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[ "OBJECTIVE To determine rates of suicide associated with pregnancy by the type of pregnancy.", "DESIGN Register linkage study.", "Information on suicides in women of reproductive age was linked with the Finnish birth, abortion, and hospital discharge registers to find out how many women who committed suicide had had a completed pregnancy during her last year of life.", "SETTING Nationwide data from Finland.", "SUBJECTS Women who committed suicide in 1987-94.", "RESULTS There were 73 suicides associated with pregnancy, representing 5.4% of all suicides in women in this age group.", "The mean annual suicide rate was 11.3 per 100,000.", "The suicide rate associated with birth was significantly lower (5.9) and the rates associated with miscarriage (18.1) and induced abortion (34.7) were significantly higher than in the population.", "The risk associated with birth was higher among teenagers and that associated with abortion was increased in all age groups.", "Women who had committed a suicide tended to come from lower social classes and were more likely to be unmarried than other women who had had a completed pregnancy.", "CONCLUSIONS The increased risk of suicide after an induced abortion indicates either common risk factors for both or harmful effects of induced abortion on mental health." ]

[ 7 ]

[ "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement.", "In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body.", "We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover.", "CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly.", "CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion.", "Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs.", "We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections." ]

[ 4 ]

[ "The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals.", "This variability critically determines the impact a disease has on a patient's life but is very poorly understood.", "Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis.", "We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria.", "Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10.", "Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses." ]

[ 4 ]

[ "The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals.", "This variability critically determines the impact a disease has on a patient's life but is very poorly understood.", "Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis.", "We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria.", "Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10.", "Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses." ]

[ 3 ]

[ "The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals.", "This variability critically determines the impact a disease has on a patient's life but is very poorly understood.", "Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis.", "We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria.", "Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10.", "Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses." ]

[ 4 ]

[ "Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production.", "UCP1 is also found outside classical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'.", "In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype, but whether a causal relationship exists is not clear.", "Here we report that human brite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks.", "Adipocytes formed from these progenitors transform in response to adenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining feature of the beige/brite phenotype, while displaying uncoupled respiration.", "When implanted into normal chow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rg(null) (NSG) mice, brite/beige adipocytes activated in vitro enhance systemic glucose tolerance.", "These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity.", "Pro-angiogenic conditions therefore drive the proliferation of human beige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism." ]

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[ "Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production.", "UCP1 is also found outside classical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'.", "In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype, but whether a causal relationship exists is not clear.", "Here we report that human brite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks.", "Adipocytes formed from these progenitors transform in response to adenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining feature of the beige/brite phenotype, while displaying uncoupled respiration.", "When implanted into normal chow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rg(null) (NSG) mice, brite/beige adipocytes activated in vitro enhance systemic glucose tolerance.", "These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity.", "Pro-angiogenic conditions therefore drive the proliferation of human beige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism." ]

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[ "Importance Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.", "Objectives To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.", "Design, Setting, and Patients Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014.", "Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized.", "Randomization was stratified by metformin use.", "Interventions Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.", "Main Outcomes and Measures The primary end point was change in hemoglobing A1c (HbA1c) from baseline to week 26.", "Secondary end points included change from baseline in body weight and adverse events.", "Results Baseline characteristics were comparable across treatment groups.", "Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial.", "Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, −0.7% to −1.9%) and subcutaneous semaglutide (−1.9%) and placebo (−0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, –0.4% to –1.6%; P = .01 for 2.5 mg, <.001 for all other dosages).", "Reductions in body weight were greater with oral semaglutide (dosage-dependent range, −2.1 kg to −6.9 kg) and subcutaneous semaglutide (−6.4 kg) vs placebo (−1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, –0.9 to –5.7 kg; P < .001).", "Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common.", "Conclusions and Relevance Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks.", "These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety.", "Trial Registration clinicaltrials.gov Identifier: NCT01923181" ]

[ 12 ]

[ "Importance Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.", "Objectives To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.", "Design, Setting, and Patients Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014.", "Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized.", "Randomization was stratified by metformin use.", "Interventions Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.", "Main Outcomes and Measures The primary end point was change in hemoglobing A1c (HbA1c) from baseline to week 26.", "Secondary end points included change from baseline in body weight and adverse events.", "Results Baseline characteristics were comparable across treatment groups.", "Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial.", "Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, −0.7% to −1.9%) and subcutaneous semaglutide (−1.9%) and placebo (−0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, –0.4% to –1.6%; P = .01 for 2.5 mg, <.001 for all other dosages).", "Reductions in body weight were greater with oral semaglutide (dosage-dependent range, −2.1 kg to −6.9 kg) and subcutaneous semaglutide (−6.4 kg) vs placebo (−1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, –0.9 to –5.7 kg; P < .001).", "Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common.", "Conclusions and Relevance Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks.", "These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety.", "Trial Registration clinicaltrials.gov Identifier: NCT01923181" ]

[ 12 ]

[ "Cardiovascular disease is a leading cause of death worldwide.", "The limited capability of heart tissue to regenerate has prompted methodological developments for creating de novo cardiomyocytes, both in vitro and in vivo.", "Beyond uses in cell replacement therapy, patient-specific cardiomyocytes may find applications in drug testing, drug discovery, and disease modeling.", "Recently, approaches for generating cardiomyocytes have expanded to encompass three major sources of starting cells: human pluripotent stem cells (hPSCs), adult heart-derived cardiac progenitor cells (CPCs), and reprogrammed fibroblasts.", "We discuss state-of-the-art methods for generating de novo cardiomyocytes from hPSCs and reprogrammed fibroblasts, highlighting potential applications and future challenges." ]

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[ "The functional heart is comprised of distinct mesoderm-derived lineages including cardiomyocytes, endothelial cells and vascular smooth muscle cells.", "Studies in the mouse embryo and the mouse embryonic stem cell differentiation model have provided evidence indicating that these three lineages develop from a common Flk-1+ (kinase insert domain protein receptor, also known as Kdr) cardiovascular progenitor that represents one of the earliest stages in mesoderm specification to the cardiovascular lineages.", "To determine whether a comparable progenitor is present during human cardiogenesis, we analysed the development of the cardiovascular lineages in human embryonic stem cell differentiation cultures.", "Here we show that after induction with combinations of activin A, bone morphogenetic protein 4 (BMP4), basic fibroblast growth factor (bFGF, also known as FGF2), vascular endothelial growth factor (VEGF, also known as VEGFA) and dickkopf homolog 1 (DKK1) in serum-free media, human embryonic-stem-cell-derived embryoid bodies generate a KDRlow/C-KIT(CD117)neg population that displays cardiac, endothelial and vascular smooth muscle potential in vitro and, after transplantation, in vivo.", "When plated in monolayer cultures, these KDRlow/C-KITneg cells differentiate to generate populations consisting of greater than 50% contracting cardiomyocytes.", "Populations derived from the KDRlow/C-KITneg fraction give rise to colonies that contain all three lineages when plated in methylcellulose cultures.", "Results from limiting dilution studies and cell-mixing experiments support the interpretation that these colonies are clones, indicating that they develop from a cardiovascular colony-forming cell.", "Together, these findings identify a human cardiovascular progenitor that defines one of the earliest stages of human cardiac development." ]

[ 1 ]

[ "Reproductive cessation is perhaps the earliest aging phenotype that humans experience.", "Similarly, reproduction of Caenorhabditis elegans ceases in mid-adulthood.", "Although somatic aging has been studied in both worms and humans, mechanisms regulating reproductive aging are not yet understood.", "Here, we show that TGF-β Sma/Mab and Insulin/IGF-1 signaling regulate C. elegans reproductive aging by modulating multiple aspects of the reproductive process, including embryo integrity, oocyte fertilizability, chromosome segregation fidelity, DNA damage resistance, and oocyte and germline morphology.", "TGF-β activity regulates reproductive span and germline/oocyte quality noncell-autonomously and is temporally and transcriptionally separable from its regulation of growth.", "Chromosome segregation, cell cycle, and DNA damage response genes are upregulated in TGF-β mutant oocytes, decline in aged mammalian oocytes, and are critical for oocyte quality maintenance.", "Our data suggest that C. elegans and humans share many aspects of reproductive aging, including the correlation between reproductive aging and declining oocyte quality and mechanisms determining oocyte quality." ]

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[ "OBJECTIVES To explore the use of local civil registration data to assess the perinatal mortality in a typical rural county in a less developed province in China, 1999-2000.", "DESIGN Retrospective cohort study.", "Pregnancies in a cohort of women followed from registration of pregnancy to outcome of infant seven days after birth.", "SETTING Routine family planning records in 20 rural townships in eastern China.", "SUBJECTS 3697 pregnancies registered by the local family planning system during 1999.", "MAIN OUTCOME MEASURES Abortions, stillbirths, early neonatal mortality, perinatal mortality.", "RESULTS Only three cases were lost to follow up.", "The average age of the women at pregnancy was 25.9 years.", "Three hundred and twelve pregnancies were aborted and 240 ended in miscarriage (total 552, 15%).", "The perinatal mortality rate was 69 per 1000 births, the rate of stillbirth was 24 per 1000 births, and the early neonatal mortality was 46 per 1000 live births.", "The early neonatal mortality was 29 in boys and 69 in girls per 1000 live births.", "The perinatal mortality rate increased notably with parity and was higher in townships having lower income per capita.", "CONCLUSIONS The family planning system at the most local level is a useful data source for studying perinatal mortality in rural China.", "The perinatal mortality rate in the study county was higher than previously reported for both rural and urban areas in China.", "The results by parity and sex of the infant raise concern over the impact of the one child policy." ]

