio-demographic Index (SDI).", "FINDINGS Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%.", "Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period.", "All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs.", "In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]).", "From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines.", "Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use.", "Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI.", "In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015.", "Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa.", "INTERPRETATION Declines in some key environmental risks have contributed to declines in critical infectious diseases.", "Some risks appear to be invariant to SDI.", "Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention.", "Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining.", "Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden.", "FUNDING Bill & Melinda Gates Foundation." ]

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[ "Understanding the genetic basis of adaptation is a central problem in biology.", "However, revealing the underlying molecular mechanisms has been challenging as changes in fitness may result from perturbations to many pathways, any of which may contribute relatively little.", "We have developed a combined experimental/computational framework to address this problem and used it to understand the genetic basis of ethanol tolerance in Escherichia coli.", "We used fitness profiling to measure the consequences of single-locus perturbations in the context of ethanol exposure.", "A module-level computational analysis was then used to reveal the organization of the contributing loci into cellular processes and regulatory pathways (e.g. osmoregulation and cell-wall biogenesis) whose modifications significantly affect ethanol tolerance.", "Strikingly, we discovered that a dominant component of adaptation involves metabolic rewiring that boosts intracellular ethanol degradation and assimilation.", "Through phenotypic and metabolomic analysis of laboratory-evolved ethanol-tolerant strains, we investigated naturally accessible pathways of ethanol tolerance.", "Remarkably, these laboratory-evolved strains, by and large, follow the same adaptive paths as inferred from our coarse-grained search of the fitness landscape." ]

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[ "Understanding the genetic basis of adaptation is a central problem in biology.", "However, revealing the underlying molecular mechanisms has been challenging as changes in fitness may result from perturbations to many pathways, any of which may contribute relatively little.", "We have developed a combined experimental/computational framework to address this problem and used it to understand the genetic basis of ethanol tolerance in Escherichia coli.", "We used fitness profiling to measure the consequences of single-locus perturbations in the context of ethanol exposure.", "A module-level computational analysis was then used to reveal the organization of the contributing loci into cellular processes and regulatory pathways (e.g. osmoregulation and cell-wall biogenesis) whose modifications significantly affect ethanol tolerance.", "Strikingly, we discovered that a dominant component of adaptation involves metabolic rewiring that boosts intracellular ethanol degradation and assimilation.", "Through phenotypic and metabolomic analysis of laboratory-evolved ethanol-tolerant strains, we investigated naturally accessible pathways of ethanol tolerance.", "Remarkably, these laboratory-evolved strains, by and large, follow the same adaptive paths as inferred from our coarse-grained search of the fitness landscape." ]

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[ "Understanding the genetic basis of adaptation is a central problem in biology.", "However, revealing the underlying molecular mechanisms has been challenging as changes in fitness may result from perturbations to many pathways, any of which may contribute relatively little.", "We have developed a combined experimental/computational framework to address this problem and used it to understand the genetic basis of ethanol tolerance in Escherichia coli.", "We used fitness profiling to measure the consequences of single-locus perturbations in the context of ethanol exposure.", "A module-level computational analysis was then used to reveal the organization of the contributing loci into cellular processes and regulatory pathways (e.g. osmoregulation and cell-wall biogenesis) whose modifications significantly affect ethanol tolerance.", "Strikingly, we discovered that a dominant component of adaptation involves metabolic rewiring that boosts intracellular ethanol degradation and assimilation.", "Through phenotypic and metabolomic analysis of laboratory-evolved ethanol-tolerant strains, we investigated naturally accessible pathways of ethanol tolerance.", "Remarkably, these laboratory-evolved strains, by and large, follow the same adaptive paths as inferred from our coarse-grained search of the fitness landscape." ]

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[ "Understanding the genetic basis of adaptation is a central problem in biology.", "However, revealing the underlying molecular mechanisms has been challenging as changes in fitness may result from perturbations to many pathways, any of which may contribute relatively little.", "We have developed a combined experimental/computational framework to address this problem and used it to understand the genetic basis of ethanol tolerance in Escherichia coli.", "We used fitness profiling to measure the consequences of single-locus perturbations in the context of ethanol exposure.", "A module-level computational analysis was then used to reveal the organization of the contributing loci into cellular processes and regulatory pathways (e.g. osmoregulation and cell-wall biogenesis) whose modifications significantly affect ethanol tolerance.", "Strikingly, we discovered that a dominant component of adaptation involves metabolic rewiring that boosts intracellular ethanol degradation and assimilation.", "Through phenotypic and metabolomic analysis of laboratory-evolved ethanol-tolerant strains, we investigated naturally accessible pathways of ethanol tolerance.", "Remarkably, these laboratory-evolved strains, by and large, follow the same adaptive paths as inferred from our coarse-grained search of the fitness landscape." ]

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[ "Understanding the genetic basis of adaptation is a central problem in biology.", "However, revealing the underlying molecular mechanisms has been challenging as changes in fitness may result from perturbations to many pathways, any of which may contribute relatively little.", "We have developed a combined experimental/computational framework to address this problem and used it to understand the genetic basis of ethanol tolerance in Escherichia coli.", "We used fitness profiling to measure the consequences of single-locus perturbations in the context of ethanol exposure.", "A module-level computational analysis was then used to reveal the organization of the contributing loci into cellular processes and regulatory pathways (e.g. osmoregulation and cell-wall biogenesis) whose modifications significantly affect ethanol tolerance.", "Strikingly, we discovered that a dominant component of adaptation involves metabolic rewiring that boosts intracellular ethanol degradation and assimilation.", "Through phenotypic and metabolomic analysis of laboratory-evolved ethanol-tolerant strains, we investigated naturally accessible pathways of ethanol tolerance.", "Remarkably, these laboratory-evolved strains, by and large, follow the same adaptive paths as inferred from our coarse-grained search of the fitness landscape." ]