[ 10 ]

[ "BACKGROUND Hepatitis C virus (HCV) is estimated to affect 130-180 million people worldwide.", "Although its origin is unknown, patterns of viral diversity suggest that HCV genotype 1 probably originated from West Africa.", "Previous attempts to estimate the spatiotemporal parameters of the virus, both globally and regionally, have suggested that epidemic HCV transmission began in 1900 and grew steadily until the late 1980s.", "However, epidemiological data suggest that the expansion of HCV may have occurred after the Second World War.", "The aim of our study was to elucidate the timescale and route of the global spread of HCV.", "METHODS AND FINDINGS We show that the rarely sequenced HCV region (E2P7NS2) is more informative for molecular epidemiology studies than the more commonly used NS5B region.", "We applied phylodynamic methods to a substantial set of new E2P7NS2 and NS5B sequences, together with all available global HCV sequences with information in both of these genomic regions, in order to estimate the timescale and nature of the global expansion of the most prevalent HCV subtypes, 1a and 1b.", "We showed that transmission of subtypes 1a and 1b \"exploded\" between 1940 and 1980, with the spread of 1b preceding that of 1a by at least 16 y (95% confidence interval 15-17).", "Phylogeographic analysis of all available NS5B sequences suggests that HCV subtypes 1a and 1b disseminated from the developed world to the developing countries.", "CONCLUSIONS The evolutionary rate of HCV appears faster than previously suggested.", "The global spread of HCV coincided with the widespread use of transfused blood and blood products and with the expansion of intravenous drug use but slowed prior to the wide implementation of anti-HCV screening.", "Differences in the transmission routes associated with subtypes 1a and 1b provide an explanation of the relatively earlier expansion of 1b.", "Our data show that the most plausible route of the HCV dispersal was from developed countries to the developing world.", "Please see later in the article for the Editors' Summary." ]

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[ "CONTEXT The incidence of distal forearm fractures in children peaks around the time of the pubertal growth spurt, possibly because physical activity increases at the time of a transient deficit in cortical bone mass due to the increased calcium demand during maximal skeletal growth.", "Changes in physical activity or diet may therefore influence risk of forearm fracture.", "OBJECTIVE To determine whether there has been a change in the incidence of distal forearm fractures in children in recent years.", "DESIGN, SETTING, AND PATIENTS Population-based study among Rochester, Minn, residents younger than 35 years with distal forearm fractures in 1969-1971, 1979-1981, 1989-1991, and 1999-2001.", "MAIN OUTCOME MEASURE Estimated incidence of distal forearm fractures in 4 time periods.", "RESULTS Comparably age- and sex-adjusted annual incidence rates per 100 000 increased from 263.3 (95% confidence interval [CI], 231.1-295.4) in 1969-1971 to 322.3 (95% CI, 285.3-359.4) in 1979-1981 and to 399.8 (95% CI, 361.0-438.6) in 1989-1991 before leveling off at 372.9 (95% CI, 339.1-406.7) in 1999-2001.", "Age-adjusted incidence rates per 100 000 were 32% greater among male residents in 1999-2001 compared with 1969-1971 (409.4 [95% CI, 359.9-459.0] vs 309.4 [95% CI, 259.3-359.5]; P =.01) and 56% greater among female residents in the same time periods (334.3 [95% CI, 288.6-380.1] vs 214.6 [95% CI, 174.9-254.4]; P<.001).", "The peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8 and 11 years in girls.", "CONCLUSIONS There has been a statistically significant increase in the incidence of distal forearm fractures in children and adolescents, but whether this is due to changing patterns of physical activity, decreased bone acquisition due to poor calcium intake, or both is unclear at present.", "Given the large number of childhood fractures, however, studies are needed to define the cause(s) of this increase." ]

[ 0 ]

[ "CONTEXT The incidence of distal forearm fractures in children peaks around the time of the pubertal growth spurt, possibly because physical activity increases at the time of a transient deficit in cortical bone mass due to the increased calcium demand during maximal skeletal growth.", "Changes in physical activity or diet may therefore influence risk of forearm fracture.", "OBJECTIVE To determine whether there has been a change in the incidence of distal forearm fractures in children in recent years.", "DESIGN, SETTING, AND PATIENTS Population-based study among Rochester, Minn, residents younger than 35 years with distal forearm fractures in 1969-1971, 1979-1981, 1989-1991, and 1999-2001.", "MAIN OUTCOME MEASURE Estimated incidence of distal forearm fractures in 4 time periods.", "RESULTS Comparably age- and sex-adjusted annual incidence rates per 100 000 increased from 263.3 (95% confidence interval [CI], 231.1-295.4) in 1969-1971 to 322.3 (95% CI, 285.3-359.4) in 1979-1981 and to 399.8 (95% CI, 361.0-438.6) in 1989-1991 before leveling off at 372.9 (95% CI, 339.1-406.7) in 1999-2001.", "Age-adjusted incidence rates per 100 000 were 32% greater among male residents in 1999-2001 compared with 1969-1971 (409.4 [95% CI, 359.9-459.0] vs 309.4 [95% CI, 259.3-359.5]; P =.01) and 56% greater among female residents in the same time periods (334.3 [95% CI, 288.6-380.1] vs 214.6 [95% CI, 174.9-254.4]; P<.001).", "The peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8 and 11 years in girls.", "CONCLUSIONS There has been a statistically significant increase in the incidence of distal forearm fractures in children and adolescents, but whether this is due to changing patterns of physical activity, decreased bone acquisition due to poor calcium intake, or both is unclear at present.", "Given the large number of childhood fractures, however, studies are needed to define the cause(s) of this increase." ]

[ 0 ]

[ "Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions.", "However, their expression patterns and regulatory functions during normal and malignant human hematopoiesis are incompletely understood.", "Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system.", "Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis.", "Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells.", "Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.", "While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear.", "Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy." ]

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[ "Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals.", "Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems.", "Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins.", "The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell.", "We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output." ]

[ 2, 3 ]

[ "Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals.", "Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems.", "Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins.", "The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell.", "We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output." ]

[ 4 ]

[ "BACKGROUND Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs).", "We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development.", "METHODS We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015.", "We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year.", "We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita.", "We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate.", "FINDINGS Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs).", "Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs.", "Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined.", "Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies.", "From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95% uncertainty interval 2·9-3·0) for men and 3·5 years (3·4-3·7) for women, while HALE at age 65 years improved by 0·85 years (0·78-0·92) and 1·2 years (1·1-1·3), respectively.", "Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability.", "Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI.", "At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs.", "INTERPRETATION Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity.", "The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility.", "Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress.", "Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum.", "FUNDING Bill & Melinda Gates Foundation." ]

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[ "Pluripotent embryonic stem cells (ESCs) maintain self-renewal and the potential for rapid response to differentiation cues.", "Both ESC features are subject to epigenetic regulation.", "Here we show that the histone acetyltransferase Mof plays an essential role in the maintenance of ESC self-renewal and pluripotency.", "ESCs with Mof deletion lose characteristic morphology, alkaline phosphatase (AP) staining, and differentiation potential.", "They also have aberrant expression of the core transcription factors Nanog, Oct4, and Sox2.", "Importantly, the phenotypes of Mof null ESCs can be partially suppressed by Nanog overexpression, supporting the idea that Mof functions as an upstream regulator of Nanog in ESCs.", "Genome-wide ChIP-sequencing and transcriptome analyses further demonstrate that Mof is an integral component of the ESC core transcriptional network and that Mof primes genes for diverse developmental programs.", "Mof is also required for Wdr5 recruitment and H3K4 methylation at key regulatory loci, highlighting the complexity and interconnectivity of various chromatin regulators in ESCs." ]

[ 7 ]

[ "CONTEXT The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen.", "The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme.", "OBJECTIVE To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen.", "DESIGN, SETTING, AND PATIENTS Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer.", "The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%).", "Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy.", "DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity.", "Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism.", "MAIN OUTCOME MEASURES Time to recurrence, event-free survival, disease-free survival, and overall survival.", "RESULTS Median follow-up was 6.3 years.", "At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively.", "Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28).", "Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51).", "CONCLUSION Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes." ]

[ 11, 12, 13 ]