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[ "OBJECTIVE To evaluate the effects of dietary and lifestyle interventions in pregnancy on maternal and fetal weight and to quantify the effects of these interventions on obstetric outcomes.", "DESIGN Systematic review and meta-analysis.", "DATA SOURCES Major databases from inception to January 2012 without language restrictions.", "STUDY SELECTION Randomised controlled trials that evaluated any dietary or lifestyle interventions with potential to influence maternal weight during pregnancy and outcomes of pregnancy.", "DATA SYNTHESIS Results summarised as relative risks for dichotomous data and mean differences for continuous data.", "RESULTS We identified 44 relevant randomised controlled trials (7278 women) evaluating three categories of interventions: diet, physical activity, and a mixed approach.", "Overall, there was 1.42 kg reduction (95% confidence interval 0.95 to 1.89 kg) in gestational weight gain with any intervention compared with control.", "With all interventions combined, there were no significant differences in birth weight (mean difference -50 g, -100 to 0 g) and the incidence of large for gestational age (relative risk 0.85, 0.66 to 1.09) or small for gestational age (1.00, 0.78 to 1.28) babies between the groups, though by itself physical activity was associated with reduced birth weight (mean difference -60 g, -120 to -10 g).", "Interventions were associated with a reduced the risk of pre-eclampsia (0.74, 0.60 to 0.92) and shoulder dystocia (0.39, 0.22 to 0.70), with no significant effect on other critically important outcomes.", "Dietary intervention resulted in the largest reduction in maternal gestational weight gain (3.84 kg, 2.45 to 5.22 kg), with improved pregnancy outcomes compared with other interventions.", "The overall evidence rating was low to very low for important outcomes such as pre-eclampsia, gestational diabetes, gestational hypertension, and preterm delivery.", "CONCLUSIONS Dietary and lifestyle interventions in pregnancy can reduce maternal gestational weight gain and improve outcomes for both mother and baby.", "Among the interventions, those based on diet are the most effective and are associated with reductions in maternal gestational weight gain and improved obstetric outcomes." ]

[ 8, 11, 12 ]

[ "BACKGROUND Although cigarette smoking, excessive alcohol drinking, obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to the risk of multiple chronic diseases and premature death, little is known about the combined impact on mortality outcomes, in particular among Chinese and other non-Western populations.", "The objective of this study was to quantify the overall impact of lifestyle-related factors beyond that of active cigarette smoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women.", "METHODS AND FINDINGS We used data from the Shanghai Women's Health Study, an ongoing population-based prospective cohort study in China.", "Participants included 71,243 women aged 40 to 70 years enrolled during 1996-2000 who never smoked or drank alcohol regularly.", "A healthy lifestyle score was created on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes (normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse's smoking, higher daily fruit and vegetable intake).", "The score ranged from zero (least healthy) to five (most healthy) points.", "During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovascular disease (CVD) and 1,351 from cancer.", "Adjusted hazard ratios for mortality decreased progressively with an increasing number of healthy lifestyle factors.", "Compared to women with a score of zero, hazard ratios (95% confidence intervals) for women with four to five factors were 0.57 (0.44-0.74) for total mortality, 0.29 (0.16-0.54) for CVD mortality, and 0.76 (0.54-1.06) for cancer mortality.", "The inverse association between the healthy lifestyle score and mortality was seen consistently regardless of chronic disease status at baseline.", "The population attributable risks for not having 4-5 healthy lifestyle factors were 33% for total deaths, 59% for CVD deaths, and 19% for cancer deaths.", "CONCLUSIONS In this first study, to our knowledge, to quantify the combined impact of lifestyle-related factors on mortality outcomes in Chinese women, a healthier lifestyle pattern-including being of normal weight, lower central adiposity, participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetable intake-was associated with reductions in total and cause-specific mortality among lifetime nonsmoking and nondrinking women, supporting the importance of overall lifestyle modification in disease prevention.", "Please see later in the article for the Editors' Summary." ]

[ 8, 10, 11 ]

[ "BACKGROUND Although cigarette smoking, excessive alcohol drinking, obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to the risk of multiple chronic diseases and premature death, little is known about the combined impact on mortality outcomes, in particular among Chinese and other non-Western populations.", "The objective of this study was to quantify the overall impact of lifestyle-related factors beyond that of active cigarette smoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women.", "METHODS AND FINDINGS We used data from the Shanghai Women's Health Study, an ongoing population-based prospective cohort study in China.", "Participants included 71,243 women aged 40 to 70 years enrolled during 1996-2000 who never smoked or drank alcohol regularly.", "A healthy lifestyle score was created on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes (normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse's smoking, higher daily fruit and vegetable intake).", "The score ranged from zero (least healthy) to five (most healthy) points.", "During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovascular disease (CVD) and 1,351 from cancer.", "Adjusted hazard ratios for mortality decreased progressively with an increasing number of healthy lifestyle factors.", "Compared to women with a score of zero, hazard ratios (95% confidence intervals) for women with four to five factors were 0.57 (0.44-0.74) for total mortality, 0.29 (0.16-0.54) for CVD mortality, and 0.76 (0.54-1.06) for cancer mortality.", "The inverse association between the healthy lifestyle score and mortality was seen consistently regardless of chronic disease status at baseline.", "The population attributable risks for not having 4-5 healthy lifestyle factors were 33% for total deaths, 59% for CVD deaths, and 19% for cancer deaths.", "CONCLUSIONS In this first study, to our knowledge, to quantify the combined impact of lifestyle-related factors on mortality outcomes in Chinese women, a healthier lifestyle pattern-including being of normal weight, lower central adiposity, participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetable intake-was associated with reductions in total and cause-specific mortality among lifetime nonsmoking and nondrinking women, supporting the importance of overall lifestyle modification in disease prevention.", "Please see later in the article for the Editors' Summary." ]