[ "The oncogenic BCR/ABL tyrosine kinase induces constitutive DNA damage in Philadelphia chromosome (Ph)-positive leukemia cells.", "We find that BCR/ABL-induced reactive oxygen species (ROSs) cause chronic oxidative DNA damage resulting in double-strand breaks (DSBs) in S and G(2)/M cell cycle phases.", "These lesions are repaired by BCR/ABL-stimulated homologous recombination repair (HRR) and nonhomologous end-joining (NHEJ) mechanisms.", "A high mutation rate is detected in HRR products in BCR/ABL-positive cells, but not in the normal counterparts.", "In addition, large deletions are found in NHEJ products exclusively in BCR/ABL cells.", "We propose that the following series of events may contribute to genomic instability of Ph-positive leukemias: BCR/ABL --> ROSs --> oxidative DNA damage --> DSBs in proliferating cells --> unfaithful HRR and NHEJ repair." ]

[ 0, 1, 5 ]

[ "TAL (transcription activator-like) effectors, secreted by phytopathogenic bacteria, recognize host DNA sequences through a central domain of tandem repeats.", "Each repeat comprises 33 to 35 conserved amino acids and targets a specific base pair by using two hypervariable residues [known as repeat variable diresidues (RVDs)] at positions 12 and 13.", "Here, we report the crystal structures of an 11.5-repeat TAL effector in both DNA-free and DNA-bound states.", "Each TAL repeat comprises two helices connected by a short RVD-containing loop.", "The 11.5 repeats form a right-handed, superhelical structure that tracks along the sense strand of DNA duplex, with RVDs contacting the major groove.", "The 12th residue stabilizes the RVD loop, whereas the 13th residue makes a base-specific contact.", "Understanding DNA recognition by TAL effectors may facilitate rational design of DNA-binding proteins with biotechnological applications." ]

[ 0, 1 ]

[ "CONTEXT During pregnancy, serum levels of estrogen, progesterone, and other hormones are markedly higher than during other periods of life.", "Pregnancy hormones primarily are produced in the placenta, and signs of placental impairment may serve as indirect markers of hormone exposures during pregnancy.", "During pregnancy, these markers have been inconsistently associated with subsequent risk of breast cancer in the mother.", "OBJECTIVE To examine associations between indirect markers of hormonal exposures, such as placental weight and other pregnancy characteristics, and maternal risk of developing breast cancer.", "DESIGN AND SETTING Population-based cohort study using data from the Swedish Birth Register, the Swedish Cancer Register, the Swedish Cause of Death Register, and the Swedish Register of Population and Population Changes.", "PARTICIPANTS Women included in the Sweden Birth Register who delivered singletons between 1982 and 1989, with complete information on date of birth and gestational age.", "Women were followed up until the occurrence of breast cancer, death, or end of follow-up (December 31, 2001).", "Cox proportional hazards models were used to estimate associations between hormone exposures and risks of breast cancer.", "MAIN OUTCOME MEASURE Incidence of invasive breast cancer.", "RESULTS Of 314,019 women in the cohort, 2216 (0.7%) developed breast cancer during the follow-up through 2001, of whom 2100 (95%) were diagnosed before age 50 years.", "Compared with women who had placentas weighing less than 500 g in 2 consecutive pregnancies, the risk of breast cancer was increased among women whose placentas weighed between 500 and 699 g in their first pregnancy and at least 700 g in their second pregnancy (or vice versa) (adjusted hazard ratio, 1.82; 95% confidence interval [CI], 1.07-3.08), and the corresponding risk was doubled among women whose placentas weighed at least 700 g in both pregnancies (adjusted hazard ratio, 2.05; 95% CI, 1.15-3.64).", "A high birth weight (> or =4000 g) in 2 successive births was associated with an increased risk of breast cancer before but not after adjusting for placental weight and other covariates (adjusted hazard ratio, 1.10; 95% CI, 0.76-1.59).", "CONCLUSIONS Placental weight is positively associated with maternal risk of breast cancer.", "These results further support the hypothesis that pregnancy hormones are important modifiers of subsequent maternal breast cancer risk." ]

[ 10, 12 ]

[ "Summary Background Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions.", "With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older.", "Methods Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs.", "We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health.", "Findings Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2·2% (95% uncertainty interval [UI] 1·5–3·0) of age-standardised female deaths and 6·8% (5·8–8·0) of age-standardised male deaths.", "Among the population aged 15–49 years, alcohol use was the leading risk factor globally in 2016, with 3·8% (95% UI 3·2–4·3) of female deaths and 12·2% (10·8–13·6) of male deaths attributable to alcohol use.", "For the population aged 15–49 years, female attributable DALYs were 2·3% (95% UI 2·0–2·6) and male attributable DALYs were 8·9% (7·8–9·9).", "The three leading causes of attributable deaths in this age group were tuberculosis (1·4% [95% UI 1·0–1·7] of total deaths), road injuries (1·2% [0·7–1·9]), and self-harm (1·1% [0·6–1·5]).", "For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27·1% (95% UI 21·2–33·3) of total alcohol-attributable female deaths and 18·9% (15·3–22·6) of male deaths.", "The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0·0–0·8) standard drinks per week.", "Interpretation Alcohol use is a leading risk factor for global disease burden and causes substantial health loss.", "We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero.", "These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.", "Funding Bill & Melinda Gates Foundation." ]

[ 8, 11 ]

[ "BACKGROUND Self-harm and suicide are common in prisoners, yet robust information on the full extent and characteristics of people at risk of self-harm is scant.", "Furthermore, understanding how frequently self-harm is followed by suicide, and in which prisoners this progression is most likely to happen, is important.", "We did a case-control study of all prisoners in England and Wales to ascertain the prevalence of self-harm in this population, associated risk factors, clustering effects, and risk of subsequent suicide after self-harm.", "METHODS Records of self-harm incidents in all prisons in England and Wales were gathered routinely between January, 2004, and December, 2009.", "We did a case-control comparison of prisoners who self-harmed and those who did not between January, 2006, and December, 2009.", "We also used a Bayesian approach to look at clustering of people who self-harmed.", "Prisoners who self-harmed and subsequently died by suicide in prison were compared with other inmates who self-harmed.", "FINDINGS 139,195 self-harm incidents were recorded in 26,510 individual prisoners between 2004 and 2009; 5-6% of male prisoners and 20-24% of female inmates self-harmed every year.", "Self-harm rates were more than ten times higher in female prisoners than in male inmates.", "Repetition of self-harm was common, particularly in women and teenage girls, in whom a subgroup of 102 prisoners accounted for 17,307 episodes.", "In both sexes, self-harm was associated with younger age, white ethnic origin, prison type, and a life sentence or being unsentenced; in female inmates, committing a violent offence against an individual was also a factor.", "Substantial evidence was noted of clustering in time and location of prisoners who self-harmed (adjusted intra-class correlation 0·15, 95% CI 0·11-0·18).", "109 subsequent suicides in prison were reported in individuals who self-harmed; the risk was higher in those who self-harmed than in the general prison population, and more than half the deaths occurred within a month of self-harm.", "Risk factors for suicide after self-harm in male prisoners were older age and a previous self-harm incident of high or moderate lethality; in female inmates, a history of more than five self-harm incidents within a year was associated with subsequent suicide.", "INTERPRETATION The burden of self-harm in prisoners is substantial, particularly in women.", "Self-harm in prison is associated with subsequent suicide in this setting.", "Prevention and treatment of self-harm in prisoners is an essential component of suicide prevention in prisons.", "FUNDING Wellcome Trust, National Institute for Health Research, National Offender Management Service, and Department of Health." ]

[ 7, 8 ]

[ "The bacterial type VI secretion system (T6SS) is an organelle that is structurally and mechanistically analogous to an intracellular membrane-attached contractile phage tail.", "Recent studies determined that a rapid conformational change in the structure of a sheath protein complex propels T6SS spike and tube components along with antibacterial and antieukaryotic effectors out of predatory T6SS(+) cells and into prey cells.", "The contracted organelle is then recycled in an ATP-dependent process.", "T6SS is regulated at transcriptional and posttranslational levels, the latter involving detection of membrane perturbation in some species.", "In addition to directly targeting eukaryotic cells, the T6SS can also target other bacteria coinfecting a mammalian host, highlighting the importance of the T6SS not only for bacterial survival in environmental ecosystems, but also in the context of infection and disease.", "This review highlights these and other advances in our understanding of the structure, mechanical function, assembly, and regulation of the T6SS." ]

[]

[ "Granulomas are the pathological hallmark of tuberculosis (TB).", "However, their function and mechanisms of formation remain poorly understood.", "To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner.", "Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas.", "We found that the centers of granulomas have a pro-inflammatory environment that is characterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatory eicosanoids.", "Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatory signature.", "These findings are consistent across a set of six human subjects and in rabbits.", "Although the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma.", "From the protein and lipid snapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma." ]

[ 5 ]

[ "Importance Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics.", "These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making.", "Objectives To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk.", "Design and Setting Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017.", "Exposures Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time.", "Main Outcomes and Measures A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications.", "Results From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics).", "There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics.", "The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%).", "In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02).", "Conclusions and Relevance Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event.", "Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle." ]

[ 9 ]

[ "CONTEXT Recent animal studies have found that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lipid-lowering drugs (statins) substantially increase bone formation, but whether statin use in humans results in clinically meaningful bone formation or a reduction in the risk of osteoporotic fractures is not known.", "OBJECTIVE To determine whether the use of statins is associated with reduced hip fracture risk.", "DESIGN Case-control study.", "SETTING AND PATIENTS A total of 6110 New Jersey residents aged 65 years or older and enrolled in Medicare and either Medicaid or the Pharmacy Assistance for the Aged and Disabled program.", "Case patients (n=1222) underwent surgical repair of a hip fracture in 1994.", "Control patients (n=4888) were identified at a ratio of 4:1 and frequency-matched to case patients for age and sex.", "MAIN OUTCOME MEASURE Adjusted odds ratio (OR) of hip fracture by statin use in the 180 days and 3 years prior to the index date (the earliest date of admission for surgery), adjusted for demographic and clinical characteristics and health care utilization.", "RESULTS Use of statins in either the prior 180 days (adjusted OR, 0.50; 95% confidence interval [CI], 0.33-0.76) or prior 3 years (adjusted OR, 0.57; 95% CI, 0.40-0.82) was associated with a significant reduction in the risk of hip fracture, even after controlling for variables such as race, insurance status, psychoactive medications, estrogen and thiazide use, ischemic heart disease, cancer, and diabetes mellitus.", "No significant relationship was observed between use of nonstatin lipid-lowering agents and hip fracture risk.", "Clear relationships were observed between the degree of reduction in hip fracture risk and the extent of statin use; there was no evidence of such relationships with nonstatin lipid-lowering agents.", "After adjusting for extent of statin use in the prior 3 years, current use (on the index date) was associated with a 71% reduction in risk (adjusted OR, 0.29; 95% CI, 0.10-0.81).", "The relationship between statin use and hip fracture risk persisted after controlling for variables such as the number of medications, the Charlson comorbidity index score, and hospitalization or nursing home stay in the last 180 days, as well as after excluding patients who were in a nursing home prior to their index date or who died in the year after their index date.", "Use of nonstatin lipid-lowering agents was not observed to be associated with reduction in hip fracture risk in any of these alternative models or analyses.", "CONCLUSIONS These findings support an association between statin use by elderly patients and reduction in the risk of hip fracture.", "Controlled trials are needed to exclude the possibility of unmeasured confounders.", "JAMA.", "2000;283:3211-3216" ]

[ 7, 9, 10, 13 ]

[ "OBJECTIVE To assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS).", "DESIGN Nationwide register based cohort study.", "SETTING Denmark, 1996-2011.", "PARTICIPANTS 999,378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30,091; maternal use after birth, n=21,557; use in infants, n=6591), surgery for IHPS, and potential confounders.", "MAIN OUTCOME MEASURES Surgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth.", "RESULTS 880 infants developed IHPS (0.9 cases per 1000 births).", "Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively.", "The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and -0.11 (-0.26 to 0.31).", "The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (-0.31 to 0.50) and 0.67 (-0.06 to 2.02).", "CONCLUSIONS Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk.", "Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS.", "A possible association was also found with use during late pregnancy." ]

[ 9, 10 ]

[ "Background Macrosomia is associated with considerable neonatal and maternal morbidity.", "Factors that predict macrosomia are poorly understood.", "The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion.", "We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice." ]

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[ "Clomifene is widely used for inducing ovulation.1 It is structurally related to diethylstilbestrol, which has been linked to vaginal and cervical clear cell adenocarcinoma in women exposed in utero.", "The adverse effect is less severe in sons, although links to testicular cancer and urogenital anomalies, such as epididymal cysts, have been reported.2 3 A recent study also found an increased risk of hypospadias in the sons of women exposed to diethylstilbestrol in utero.4 Clomifene has a half life of about five days, but its metabolites have been found in blood samples on day 22 of the menstrual cycle and in faeces up to six weeks after administration.5 The occurrence of hypospadias may be increasing.", "Little is known about the risk of hypospadias in boys born to women who have used clomifene to induce ovulation.", "### Methods and results Our case-control study was done in the Danish counties of North Jutland, Aarhus, Viborg, and …" ]

[ 1 ]

[ "Oct4 is a well-known transcription factor that plays fundamental roles in stem cell self-renewal, pluripotency, and somatic cell reprogramming.", "However, limited information is available on Oct4-associated protein complexes and their intrinsic protein-protein interactions that dictate Oct4's critical regulatory activities.", "Here we employed an improved affinity purification approach combined with mass spectrometry to purify Oct4 protein complexes in mouse embryonic stem cells (mESCs), and discovered many novel Oct4 partners important for self-renewal and pluripotency of mESCs.", "Notably, we found that Oct4 is associated with multiple chromatin-modifying complexes with documented as well as newly proved functional significance in stem cell maintenance and somatic cell reprogramming.", "Our study establishes a solid biochemical basis for genetic and epigenetic regulation of stem cell pluripotency and provides a framework for exploring alternative factor-based reprogramming strategies." ]

[ 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." ]

[ 3 ]

[ "OBJECTIVE To assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS).", "DESIGN Nationwide register based cohort study.", "SETTING Denmark, 1996-2011.", "PARTICIPANTS 999,378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30,091; maternal use after birth, n=21,557; use in infants, n=6591), surgery for IHPS, and potential confounders.", "MAIN OUTCOME MEASURES Surgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth.", "RESULTS 880 infants developed IHPS (0.9 cases per 1000 births).", "Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively.", "The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and -0.11 (-0.26 to 0.31).", "The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (-0.31 to 0.50) and 0.67 (-0.06 to 2.02).", "CONCLUSIONS Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk.", "Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS.", "A possible association was also found with use during late pregnancy." ]

[ 9, 10 ]

[ "BACKGROUND The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown.", "We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010.", "METHODS We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies.", "We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year.", "We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies.", "FINDINGS We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide.", "Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies.", "On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries.", "Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals.", "INTERPRETATION Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children.", "Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection.", "Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities.", "FUNDING WHO." ]

[ 5 ]

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

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[ "Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission.", "We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease.", "Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium.", "As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates.", "Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis.", "Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised." ]

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[ "Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission.", "We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease.", "Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium.", "As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates.", "Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis.", "Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised." ]

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[ "Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission.", "We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease.", "Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium.", "As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates.", "Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis.", "Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised." ]

[ 1, 2 ]

[ "Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis.", "We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death.", "Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death.", "Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma.", "Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and β-catenin activation.", "Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis.", "Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention." ]

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[ "Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis.", "Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis.", "These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors.", "Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33.", "These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells.", "S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia.", "Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype.", "These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS." ]

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[ "Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens.", "It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself.", "We show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy.", "Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR.", "We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling.", "Our results provide biological explanations for the antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials." ]

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[ "Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens.", "It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself.", "We show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy.", "Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR.", "We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling.", "Our results provide biological explanations for the antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials." ]

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[ "Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens.", "It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself.", "We show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy.", "Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR.", "We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling.", "Our results provide biological explanations for the antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials." ]

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[ "Systematic literature reviews are widely used as an aid to evidence based decision making.", "For example, reviews of randomised controlled trials are regularly used to answer questions about the effectiveness of healthcare interventions.", "The high profile of systematic reviews as a cornerstone of evidence based medicine, however, has led to several misconceptions about their purpose and methods.", "Among these is the belief that systematic reviews are applicable only to randomised controlled trials and that they are incapable of dealing with other forms of evidence, such as from non-randomised studies or qualitative research.", "The systematic literature review is a method of locating, appraising, and synthesising evidence.", "The value of regularly updated systematic reviews in the assessment of effectiveness of healthcare interventions was dramatically illustrated by Antman and colleagues, who showed that review articles failed to mention advances in treatment identified by an updated systematic review.1 It is nearly a quarter of a century since Gene Glass coined the term “meta-analysis” to refer to the quantitative synthesis of the results of primary studies.2 The importance of making explicit efforts to limit bias in the review of literature, however, has been emphasised by social scientists at least since the 1960s.3 In recent years systematic reviews have found an important role in health services research, and the growing interest in evidence based approaches to decision making makes it likely that their use will increase.", "Not everybody accepts that systematic reviews are necessary or desirable, and as one moves further away from the clinical applications of systematic reviews cynicism about their utility grows.", "Several arguments are commonly used to reject a wider role for systematic reviews, and these arguments are often based on major misconceptions about the history, purpose, methods, and uses of systematic reviews.", "I have examined eight common myths about …" ]

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[ "Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription.", "Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation.", "Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability.", "Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation.", "With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased the levels of these proteins.", "We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels.", "Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation." ]

[ 1, 3, 4, 5, 6 ]

[ "Animal host defense against infection requires the expression of defense genes at the right place and the right time.", "Understanding such tight control of host defense requires the elucidation of the transcription factors involved.", "By using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense.", "HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection.", "TFEB was also rapidly activated in murine macrophages upon S. aureus infection and was required for proper transcriptional induction of several proinflammatory cytokines and chemokines.", "Thus, our data suggest that TFEB is a previously unappreciated, evolutionarily ancient transcription factor in the host response to infection." ]