[ 8, 10, 11 ]

[ "The Global HIV Vaccine Enterprise convened a two-day workshop in May of 2007 to discuss humoral immune responses to HIV and approaches to design vaccines that induce viral neutralizing and other potentially protective antibody responses.", "The goals of this workshop were to identify key scientific issues, gaps, and opportunities that have emerged since the Enterprise Strategic Plan was first published in 2005 [1], and to make recommendations that Enterprise stakeholders can use to plan new activities.", "Most effective viral vaccines work, at least in part, by generating antibodies that inactivate or neutralize the invading virus, and the existing data strongly suggest that an optimally effective HIV-1 vaccine should elicit potent antiviral neutralizing antibodies.", "However, unlike acute viral pathogens, HIV-1 chronically replicates in the host and evades the antibody response.", "This immune evasion, along with the large genetic variation among HIV-1 strains worldwide, has posed major obstacles to vaccine development.", "Current HIV vaccine candidates do not elicit neutralizing antibodies against most circulating virus strains, and thus the induction of a protective antibody response remains a major priority for HIV-1 vaccine development.", "For an antibody-based HIV-1 vaccine, progress in vaccine design is generally gauged by in vitro assays that measure the ability of vaccine-induced antibodies to neutralize a broad spectrum of viral isolates representing the major genetic subtypes (clades) of HIV-1 [2].", "Although it is not known what magnitude and breadth of neutralization will predict protection in vaccine recipients, it is clear that current vaccine immunogens elicit antibodies that neutralize only a minority of circulating isolates.", "Thus, much progress needs to be made in this area.", "Also, though virus neutralization is considered a critical benchmark for a vaccine, this may not be the only benchmark for predicting success with antibody-based HIV-1 vaccine immunogens.", "The main targets for neutralizing antibodies to HIV-1 are the surface gp120 and trans-membrane gp41 envelope glycoproteins (Env) that mediate receptor and coreceptor binding and the subsequent membrane fusion events that allow the virus to gain entry into cells [3].", "Antibodies neutralize the virus by binding these viral spikes and blocking virus entry into susceptible cells, such as CD4+ T cells [4,5].", "In order to chronically replicate in the host, the virus exploits several mechanisms to shield itself against antibody recognition, including a dense outer coating of sugar molecules (N-linked glycans) and the strategic positioning of cysteine–cysteine loop structures on the gp120 molecule [6–8].", "These shielding mechanisms, although highly effective, have vulnerabilities imposed by fitness constraints.", "Information on the precise location and molecular structure of these vulnerable regions could be valuable for the rational design of improved vaccine immunogens.", "Participants in the workshop identified four areas that, if given proper attention, could provide key information that would bring the field closer to an effective antibody-based HIV-1 vaccine: (1) structure-assisted immunogen design, (2) role of Fc receptors and complement, (3) assay standardization and validation, and (4) immunoregulation of B cell responses." ]

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[ "OBJECTIVE To determine whether higher past exposure to particulate air pollution is associated with prevalent high symptoms of anxiety.", "DESIGN Observational cohort study.", "SETTING Nurses' Health Study.", "PARTICIPANTS 71,271 women enrolled in the Nurses' Health Study residing throughout the contiguous United States who had valid estimates on exposure to particulate matter for at least one exposure period of interest and data on anxiety symptoms.", "MAIN OUTCOME MEASURES Meaningfully high symptoms of anxiety, defined as a score of 6 points or greater on the phobic anxiety subscale of the Crown-Crisp index, administered in 2004.", "RESULTS The 71,271 eligible women were aged between 57 and 85 years (mean 70 years) at the time of assessment of anxiety symptoms, with a prevalence of high anxiety symptoms of 15%.", "Exposure to particulate matter was characterized using estimated average exposure to particulate matter <2.5 μm in diameter (PM2.5) and 2.5 to 10 μm in diameter (PM2.5-10) in the one month, three months, six months, one year, and 15 years prior to assessment of anxiety symptoms, and residential distance to the nearest major road two years prior to assessment.", "Significantly increased odds of high anxiety symptoms were observed with higher exposure to PM2.5 for multiple averaging periods (for example, odds ratio per 10 µg/m(3) increase in prior one month average PM2.5: 1.12, 95% confidence interval 1.06 to 1.19; in prior 12 month average PM2.5: 1.15, 1.06 to 1.26).", "Models including multiple exposure windows suggested short term averaging periods were more relevant than long term averaging periods.", "There was no association between anxiety and exposure to PM2.5-10.", "Residential proximity to major roads was not related to anxiety symptoms in a dose dependent manner.", "CONCLUSIONS Exposure to fine particulate matter (PM2.5) was associated with high symptoms of anxiety, with more recent exposures potentially more relevant than more distant exposures.", "Research evaluating whether reductions in exposure to ambient PM2.5 would reduce the population level burden of clinically relevant symptoms of anxiety is warranted." ]

[ 7, 11 ]

[ "BMP is thought to induce hESC differentiation toward multiple lineages including mesoderm and trophoblast.", "The BMP-induced trophoblast phenotype is a long-standing paradox in stem cell biology.", "Here we readdressed BMP function in hESCs and mouse epiblast-derived cells.", "We found that BMP4 cooperates with FGF2 (via ERK) to induce mesoderm and to inhibit endoderm differentiation.", "These conditions induced cells with high levels of BRACHYURY (BRA) that coexpressed CDX2.", "BRA was necessary for and preceded CDX2 expression; both genes were essential for expression not only of mesodermal genes but also of trophoblast-associated genes.", "Maximal expression of the latter was seen in the absence of FGF but these cells coexpressed mesodermal genes and moreover they differed in cell surface and epigenetic properties from placental trophoblast.", "We conclude that BMP induces human and mouse pluripotent stem cells primarily to form mesoderm, rather than trophoblast, acting through BRA and CDX2." ]

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[ "Tumor recurrence represents a major clinical challenge.", "Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors.", "This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence.", "Screening for this innate response predicted accurately in which mice recurrence would occur.", "Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete.", "By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured.", "These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment." ]

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[ "Tumor recurrence represents a major clinical challenge.", "Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors.", "This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence.", "Screening for this innate response predicted accurately in which mice recurrence would occur.", "Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete.", "By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured.", "These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment." ]

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[ "Osteogenesis during bone modeling and remodeling is coupled with angiogenesis.", "A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31hiEmcnhi), couples angiogenesis and osteogenesis.", "Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31hiEmcnhi vessel formation during bone modeling and remodeling.", "Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase–positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31hiEmcnhi vessels compared to wild-type mice.", "In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31hiEmcnhi vessels are significantly lower compared to sham-operated controls.", "Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31hiEmcnhi vessel number and stimulates bone formation in OVX mice.", "Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation." ]

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[ "FACT, a heterodimer of Spt16 and Pob3, is an essential histone chaperone.", "We show that the H2A-H2B binding activity that is central to FACT function resides in short acidic regions near the C termini of each subunit.", "Mutations throughout these regions affect binding and cause correlated phenotypes that range from mild to lethal, with the largest individual contributions unexpectedly coming from an aromatic residue and a nearby carboxylate residue within each domain.", "Spt16 and Pob3 bind overlapping sites on H2A-H2B, and Spt16-Pob3 heterodimers simultaneously bind two H2A-H2B dimers, the same stoichiometry as the components of a nucleosome.", "An Spt16:H2A-H2B crystal structure explains the biochemical and genetic data, provides a model for Pob3 binding, and implies a mechanism for FACT reorganization that we confirm biochemically.", "Moreover, unexpected similarity to binding of ANP32E and Swr1 with H2A.Z-H2B reveals that diverse H2A-H2B chaperones use common mechanisms of histone binding and regulating nucleosome functions." ]

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[ "CONTEXT Exogenous estrogen use may lower risk of dementia in postmenopausal women.", "A relationship between long-term exposure to endogenous estrogens and incident dementia has been hypothesized but not studied.", "OBJECTIVE To determine whether a longer reproductive period, as an indicator of longer exposure to endogenous estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause.", "DESIGN AND SETTING The Rotterdam Study, a population-based prospective cohort study conducted in the Netherlands.", "PARTICIPANTS A total of 3601 women aged 55 years or older who did not have dementia at baseline (1990-1993) and had information on age at menarche, age at menopause, and type of menopause.", "Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for development of dementia.", "MAIN OUTCOME MEASURES Incidence of dementia, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria, and AD, based on National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria, compared by quartiles of reproductive period among women with natural menopause.", "RESULTS During 21 046 person-years of follow-up (median follow-up, 6.3 years), 199 women developed dementia, including 159 who developed AD.", "After adjusting for age, dementia was not clearly associated with length of reproductive period.", "However, after adjusting for multiple covariates, women with natural menopause and more reproductive years had an increased risk of dementia (adjusted rate ratio [RR] for women with >39 reproductive years [highest quartile] compared with <34 reproductive years [lowest quartile], 1.78; 95% confidence interval [CI], 1.12-2.84).", "The adjusted RR per year of increase was 1.04 (95% CI, 1.01-1.08).", "For risk of AD, the adjusted RRs were 1.51 (95% CI, 0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively.", "Risk of dementia associated with a longer reproductive period was most pronounced in APOE epsilon4 carriers (adjusted RR for >39 reproductive years compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI, 1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed.", "CONCLUSION Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause." ]

[ 12 ]

[ "CONTEXT Exogenous estrogen use may lower risk of dementia in postmenopausal women.", "A relationship between long-term exposure to endogenous estrogens and incident dementia has been hypothesized but not studied.", "OBJECTIVE To determine whether a longer reproductive period, as an indicator of longer exposure to endogenous estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause.", "DESIGN AND SETTING The Rotterdam Study, a population-based prospective cohort study conducted in the Netherlands.", "PARTICIPANTS A total of 3601 women aged 55 years or older who did not have dementia at baseline (1990-1993) and had information on age at menarche, age at menopause, and type of menopause.", "Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for development of dementia.", "MAIN OUTCOME MEASURES Incidence of dementia, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria, and AD, based on National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria, compared by quartiles of reproductive period among women with natural menopause.", "RESULTS During 21 046 person-years of follow-up (median follow-up, 6.3 years), 199 women developed dementia, including 159 who developed AD.", "After adjusting for age, dementia was not clearly associated with length of reproductive period.", "However, after adjusting for multiple covariates, women with natural menopause and more reproductive years had an increased risk of dementia (adjusted rate ratio [RR] for women with >39 reproductive years [highest quartile] compared with <34 reproductive years [lowest quartile], 1.78; 95% confidence interval [CI], 1.12-2.84).", "The adjusted RR per year of increase was 1.04 (95% CI, 1.01-1.08).", "For risk of AD, the adjusted RRs were 1.51 (95% CI, 0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively.", "Risk of dementia associated with a longer reproductive period was most pronounced in APOE epsilon4 carriers (adjusted RR for >39 reproductive years compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI, 1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed.", "CONCLUSION Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause." ]

[ 12 ]