[ 4 ]

[ "A number of proteins and drugs have been implicated in the process of transcriptional elongation by RNA polymerase (Pol) II, but the factors that govern the elongation rate (nucleotide additions per min) and processivity (nucleotide additions per initiation event) in vivo are poorly understood.", "Here, we show that a mutation in the Rpb2 subunit of Pol II reduces both the elongation rate and processivity in vivo.", "In contrast, none of the putative elongation factors tested affect the elongation rate, although mutations in the THO complex and in Spt4 significantly reduce processivity.", "The drugs 6-azauracil and mycophenolic acid reduce both the elongation rate and processivity, and this processivity defect is aggravated by mutations in Spt4, TFIIS, and CTDK-1.", "Our results suggest that, in vivo, a reduced rate of Pol II elongation leads to premature dissociation along the chromatin template and that Pol II processivity can be uncoupled from elongation rate." ]

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[ "Proper execution of transcriptional programs is a key requirement of gene expression regulation, demanding accurate control of timing and amplitude.", "How precisely the transcription machinery fulfills this task is not known.", "Using an in situ hybridization approach that detects single mRNA molecules, we measured mRNA abundance and transcriptional activity within single Saccharomyces cerevisiae cells.", "We found that expression levels for particular genes are higher than initially reported and can vary substantially among cells.", "However, variability for most constitutively expressed genes is unexpectedly small.", "Combining single-transcript measurements with computational modeling indicates that low expression variation is achieved by transcribing genes using single transcription-initiation events that are clearly separated in time, rather than by transcriptional bursts.", "In contrast, PDR5, a gene regulated by the transcription coactivator complex SAGA, is expressed using transcription bursts, resulting in larger variation.", "These data directly demonstrate the existence of multiple expression modes used to modulate the transcriptome." ]

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[ "A number of proteins and drugs have been implicated in the process of transcriptional elongation by RNA polymerase (Pol) II, but the factors that govern the elongation rate (nucleotide additions per min) and processivity (nucleotide additions per initiation event) in vivo are poorly understood.", "Here, we show that a mutation in the Rpb2 subunit of Pol II reduces both the elongation rate and processivity in vivo.", "In contrast, none of the putative elongation factors tested affect the elongation rate, although mutations in the THO complex and in Spt4 significantly reduce processivity.", "The drugs 6-azauracil and mycophenolic acid reduce both the elongation rate and processivity, and this processivity defect is aggravated by mutations in Spt4, TFIIS, and CTDK-1.", "Our results suggest that, in vivo, a reduced rate of Pol II elongation leads to premature dissociation along the chromatin template and that Pol II processivity can be uncoupled from elongation rate." ]

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[ "Proper execution of transcriptional programs is a key requirement of gene expression regulation, demanding accurate control of timing and amplitude.", "How precisely the transcription machinery fulfills this task is not known.", "Using an in situ hybridization approach that detects single mRNA molecules, we measured mRNA abundance and transcriptional activity within single Saccharomyces cerevisiae cells.", "We found that expression levels for particular genes are higher than initially reported and can vary substantially among cells.", "However, variability for most constitutively expressed genes is unexpectedly small.", "Combining single-transcript measurements with computational modeling indicates that low expression variation is achieved by transcribing genes using single transcription-initiation events that are clearly separated in time, rather than by transcriptional bursts.", "In contrast, PDR5, a gene regulated by the transcription coactivator complex SAGA, is expressed using transcription bursts, resulting in larger variation.", "These data directly demonstrate the existence of multiple expression modes used to modulate the transcriptome." ]

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[ "Human astrocytes are larger and more complex than those of infraprimate mammals, suggesting that their role in neural processing has expanded with evolution.", "To assess the cell-autonomous and species-selective properties of human glia, we engrafted human glial progenitor cells (GPCs) into neonatal immunodeficient mice.", "Upon maturation, the recipient brains exhibited large numbers and high proportions of both human glial progenitors and astrocytes.", "The engrafted human glia were gap-junction-coupled to host astroglia, yet retained the size and pleomorphism of hominid astroglia, and propagated Ca2+ signals 3-fold faster than their hosts.", "Long-term potentiation (LTP) was sharply enhanced in the human glial chimeric mice, as was their learning, as assessed by Barnes maze navigation, object-location memory, and both contextual and tone fear conditioning.", "Mice allografted with murine GPCs showed no enhancement of either LTP or learning.", "These findings indicate that human glia differentially enhance both activity-dependent plasticity and learning in mice." ]

[ 2 ]

[ "Age-related changes in the niche have long been postulated to impair the function of somatic stem cells.", "Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs).", "Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers.", "By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche.", "Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration.", "Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism." ]

[ 2, 4 ]

[ "Age-related changes in the niche have long been postulated to impair the function of somatic stem cells.", "Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs).", "Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers.", "By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche.", "Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration.", "Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism." ]

[ 2, 4 ]

[ "Anandamide, an endogenous ligand for central cannabinoid receptors, is released from neurons on depolarization and rapidly inactivated.", "Anandamide inactivation is not completely understood, but it may occur by transport into cells or by enzymatic hydrolysis.", "The compound N-(4-hydroxyphenyl)arachidonylamide (AM404) was shown to inhibit high-affinity anandamide accumulation in rat neurons and astrocytes in vitro, an indication that this accumulation resulted from carrier-mediated transport.", "Although AM404 did not activate cannabinoid receptors or inhibit anandamide hydrolysis, it enhanced receptor-mediated anandamide responses in vitro and in vivo.", "The data indicate that carrier-mediated transport may be essential for termination of the biological effects of anandamide, and may represent a potential drug target." ]

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[ "OBJECTIVE To examine the effect of ethnicity on the relation between tuberculosis and deprivation.", "DESIGN Retrospective ecological study comparing incidence of tuberculosis in white and south Asian residents of the 39 electoral wards in Birmingham with ethnic specific indices of deprivation.", "SETTING Birmingham, 1989-93.", "SUBJECTS 1516 notified cases of tuberculosis.", "MAIN OUTCOME MEASURES Rates of tuberculosis and measures of deprivation.", "RESULTS Univariate analysis showed significant associations of tuberculosis rates for the whole population with several indices of deprivation (P<0.01) and with the proportion of the population of south Asian origin (P<0.01).", "All deprivation covariates were positively associated with each other but on multiple regression, higher level of overcrowding was independently associated with tuberculosis rates.", "For the white population, overcrowding was associated with tuberculosis rates independently of other variables (P=0.0036).", "No relation with deprivation was found for the south Asian population in either single or multivariable analyses.", "CONCLUSIONS Poverty is significantly associated with tuberculosis in the white population, but no such relation exists for those of Asian ethnicity.", "These findings suggest that causal factors, and therefore potential interventions, will also differ by ethnic group." ]

[ 6, 7 ]

[ "This paper seeks to establish the strength of association between contemporary tuberculosis (TB) in England and Wales and several potential aetiological factors.", "It presents an ecological analysis of standardised annual TB mortality rates for the 403 local authority districts between 1982 and 1992, disaggregated by age and sex.", "Social, demographic and ethnicity measures from the 1981 and 1991 censuses and standardised annual AIDS-related mortality rates for young men are used to calculate Poisson regression models.", "A strong association was found between all TB mortality groups and overcrowding at the household level.", "For women, no other measures improved the explanatory power of the models.", "In multiple regressions, both poverty and AIDS-related mortality explained additional variation in the model for younger men.", "The link between ethnicity and tuberculosis notifications was not reflected in this analysis of mortality.", "For all groups no evidence of a positive relationship with ethnicity was found, once overcrowding had been accounted for.", "The significance of household as opposed to district level crowding suggests that prolonged contact is required for disease transmission.", "Regression analysis indicates that it is the overcrowding and poverty among ethnic populations that is significant for their tuberculosis mortality.", "The fact that the relationship between AIDS and TB is confined to the group most typical of AIDS patients provides evidence that AIDS has little influence on the level of tuberculosis mortality in the wider population.", "Explanations for the observed relationship include preferential certification, migration for treatment and shortcomings in health care provision." ]

[ 3, 9 ]

[ "Granulomas are the pathological hallmark of tuberculosis (TB).", "However, their function and mechanisms of formation remain poorly understood.", "To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner.", "Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas.", "We found that the centers of granulomas have a pro-inflammatory environment that is characterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatory eicosanoids.", "Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatory signature.", "These findings are consistent across a set of six human subjects and in rabbits.", "Although the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma.", "From the protein and lipid snapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma." ]

[ 4, 5, 7 ]

[ "Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival.", "Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation.", "Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis.", "Taken together, these findings provide exciting new potential targets for therapeutic intervention." ]

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[ "Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival.", "Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation.", "Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis.", "Taken together, these findings provide exciting new potential targets for therapeutic intervention." ]

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[ "Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy–induced second malignant neoplasms (SMNs).", "We identified two variants at chromosome 6q21 associated with SMNs in survivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults.", "The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure.", "These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs." ]