[ "CONTEXT Exogenous estrogen use may lower risk of dementia in postmenopausal women.", "A relationship between long-term exposure to endogenous estrogens and incident dementia has been hypothesized but not studied.", "OBJECTIVE To determine whether a longer reproductive period, as an indicator of longer exposure to endogenous estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause.", "DESIGN AND SETTING The Rotterdam Study, a population-based prospective cohort study conducted in the Netherlands.", "PARTICIPANTS A total of 3601 women aged 55 years or older who did not have dementia at baseline (1990-1993) and had information on age at menarche, age at menopause, and type of menopause.", "Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for development of dementia.", "MAIN OUTCOME MEASURES Incidence of dementia, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria, and AD, based on National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria, compared by quartiles of reproductive period among women with natural menopause.", "RESULTS During 21 046 person-years of follow-up (median follow-up, 6.3 years), 199 women developed dementia, including 159 who developed AD.", "After adjusting for age, dementia was not clearly associated with length of reproductive period.", "However, after adjusting for multiple covariates, women with natural menopause and more reproductive years had an increased risk of dementia (adjusted rate ratio [RR] for women with >39 reproductive years [highest quartile] compared with <34 reproductive years [lowest quartile], 1.78; 95% confidence interval [CI], 1.12-2.84).", "The adjusted RR per year of increase was 1.04 (95% CI, 1.01-1.08).", "For risk of AD, the adjusted RRs were 1.51 (95% CI, 0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively.", "Risk of dementia associated with a longer reproductive period was most pronounced in APOE epsilon4 carriers (adjusted RR for >39 reproductive years compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI, 1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed.", "CONCLUSION Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause." ]

[ 12 ]

[ "CONTEXT Exogenous estrogen use may lower risk of dementia in postmenopausal women.", "A relationship between long-term exposure to endogenous estrogens and incident dementia has been hypothesized but not studied.", "OBJECTIVE To determine whether a longer reproductive period, as an indicator of longer exposure to endogenous estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause.", "DESIGN AND SETTING The Rotterdam Study, a population-based prospective cohort study conducted in the Netherlands.", "PARTICIPANTS A total of 3601 women aged 55 years or older who did not have dementia at baseline (1990-1993) and had information on age at menarche, age at menopause, and type of menopause.", "Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for development of dementia.", "MAIN OUTCOME MEASURES Incidence of dementia, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria, and AD, based on National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria, compared by quartiles of reproductive period among women with natural menopause.", "RESULTS During 21 046 person-years of follow-up (median follow-up, 6.3 years), 199 women developed dementia, including 159 who developed AD.", "After adjusting for age, dementia was not clearly associated with length of reproductive period.", "However, after adjusting for multiple covariates, women with natural menopause and more reproductive years had an increased risk of dementia (adjusted rate ratio [RR] for women with >39 reproductive years [highest quartile] compared with <34 reproductive years [lowest quartile], 1.78; 95% confidence interval [CI], 1.12-2.84).", "The adjusted RR per year of increase was 1.04 (95% CI, 1.01-1.08).", "For risk of AD, the adjusted RRs were 1.51 (95% CI, 0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively.", "Risk of dementia associated with a longer reproductive period was most pronounced in APOE epsilon4 carriers (adjusted RR for >39 reproductive years compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI, 1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed.", "CONCLUSION Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause." ]

[ 12 ]

[ "Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear.", "The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool.", "By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation.", "We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence.", "We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair.", "Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair." ]

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[ "BACKGROUND Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity.", "It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively.", "However, the role of FGF21 in the cardiovascular system remains elusive.", "METHODS AND RESULTS The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E(-/-) mice.", "FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E(-/-) mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia.", "Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E(-/-)mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia.", "Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E(-/-) mice.", "By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2.", "CONCLUSIONS FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels." ]

[ 5 ]

[ "A solid tumor is an organ composed of cancer and host cells embedded in an extracellular matrix and nourished by blood vessels.", "A prerequisite to understanding tumor pathophysiology is the ability to distinguish and monitor each component in dynamic studies.", "Standard fluorophores hamper simultaneous intravital imaging of these components.", "Here, we used multiphoton microscopy techniques and transgenic mice that expressed green fluorescent protein, and combined them with the use of quantum dot preparations.", "We show that these fluorescent semiconductor nanocrystals can be customized to concurrently image and differentiate tumor vessels from both the perivascular cells and the matrix.", "Moreover, we used them to measure the ability of particles of different sizes to access the tumor.", "Finally, we successfully monitored the recruitment of quantum dot–labeled bone marrow–derived precursor cells to the tumor vasculature.", "These examples show the versatility of quantum dots for studying tumor pathophysiology and creating avenues for treatment." ]

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[ "BACKGROUND The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke.", "A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult.", "A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption.", "We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials.", "METHODS We established a collaboration of genetic studies consisting of 237 datasets including 59,995 individuals with data for homocysteine and 20,885 stroke events.", "We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45,549 individuals, 2314 stroke events, 269 transient ischaemic attacks).", "FINDINGS The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, -0·85 to 1·11).", "The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25).", "Most randomised trials took place in regions with high or increasing population folate concentrations.", "The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11).", "Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region.", "INTERPRETATION In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke.", "Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias.", "If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption.", "FUNDING Full funding sources listed at end of paper (see Acknowledgments)." ]

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[ "CONTEXT Although cerebral palsy (CP) among extremely premature infants has been reported as a major morbidity outcome, there are difficulties comparing published CP rates from many sites over various birth years.", "OBJECTIVE To assess the changes in population-based, gestational age-specific prevalence rates of CP among extremely premature infants over 30 years.", "DESIGN Prospective population-based longitudinal outcome study.", "SETTING AND PARTICIPANTS In Northern Alberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were liveborn from 1974 through 2003.", "By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and 858 (37%) had received multidisciplinary neurodevelopmental assessment.", "MAIN OUTCOME MEASURE Population-based prevalence rates of CP were determined.", "Logistic regression with linear spline was used to assess changes in CP prevalence over time.", "RESULTS At age 2 years, 122 (14.2%) of 858 survivors had CP.", "This diagnosis was confirmed for each child by age 3 years or older.", "Among those whose gestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001), while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994 (P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001).", "Among those whose gestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and 80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until the years 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001).", "For all survivors born in the years 2001-2003, CP prevalence was 19 per 1000 live births.", "CONCLUSION Population-based CP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weight ranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality, reversing trends prior to 1992-1994." ]

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[ "The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism.", "Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival.", "These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems.", "Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues." ]

[ 0 ]

[ "The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism.", "Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival.", "These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems.", "Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues." ]

[ 0 ]

[ "Deamidation of N-terminal Gln by Nt(Q)-amidase, an N-terminal amidohydrolase, is a part of the N-end rule pathway of protein degradation.", "We detected the activity of Nt(Q)-amidase, termed Ntaq1, in mouse tissues, purified Ntaq1 from bovine brains, identified its gene, and began analyzing this enzyme.", "Ntaq1 is highly conserved among animals, plants, and some fungi, but its sequence is dissimilar to sequences of other amidases.", "An earlier mutant in the Drosophila Cg8253 gene that we show here to encode Nt(Q)-amidase has defective long-term memory.", "Other studies identified protein ligands of the uncharacterized human C8orf32 protein that we show here to be the Ntaq1 Nt(Q)-amidase.", "Remarkably, \"high-throughput\" studies have recently solved the crystal structure of C8orf32 (Ntaq1).", "Our site-directed mutagenesis of Ntaq1 and its crystal structure indicate that the active site and catalytic mechanism of Nt(Q)-amidase are similar to those of transglutaminases." ]

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[ "The Sir2 deacetylase modulates organismal life-span in various species.", "However, the molecular mechanisms by which Sir2 increases longevity are largely unknown.", "We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity.", "SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells.", "SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death.", "Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance." ]

[ 5 ]

[ "Autophagy is the primary catabolic process triggered in response to starvation.", "Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy.", "Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking.", "Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts.", "Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle.", "Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes.", "Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions.", "Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes through Foxk-Sin3-mediated transcriptional control." ]

[ 3, 5 ]

[ "Regulatory T (Treg) cells, whose differentiation and function are controlled by X chromosome-encoded transcription factor Foxp3, are generated in the thymus (tTreg) and extrathymically (peripheral, pTreg), and their deficiency results in fatal autoimmunity.", "Here, we demonstrate that a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg but dispensable for tTreg cell generation, is present only in placental mammals.", "CNS1 is largely composed of mammalian-wide interspersed repeats (MIR) that have undergone retrotransposition during early mammalian radiation.", "During pregnancy, pTreg cells specific to a model paternal alloantigen were generated in a CNS1-dependent manner and accumulated in the placenta.", "Furthermore, when mated with allogeneic, but not syngeneic, males, CNS1-deficient females showed increased fetal resorption accompanied by increased immune cell infiltration and defective remodeling of spiral arteries.", "Our results suggest that, during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal-fetal tolerance." ]

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[ "Regulatory T (Treg) cells, whose differentiation and function are controlled by X chromosome-encoded transcription factor Foxp3, are generated in the thymus (tTreg) and extrathymically (peripheral, pTreg), and their deficiency results in fatal autoimmunity.", "Here, we demonstrate that a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg but dispensable for tTreg cell generation, is present only in placental mammals.", "CNS1 is largely composed of mammalian-wide interspersed repeats (MIR) that have undergone retrotransposition during early mammalian radiation.", "During pregnancy, pTreg cells specific to a model paternal alloantigen were generated in a CNS1-dependent manner and accumulated in the placenta.", "Furthermore, when mated with allogeneic, but not syngeneic, males, CNS1-deficient females showed increased fetal resorption accompanied by increased immune cell infiltration and defective remodeling of spiral arteries.", "Our results suggest that, during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal-fetal tolerance." ]

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[ "Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression.", "MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown.", "Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF.", "Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF.", "Tumour-initiating cells (TICs) exhibit elevated G-CSF.", "MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop.", "Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients.", "These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment." ]

[ 2 ]

[ "Maintaining hematopoietic stem cell (HSC) quiescence is a critical property for the life-long generation of blood cells.", "Approximately 75% of cells in a highly enriched long-term repopulating HSC (LT-HSC) pool (Lin(-)Sca1(+)c-Kit(hi)CD150(+)CD48(-)) are quiescent, with only a small percentage of the LT-HSCs in cycle.", "Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs.", "Although it is well documented that GATA-3 is expressed in HSCs, a role for GATA-3 in any prethymic progenitor cell has not been established.", "In the present study, we show that Gata3-null mutant mice generate fewer LT-HSCs and that fewer Gata3-null LT-HSCs are in cycle.", "Furthermore, Gata3 mutant hematopoietic progenitor cells fail to be recruited into an increased cycling state after 5-fluorouracil-induced myelosuppression.", "Therefore, GATA-3 is required for the maintenance of a normal number of LT-HSCs and for their entry into the cell cycle." ]

[ 5, 6 ]

[ "Maintaining hematopoietic stem cell (HSC) quiescence is a critical property for the life-long generation of blood cells.", "Approximately 75% of cells in a highly enriched long-term repopulating HSC (LT-HSC) pool (Lin(-)Sca1(+)c-Kit(hi)CD150(+)CD48(-)) are quiescent, with only a small percentage of the LT-HSCs in cycle.", "Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs.", "Although it is well documented that GATA-3 is expressed in HSCs, a role for GATA-3 in any prethymic progenitor cell has not been established.", "In the present study, we show that Gata3-null mutant mice generate fewer LT-HSCs and that fewer Gata3-null LT-HSCs are in cycle.", "Furthermore, Gata3 mutant hematopoietic progenitor cells fail to be recruited into an increased cycling state after 5-fluorouracil-induced myelosuppression.", "Therefore, GATA-3 is required for the maintenance of a normal number of LT-HSCs and for their entry into the cell cycle." ]

[ 4, 6 ]