[ 1 ]

[ "Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation.", "Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2).", "In order to test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not only reduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2.", "Reduced IL-2 production achieved by either genetic mechanism correlates with reduced function of CD4+ CD25+ regulatory T cells, which are critical for maintaining immune homeostasis." ]

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[ "Genome-wide association studies are now identifying disease-associated chromosome regions.", "However, even after convincing replication, the localization of the causal variant(s) requires comprehensive resequencing, extensive genotyping and statistical analyses in large sample sets leading to targeted functional studies.", "Here, we have localized the type 1 diabetes (T1D) association in the interleukin 2 receptor alpha (IL2RA) gene region to two independent groups of SNPs, spanning overlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5′ regions of IL2RA and RBM17 (odds ratio = 2.04, 95% confidence interval = 1.70–2.45; P = 1.92 × 10−28; control frequency = 0.635).", "Furthermore, we have associated IL2RA T1D susceptibility genotypes with lower circulating levels of the biomarker, soluble IL-2RA (P = 6.28 × 10−28), suggesting that an inherited lower immune responsiveness predisposes to T1D." ]

[ 2, 3 ]

[ "Numerous reports have demonstrated that CD4(+)CD25(+) regulatory T cells (Tregs) from individuals with a range of human autoimmune diseases, including type 1 diabetes, are deficient in their ability to control autologous proinflammatory responses when compared with nondiseased, control individuals.", "Treg dysfunction could be a primary, causal event or may result from perturbations in the immune system during disease development.", "Polymorphisms in genes associated with Treg function, such as IL2RA, confer a higher risk of autoimmune disease.", "Although this suggests a primary role for defective Tregs in autoimmunity, a link between IL2RA gene polymorphisms and Treg function has not been examined.", "We addressed this by examining the impact of an IL2RA haplotype associated with type 1 diabetes on Treg fitness and suppressive function.", "Studies were conducted using healthy human subjects to avoid any confounding effects of disease.", "We demonstrated that the presence of an autoimmune disease-associated IL2RA haplotype correlates with diminished IL-2 responsiveness in Ag-experienced CD4(+) T cells, as measured by phosphorylation of STAT5a, and is associated with lower levels of FOXP3 expression by Tregs and a reduction in their ability to suppress proliferation of autologous effector T cells.", "These data offer a rationale that contributes to the molecular and cellular mechanisms through which polymorphisms in the IL-2RA gene affect immune regulation, and consequently upon susceptibility to autoimmune and inflammatory diseases." ]

[ 0 ]

[ "OBJECTIVE To determine whether ultrasound imaging can reduce the risk of failed lumbar punctures or epidural catheterisations, when compared with standard palpation methods, and whether ultrasound imaging can reduce traumatic procedures, insertion attempts, and needle redirections.", "DESIGN Systematic review and meta-analysis of randomised controlled trials.", "DATA SOURCES Ovid Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2012, without restriction by language or publication status.", "REVIEW METHODS Randomised trials that compared ultrasound imaging with standard methods (no imaging) in the performance of a lumbar puncture or epidural catheterisation were identified.", "RESULTS 14 studies with a total of 1334 patients were included (674 patients assigned to the ultrasound group, 660 to the control group).", "Five studies evaluated lumbar punctures and nine evaluated epidural catheterisations.", "Six of 624 procedures conducted in the ultrasound group failed; 44 of 610 procedures in the control group failed.", "Ultrasound imaging reduced the risk of failed procedures (risk ratio 0.21 (95% confidence interval 0.10 to 0.43), P<0.001).", "Risk reduction was similar when subgroup analysis was performed for lumbar punctures (risk ratio 0.19 (0.07 to 0.56), P=0.002) or epidural catheterisations (0.23 (0.09 to 0.60), P=0.003).", "Ultrasound imaging also significantly reduced the risk of traumatic procedures (risk ratio 0.27 (0.11 to 0.67), P=0.005), the number of insertion attempts (mean difference -0.44 (-0.64 to -0.24), P<0.001), and the number of needle redirections (mean difference -1.00 (-1.24 to -0.75), P<0.001).", "CONCLUSIONS Ultrasound imaging can reduce the risk of failed or traumatic lumbar punctures and epidural catheterisations, as well as the number of needle insertions and redirections.", "Ultrasound may be a useful adjunct for these procedures." ]

[ 9, 10 ]

[ "OBJECTIVE To determine whether ultrasound imaging can reduce the risk of failed lumbar punctures or epidural catheterisations, when compared with standard palpation methods, and whether ultrasound imaging can reduce traumatic procedures, insertion attempts, and needle redirections.", "DESIGN Systematic review and meta-analysis of randomised controlled trials.", "DATA SOURCES Ovid Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2012, without restriction by language or publication status.", "REVIEW METHODS Randomised trials that compared ultrasound imaging with standard methods (no imaging) in the performance of a lumbar puncture or epidural catheterisation were identified.", "RESULTS 14 studies with a total of 1334 patients were included (674 patients assigned to the ultrasound group, 660 to the control group).", "Five studies evaluated lumbar punctures and nine evaluated epidural catheterisations.", "Six of 624 procedures conducted in the ultrasound group failed; 44 of 610 procedures in the control group failed.", "Ultrasound imaging reduced the risk of failed procedures (risk ratio 0.21 (95% confidence interval 0.10 to 0.43), P<0.001).", "Risk reduction was similar when subgroup analysis was performed for lumbar punctures (risk ratio 0.19 (0.07 to 0.56), P=0.002) or epidural catheterisations (0.23 (0.09 to 0.60), P=0.003).", "Ultrasound imaging also significantly reduced the risk of traumatic procedures (risk ratio 0.27 (0.11 to 0.67), P=0.005), the number of insertion attempts (mean difference -0.44 (-0.64 to -0.24), P<0.001), and the number of needle redirections (mean difference -1.00 (-1.24 to -0.75), P<0.001).", "CONCLUSIONS Ultrasound imaging can reduce the risk of failed or traumatic lumbar punctures and epidural catheterisations, as well as the number of needle insertions and redirections.", "Ultrasound may be a useful adjunct for these procedures." ]

[ 7, 8, 9, 10 ]

[ "DNA replication in mammals is regulated via the coordinate firing of clusters of replicons that duplicate megabase-sized chromosome segments at specific times during S-phase.", "Cytogenetic studies show that these \"replicon clusters\" coalesce as subchromosomal units that persist through multiple cell generations, but the molecular boundaries of such units have remained elusive.", "Moreover, the extent to which changes in replication timing occur during differentiation and their relationship to transcription changes has not been rigorously investigated.", "We have constructed high-resolution replication-timing profiles in mouse embryonic stem cells (mESCs) before and after differentiation to neural precursor cells.", "We demonstrate that chromosomes can be segmented into multimegabase domains of coordinate replication, which we call \"replication domains,\" separated by transition regions whose replication kinetics are consistent with large originless segments.", "The molecular boundaries of replication domains are remarkably well conserved between distantly related ESC lines and induced pluripotent stem cells.", "Unexpectedly, ESC differentiation was accompanied by the consolidation of smaller differentially replicating domains into larger coordinately replicated units whose replication time was more aligned to isochore GC content and the density of LINE-1 transposable elements, but not gene density.", "Replication-timing changes were coordinated with transcription changes for weak promoters more than strong promoters, and were accompanied by rearrangements in subnuclear position.", "We conclude that replication profiles are cell-type specific, and changes in these profiles reveal chromosome segments that undergo large changes in organization during differentiation.", "Moreover, smaller replication domains and a higher density of timing transition regions that interrupt isochore replication timing define a novel characteristic of the pluripotent state." ]

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[ "Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin.", "This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism.", "Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer.", "Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate." ]

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[ "Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291.", "We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291.", "We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects.", "All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation.", "Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation." ]

[ 1, 3 ]

[ "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 ]

[ "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 ]

[ "&NA; Despite the importance of programmed cell death‐1 (PD‐1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined.", "We found that the chromatin organizer special AT‐rich sequence‐binding protein‐1 (Satb1) restrains PD‐1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions.", "Satb1 deficienct T cells exhibited a 40‐fold increase in PD‐1 expression.", "Tumor‐derived transforming growth factor &bgr; (Tgf‐&bgr;) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter.", "Smad proteins also competed with the Satb1‐NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1‐mediated repression, Satb1‐deficient tumor‐reactive T cells lost effector activity more rapidly than wild‐type lymphocytes at tumor beds expressing PD‐1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade.", "Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation.", "Dysregulation of this pathway in tumor‐infiltrating T cells results in diminished anti‐tumor immunity.", "Graphical Abstract Figure.", "No caption available.", "HighlightsT cell activation increased the expression of Satb1 in mature CD8+ and CD4+ T cellsRecruitment of the NuRD repression complex by Satb1 inhibits expression of Pdcd1In tumors, TGF‐&bgr; inhibits Satb1 expression in T cells, increasing Pdcd1 expressionSatb1−/− T cells express high amounts of PD‐1 and have decreased anti‐tumor activity &NA; Stephen et al. show that the chromatin organizer Satb1 controls expression levels of PD‐1 upon T cell activation through the recruitment of a de‐acetylase complex to regulatory regions of the Pdcd1 gene.", "Tumor‐derived TGF‐&bgr; dysregulates this pathway, unleashing PD‐1 expression in tumor‐infiltrating T cells and decreasing anti‐tumor immunity." ]