[ "OBJECTIVE To investigate the association between gastric cancer and prior infection with Helicobacter pylori.", "DESIGN Case-control comparison of prevalence of IgG antibodies to H pylori in blood samples collected prospectively, before diagnosis of gastric cancer in the cases.", "Presence of H pylori antibody (greater than 10 micrograms IgG/ml) determined by enzyme linked immunosorbent assay (ELISA).", "SUBJECTS 29 men with a subsequent diagnosis of gastric cancer and 116 aged matched controls selected from over 22,000 middle aged men participating in two ongoing cohort studies (the British United Provident Association study and the Caerphilly collaborative heart disease study), who had provided blood samples during 1975-1982.", "RESULTS 20 of the 29 cases (69%) and 54 of the 116 controls (47%) were positive for H pylori specific antibody.", "The median specific IgG concentration was significantly higher in the cases than controls (90 micrograms/ml v 3.6 micrograms/ml, p less than 0.01).", "The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was 2.77 (95% confidence interval 1.04 to 7.97, 2p = 0.039).", "CONCLUSIONS H pylori infection may be an important cause of gastric cancer; between 35% and 55% of all cases may be associated with such an infection." ]

[ 6, 7 ]

[ "OBJECTIVE To investigate the association between gastric cancer and prior infection with Helicobacter pylori.", "DESIGN Case-control comparison of prevalence of IgG antibodies to H pylori in blood samples collected prospectively, before diagnosis of gastric cancer in the cases.", "Presence of H pylori antibody (greater than 10 micrograms IgG/ml) determined by enzyme linked immunosorbent assay (ELISA).", "SUBJECTS 29 men with a subsequent diagnosis of gastric cancer and 116 aged matched controls selected from over 22,000 middle aged men participating in two ongoing cohort studies (the British United Provident Association study and the Caerphilly collaborative heart disease study), who had provided blood samples during 1975-1982.", "RESULTS 20 of the 29 cases (69%) and 54 of the 116 controls (47%) were positive for H pylori specific antibody.", "The median specific IgG concentration was significantly higher in the cases than controls (90 micrograms/ml v 3.6 micrograms/ml, p less than 0.01).", "The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was 2.77 (95% confidence interval 1.04 to 7.97, 2p = 0.039).", "CONCLUSIONS H pylori infection may be an important cause of gastric cancer; between 35% and 55% of all cases may be associated with such an infection." ]

[ 6, 7 ]

[ "BACKGROUND The case-fatality for intentional self-poisoning in the rural developing world is 10-50-fold higher than that in industrialised countries, mostly because of the use of highly toxic pesticides and plants.", "We therefore aimed to assess whether routine treatment with multiple-dose activated charcoal, to interrupt enterovascular or enterohepatic circulations, offers benefit compared with no charcoal in such an environment.", "METHODS We did an open-label, parallel group, randomised, controlled trial of six 50 g doses of activated charcoal at 4-h intervals versus no charcoal versus one 50 g dose of activated charcoal in three Sri Lankan hospitals.", "4632 patients were randomised to receive no charcoal (n=1554), one dose of charcoal (n=1545), or six doses of charcoal (n=1533); outcomes were available for 4629 patients.", "2338 (51%) individuals had ingested pesticides, whereas 1647 (36%) had ingested yellow oleander (Thevetia peruviana) seeds.", "Mortality was the primary outcome measure.", "Analysis was by intention to treat.", "The trial is registered with controlled-trials.com as ISRCTN02920054.", "FINDINGS Mortality did not differ between the groups.", "97 (6.3%) of 1531 participants in the multiple-dose group died, compared with 105 (6.8%) of 1554 in the no charcoal group (adjusted odds ratio 0.96, 95% CI 0.70-1.33).", "No differences were noted for patients who took particular poisons, were severely ill on admission, or who presented early.", "INTERPRETATION We cannot recommend the routine use of multiple-dose activated charcoal in rural Asia Pacific; although further studies of early charcoal administration might be useful, effective affordable treatments are urgently needed." ]

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[ "The present study retrospectively analyzed 19 patients diagnosed with paraquat (PQ) poisoning with the aim to investigate the effect of activated charcoal hemoperfusion on renal function and PQ elimination.", "The results indicated that 7 patients died and 12 survived.", "Non-oliguric renal failure occurred in all of the 7 patients who died.", "Among the 12 surviving patients, 10 had normal renal function and 2 developed non-oliguric renal failure.", "There was a linear correlation between plasma and urine paraquat concentration prior to and during activated charcoal hemoperfusion.", "The equation parameters together with the correlation coefficient on admission were as follows: Y=0.5820+1.7348X (R2=0.678; F=35.768; P<0.0001).", "The equation parameters together with the correlation coefficient were as follows during activated charcoal hemoperfusion: Y=0.6827+1.2649X (R2=0.626; F=50.308; P<0.0001).", "Therefore, it was concluded that in patients with normal renal function, the elimination kinetics of PQ by the kidneys were only associated with the plasma PQ concentration.", "Activated charcoal hemoperfusion had little effect on avoiding acute kidney injury in patients with severe PQ poisoning." ]