[]

[ "&NA; Despite the importance of programmed cell death‐1 (PD‐1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined.", "We found that the chromatin organizer special AT‐rich sequence‐binding protein‐1 (Satb1) restrains PD‐1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions.", "Satb1 deficienct T cells exhibited a 40‐fold increase in PD‐1 expression.", "Tumor‐derived transforming growth factor &bgr; (Tgf‐&bgr;) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter.", "Smad proteins also competed with the Satb1‐NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1‐mediated repression, Satb1‐deficient tumor‐reactive T cells lost effector activity more rapidly than wild‐type lymphocytes at tumor beds expressing PD‐1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade.", "Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation.", "Dysregulation of this pathway in tumor‐infiltrating T cells results in diminished anti‐tumor immunity.", "Graphical Abstract Figure.", "No caption available.", "HighlightsT cell activation increased the expression of Satb1 in mature CD8+ and CD4+ T cellsRecruitment of the NuRD repression complex by Satb1 inhibits expression of Pdcd1In tumors, TGF‐&bgr; inhibits Satb1 expression in T cells, increasing Pdcd1 expressionSatb1−/− T cells express high amounts of PD‐1 and have decreased anti‐tumor activity &NA; Stephen et al. show that the chromatin organizer Satb1 controls expression levels of PD‐1 upon T cell activation through the recruitment of a de‐acetylase complex to regulatory regions of the Pdcd1 gene.", "Tumor‐derived TGF‐&bgr; dysregulates this pathway, unleashing PD‐1 expression in tumor‐infiltrating T cells and decreasing anti‐tumor immunity." ]

[]

[ "Axons and dendrites differ in both microtubule organization and in the organelles and proteins they contain.", "Here we show that the microtubule motor dynein has a crucial role in polarized transport and in controlling the orientation of axonal microtubules in Drosophila melanogaster dendritic arborization (da) neurons.", "Changes in organelle distribution within the dendritic arbors of dynein mutant neurons correlate with a proximal shift in dendritic branch position.", "Dynein is also necessary for the dendrite-specific localization of Golgi outposts and the ion channel Pickpocket.", "Axonal microtubules are normally oriented uniformly plus-end-distal; however, without dynein, axons contain both plus- and minus-end distal microtubules.", "These data suggest that dynein is required for the distinguishing properties of the axon and dendrites: without dynein, dendritic organelles and proteins enter the axon and the axonal microtubules are no longer uniform in polarity." ]

[ 4 ]

[ "BACKGROUND Transmission of dengue viruses (DENV), the leading cause of arboviral disease worldwide, is known to vary through time and space, likely owing to a combination of factors related to the human host, virus, mosquito vector, and environment.", "An improved understanding of variation in transmission patterns is fundamental to conducting surveillance and implementing disease prevention strategies.", "To test the hypothesis that DENV transmission is spatially and temporally focal, we compared geographic and temporal characteristics within Thai villages where DENV are and are not being actively transmitted.", "METHODS AND FINDINGS Cluster investigations were conducted within 100 m of homes where febrile index children with (positive clusters) and without (negative clusters) acute dengue lived during two seasons of peak DENV transmission.", "Data on human infection and mosquito infection/density were examined to precisely (1) define the spatial and temporal dimensions of DENV transmission, (2) correlate these factors with variation in DENV transmission, and (3) determine the burden of inapparent and symptomatic infections.", "Among 556 village children enrolled as neighbors of 12 dengue-positive and 22 dengue-negative index cases, all 27 DENV infections (4.9% of enrollees) occurred in positive clusters (p < 0.01; attributable risk [AR] = 10.4 per 100; 95% confidence interval 1-19.8 per 100].", "In positive clusters, 12.4% of enrollees became infected in a 15-d period and DENV infections were aggregated centrally near homes of index cases.", "As only 1 of 217 pairs of serologic specimens tested in positive clusters revealed a recent DENV infection that occurred prior to cluster initiation, we attribute the observed DENV transmission subsequent to cluster investigation to recent DENV transmission activity.", "Of the 1,022 female adult Ae.", "aegypti collected, all eight (0.8%) dengue-infected mosquitoes came from houses in positive clusters; none from control clusters or schools.", "Distinguishing features between positive and negative clusters were greater availability of piped water in negative clusters (p < 0.01) and greater number of Ae.", "aegypti pupae per person in positive clusters (p = 0.04).", "During primarily DENV-4 transmission seasons, the ratio of inapparent to symptomatic infections was nearly 1:1 among child enrollees.", "Study limitations included inability to sample all children and mosquitoes within each cluster and our reliance on serologic rather than virologic evidence of interval infections in enrollees given restrictions on the frequency of blood collections in children.", "CONCLUSIONS Our data reveal the remarkably focal nature of DENV transmission within a hyperendemic rural area of Thailand.", "These data suggest that active school-based dengue case detection prompting local spraying could contain recent virus introductions and reduce the longitudinal risk of virus spread within rural areas.", "Our results should prompt future cluster studies to explore how host immune and behavioral aspects may impact DENV transmission and prevention strategies.", "Cluster methodology could serve as a useful research tool for investigation of other temporally and spatially clustered infectious diseases." ]

[]

[ "The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine.", "However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date.", "The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection.", "Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2.", "Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo.", "This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism." ]

[ 4 ]

[ "Both rectal and vaginal mucosal surfaces serve as transmission routes for pathogenic microorganisms.", "Vaccination through large intestinal mucosa, previously proven protective for both of these mucosal sites in animal studies, can be achieved successfully by direct intracolorectal (i.c.r.) administration, but this route is clinically impractical.", "Oral vaccine delivery seems preferable but runs the risk of the vaccine's destruction in the upper gastrointestinal tract.", "Therefore, we designed a large intestine-targeted oral delivery with pH-dependent microparticles containing vaccine nanoparticles, which induced colorectal immunity in mice comparably to colorectal vaccination and protected against rectal and vaginal viral challenge.", "Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system.", "Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible new strategy for immune protection of rectal and vaginal mucosa." ]

[ 1, 3, 5 ]

[ "IMPORTANCE Combining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence.", "OBJECTIVE To determine efficacy and safety of varenicline and bupropion sustained-release (SR; combination therapy) compared with varenicline (monotherapy) in cigarette smokers.", "DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites.", "Five hundred six adult (≥18 years) cigarette smokers were randomly assigned and 315 (62%) completed the study.", "INTERVENTIONS Twelve weeks of varenicline and bupropion SR or varenicline and placebo.", "MAIN OUTCOMES AND MEASURES Primary outcome was abstinence rates at week 12, defined as prolonged (no smoking from 2 weeks after the target quit date) abstinence and 7-day point-prevalence (no smoking past 7 days) abstinence.", "Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52.", "Outcomes were biochemically confirmed.", "RESULTS At 12 weeks, 53.0% of the combination therapy group achieved prolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinence compared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05-2.12; P = .03 and OR, 1.36; 95% CI, 0.95-1.93; P = .09, respectively).", "At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04-2.22; P = .03 and OR, 1.32; 95% CI, 0.91-1.91; P = .14, respectively).", "At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared with 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93-2.07; P = .11 and OR, 1.40; 95% CI, 0.96-2.05; P = .08, respectively).", "Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03).", "CONCLUSIONS AND RELEVANCE Among cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks.", "Neither outcome was significantly different at 52 weeks.", "Further research is required to determine the role of combination therapy in smoking cessation.", "TRIAL REGISTRATION clinicaltrials.gov Identifier: http://clinicaltrials.gov/show/NCT00935818." ]

[ 9 ]

[ "Humoral immunity depends on both rapid and long-term antibody production against invading pathogens.", "This is achieved by the generation of spatially distinct extrafollicular plasmablast and follicular germinal center (GC) B cell populations, but the signals that guide responding B cells to these alternative compartments have not been fully elucidated.", "Here, we show that expression of the orphan G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) by activated B cells was essential for their movement to extrafollicular sites and induction of early plasmablast responses.", "Conversely, downregulation of EBI2 enabled B cells to access the center of follicles and promoted efficient GC formation.", "EBI2 therefore provides a previously uncharacterized dimension to B cell migration that is crucial for coordinating rapid versus long-term antibody responses." ]

[ 2, 3 ]

[ "EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein-Barr virus (EBV) infection.", "After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand.", "In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2.", "A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes.", "The identification of 7α, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions.", "Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia.", "Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases." ]

[ 3 ]