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[ "OBJECTIVE To evaluate if a specific exercise strategy, targeting the rotator cuff and scapula stabilisers, improves shoulder function and pain more than unspecific exercises in patients with subacromial impingement syndrome, thereby decreasing the need for arthroscopic subacromial decompression.", "DESIGN Randomised, participant and single assessor blinded, controlled study.", "SETTING Department of orthopaedics in a Swedish university hospital.", "PARTICIPANTS 102 patients with long standing (over six months) persistent subacromial impingement syndrome in whom earlier conservative treatment had failed, recruited through orthopaedic specialists.", "INTERVENTIONS The specific exercise strategy consisted of strengthening eccentric exercises for the rotator cuff and concentric/eccentric exercises for the scapula stabilisers in combination with manual mobilisation.", "The control exercise programme consisted of unspecific movement exercises for the neck and shoulder.", "Patients in both groups received five to six individual guided treatment sessions during 12 weeks.", "In between these supervised sessions the participants performed home exercises once or twice a day for 12 weeks.", "MAIN OUTCOME MEASURES The primary outcome was the Constant-Murley shoulder assessment score evaluating shoulder function and pain.", "Secondary outcomes were patients' global impression of change because of treatment and decision regarding surgery.", "RESULTS Most (97, 95%) participants completed the 12 week study.", "There was a significantly greater improvement in the Constant-Murley score in the specific exercise group than in the control exercise group (24 points (95% confidence interval 19 to 28.0) v 9 points (5 to 13); mean difference between group: 15 points (8.5 to 20.6)).", "Significantly more patients in the specific exercise group reported successful outcome (defined as large improvement or recovered) in the patients' global assessment of change because of treatment: 69% (35/51) v 24% (11/46); odds ratio 7.6, 3.1 to 18.9; P<0.001.", "A significantly lower proportion of patients in the specific exercise group subsequently chose to undergo surgery: 20% (10/51) v 63% (29/46); odds ratio 7.7, 3.1 to 19.4; P<0.001).", "CONCLUSION A specific exercise strategy, focusing on strengthening eccentric exercises for the rotator cuff and concentric/eccentric exercises for the scapula stabilisers, is effective in reducing pain and improving shoulder function in patients with persistent subacromial impingement syndrome.", "By extension, this exercise strategy reduces the need for arthroscopic subacromial decompression within the three month timeframe used in the study.", "TRIAL REGISTRATION Clinical trials NCT01037673." ]

[ 11 ]

[ "OBJECTIVE To evaluate if a specific exercise strategy, targeting the rotator cuff and scapula stabilisers, improves shoulder function and pain more than unspecific exercises in patients with subacromial impingement syndrome, thereby decreasing the need for arthroscopic subacromial decompression.", "DESIGN Randomised, participant and single assessor blinded, controlled study.", "SETTING Department of orthopaedics in a Swedish university hospital.", "PARTICIPANTS 102 patients with long standing (over six months) persistent subacromial impingement syndrome in whom earlier conservative treatment had failed, recruited through orthopaedic specialists.", "INTERVENTIONS The specific exercise strategy consisted of strengthening eccentric exercises for the rotator cuff and concentric/eccentric exercises for the scapula stabilisers in combination with manual mobilisation.", "The control exercise programme consisted of unspecific movement exercises for the neck and shoulder.", "Patients in both groups received five to six individual guided treatment sessions during 12 weeks.", "In between these supervised sessions the participants performed home exercises once or twice a day for 12 weeks.", "MAIN OUTCOME MEASURES The primary outcome was the Constant-Murley shoulder assessment score evaluating shoulder function and pain.", "Secondary outcomes were patients' global impression of change because of treatment and decision regarding surgery.", "RESULTS Most (97, 95%) participants completed the 12 week study.", "There was a significantly greater improvement in the Constant-Murley score in the specific exercise group than in the control exercise group (24 points (95% confidence interval 19 to 28.0) v 9 points (5 to 13); mean difference between group: 15 points (8.5 to 20.6)).", "Significantly more patients in the specific exercise group reported successful outcome (defined as large improvement or recovered) in the patients' global assessment of change because of treatment: 69% (35/51) v 24% (11/46); odds ratio 7.6, 3.1 to 18.9; P<0.001.", "A significantly lower proportion of patients in the specific exercise group subsequently chose to undergo surgery: 20% (10/51) v 63% (29/46); odds ratio 7.7, 3.1 to 19.4; P<0.001).", "CONCLUSION A specific exercise strategy, focusing on strengthening eccentric exercises for the rotator cuff and concentric/eccentric exercises for the scapula stabilisers, is effective in reducing pain and improving shoulder function in patients with persistent subacromial impingement syndrome.", "By extension, this exercise strategy reduces the need for arthroscopic subacromial decompression within the three month timeframe used in the study.", "TRIAL REGISTRATION Clinical trials NCT01037673." ]

[ 11, 12, 14 ]

[ "Signaling pathways that respond to DNA damage are essential for the maintenance of genome stability and are linked to many diseases, including cancer.", "Here, a genome-wide siRNA screen was employed to identify additional genes involved in genome stabilization by monitoring phosphorylation of the histone variant H2AX, an early mark of DNA damage.", "We identified hundreds of genes whose downregulation led to elevated levels of H2AX phosphorylation (gammaH2AX) and revealed links to cellular complexes and to genes with unclassified functions.", "We demonstrate a widespread role for mRNA-processing factors in preventing DNA damage, which in some cases is caused by aberrant RNA-DNA structures.", "Furthermore, we connect increased gammaH2AX levels to the neurological disorder Charcot-Marie-Tooth (CMT) syndrome, and we find a role for several CMT proteins in the DNA-damage response.", "These data indicate that preservation of genome stability is mediated by a larger network of biological processes than previously appreciated." ]

[ 3 ]

[ "Transcription factors, such as Oct4, are critical for establishing and maintaining pluripotent cell identity.", "Whereas the genomic locations of several pluripotency transcription factors have been reported, the spectrum of their interaction partners is underexplored.", "Here, we use an improved affinity protocol to purify Oct4-interacting proteins from mouse embryonic stem cells (ESCs).", "Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1, and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors and chromatin-modifying complexes with documented roles in self-renewal, but also many factors not previously associated with the ESC network.", "We find that Esrrb associated with the basal transcription machinery and also detect interactions between transcription factors and components of the TGF-beta, Notch, and Wnt signaling pathways.", "Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrb to several target genes.", "In conclusion, our purification protocol allowed us to bring greater definition to the circuitry controlling pluripotent cell identity." ]

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