[ "BACKGROUND We have developed techniques to implant angiogenic patches onto the epicardium over regions of infarcted cardiac tissue to stimulate revascularization of the damaged tissue.", "These experiments used a scaffold-based 3D human dermal fibroblast culture (3DFC) as an epicardial patch.", "The 3DFC contains viable cells that secrete angiogenic growth factors and has previously been shown to stimulate angiogenic activity.", "The hypothesis tested was that a viable 3DFC cardiac patch would stimulate an angiogenic response within an area of infarcted cardiac tissue.", "METHODS AND RESULTS A coronary occlusion of a branch of the left anterior descending coronary artery was performed by thermal ligation in severe combined immunodeficient mice.", "3DFCs with or without viable cells were sized to the damaged area, implanted in replicate mice onto the epicardium at the site of tissue injury, and compared with animals that received infarct surgery but no implant.", "Fourteen and 30 days after surgery, hearts were exposed and photographed, and tissue samples were prepared for histology and cytochemistry.", "Fourteen and 30 days after surgery, the damaged myocardium receiving viable 3DFC exhibited a significantly greater angiogenic response (including arterioles, venules, and capillaries) than nonviable and untreated control groups.", "CONCLUSIONS In this animal model, viable 3DFC stimulates angiogenesis within a region of cardiac infarction and can augment a repair response in damaged tissue.", "Therefore, a potential use for 3DFC is the repair of myocardial tissue damaged by infarction." ]

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[ "The bacterial type VI secretion system (T6SS) is a large multicomponent, dynamic macromolecular machine that has an important role in the ecology of many Gram-negative bacteria.", "T6SS is responsible for translocation of a wide range of toxic effector molecules, allowing predatory cells to kill both prokaryotic as well as eukaryotic prey cells.", "The T6SS organelle is functionally analogous to contractile tails of bacteriophages and is thought to attack cells by initially penetrating them with a trimeric protein complex called the VgrG spike.", "Neither the exact protein composition of the T6SS organelle nor the mechanisms of effector selection and delivery are known.", "Here we report that proteins from the PAAR (proline-alanine-alanine-arginine) repeat superfamily form a sharp conical extension on the VgrG spike, which is further involved in attaching effector domains to the spike.", "The crystal structures of two PAAR-repeat proteins bound to VgrG-like partners show that these proteins sharpen the tip of the T6SS spike complex.", "We demonstrate that PAAR proteins are essential for T6SS-mediated secretion and target cell killing by Vibrio cholerae and Acinetobacter baylyi.", "Our results indicate a new model of the T6SS organelle in which the VgrG-PAAR spike complex is decorated with multiple effectors that are delivered simultaneously into target cells in a single contraction-driven translocation event." ]

[ 2, 4 ]

[ "OBJECTIVE To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables.", "DESIGN Systematic review and meta-analysis.", "DATA SOURCES Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials.", "STUDY SELECTION Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference).", "DATA EXTRACTION Two authors independently extracted data from original research articles, including key indicators of study quality.", "We pooled the most adjusted odds ratios and weighted mean differences.", "Associations were tested in subgroups representing different patient characteristics and study quality.", "RESULTS 3357 studies were identified and reviewed for eligibility.", "31 eligible studies were included in the final analysis.", "Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26).", "Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section.", "CONCLUSION Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants.", "Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section." ]

[ 10, 12 ]

[ "CONTEXT Adequate vitamin D status for optimum bone health has received increased recognition in recent years; however, the ideal intake is not known.", "Serum 25-hydroxyvitamin D is the generally accepted indicator of vitamin D status, but no universal reference level has been reached.", "OBJECTIVE To investigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calcium homeostasis, as determined by serum intact parathyroid hormone (PTH).", "DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3 age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January 2003.", "They were administered a semi-quantitative food frequency questionnaire, which assessed vitamin D and calcium intake.", "Participants were further divided into groups according to calcium intake (<800 mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18 ng/mL, and >18 ng/mL).", "MAIN OUTCOME MEASURE Serum intact PTH as determined by calcium intake and vitamin D. RESULTS A total of 944 healthy participants completed all parts of the study.", "After adjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin D level of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of less than 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than 800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and at a calcium intake of more than 1200 mg/d, there was a significant difference between the lowest and highest vitamin D groups (P = .04).", "CONCLUSIONS As long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism.", "Vitamin D supplements are necessary for adequate vitamin D status in northern climates." ]

[ 7, 8 ]

[ "BACKGROUND Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD.", "We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults.", "METHODS In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers.", "Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases.", "All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study.", "Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park).", "Baseline measurements of participants were taken before the walk in the hospital laboratory.", "During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured.", "FINDINGS Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited.", "Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park.", "Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park.", "In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk.", "By contrast, these beneficial responses were attenuated after walking on Oxford Street.", "In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles.", "In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles.", "INTERPRETATION Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases.", "Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease.", "Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects.", "FUNDING British Heart Foundation." ]

[ 10, 11, 12, 15 ]

[ "BACKGROUND Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD.", "We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults.", "METHODS In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers.", "Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases.", "All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study.", "Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park).", "Baseline measurements of participants were taken before the walk in the hospital laboratory.", "During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured.", "FINDINGS Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited.", "Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park.", "Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park.", "In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk.", "By contrast, these beneficial responses were attenuated after walking on Oxford Street.", "In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles.", "In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles.", "INTERPRETATION Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases.", "Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease.", "Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects.", "FUNDING British Heart Foundation." ]

[ 10, 11, 12, 15 ]

[ "OBJECTIVE To provide an independent evaluation of seven day weighed dietary records, which are currently accepted as the most accurate technique for assessing habitual dietary intake in studies investigating the links between diet and health.", "DESIGN Subjects who had previously participated in the Northern Ireland diet and health study were reselected by stratified random sampling to represent the range of energy intakes in the study as assessed by the seven day weighed dietary record.", "SETTING Northern Ireland.", "SUBJECTS 31 Free living adults (16 men and 15 women).", "MAIN OUTCOME MEASURES Energy intake as measured by the seven day weighed dietary record and total energy expenditure estimated concurrently by the doubly labelled water technique.", "RESULTS Average recorded energy intakes were significantly lower than measured expenditure in the group overall (9.66 MJ/day v 12.15 MJ/day, 95% confidence interval 1.45 to 3.53 MJ/day).", "Among those in the upper third of energy intakes the mean (SE) ratio of intake to expenditure was close to 1.0, indicating accurate records (men 1.01 (0.11), women 0.96 (0.08].", "In the middle and lower thirds the ratios for men were only 0.74 (0.05) and 0.70 (0.07) respectively and for women 0.89 (0.07) and 0.61 (0.07).", "CONCLUSIONS These results show a serious bias in reporting habitual energy intake.", "If substantiated they may have wide implications for the interpretation of many nutritional studies." ]

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[ "OBJECTIVE To provide an independent evaluation of seven day weighed dietary records, which are currently accepted as the most accurate technique for assessing habitual dietary intake in studies investigating the links between diet and health.", "DESIGN Subjects who had previously participated in the Northern Ireland diet and health study were reselected by stratified random sampling to represent the range of energy intakes in the study as assessed by the seven day weighed dietary record.", "SETTING Northern Ireland.", "SUBJECTS 31 Free living adults (16 men and 15 women).", "MAIN OUTCOME MEASURES Energy intake as measured by the seven day weighed dietary record and total energy expenditure estimated concurrently by the doubly labelled water technique.", "RESULTS Average recorded energy intakes were significantly lower than measured expenditure in the group overall (9.66 MJ/day v 12.15 MJ/day, 95% confidence interval 1.45 to 3.53 MJ/day).", "Among those in the upper third of energy intakes the mean (SE) ratio of intake to expenditure was close to 1.0, indicating accurate records (men 1.01 (0.11), women 0.96 (0.08].", "In the middle and lower thirds the ratios for men were only 0.74 (0.05) and 0.70 (0.07) respectively and for women 0.89 (0.07) and 0.61 (0.07).", "CONCLUSIONS These results show a serious bias in reporting habitual energy intake.", "If substantiated they may have wide implications for the interpretation of many nutritional studies." ]

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[ "CONTEXT In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone.", "OBJECTIVE To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death.", "DESIGN, SETTING, AND PATIENTS Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003.", "INTERVENTIONS Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients).", "MAIN OUTCOME MEASURES The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death.", "RESULTS The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42).", "The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001).", "Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001).", "Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64).", "There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation.", "CONCLUSIONS Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT.", "Consequently, salvage treatment is frequently required when up-front WBRT is not used.", "TRIAL REGISTRATION umin.ac.jp/ctr Identifier: C000000412." ]

[ 6, 10 ]

[ "CONTEXT While it is established that management strategies and outcomes differ by gender for many diseases, its effect on infection has not been adequately studied.", "OBJECTIVE To investigate the role of gender among hospitalized patients treated for infection.", "DESIGN Observational cohort study conducted during a 26-month period from December 1996 through January 1999.", "SETTING University-affiliated hospital.", "PARTICIPANTS A total of 892 patients in the surgical units of the hospital with 1470 consecutive infectious episodes (782 in men and 688 in women).", "MAIN OUTCOME MEASURES Mortality during hospitalization by gender for infection episodes overall and for specific infectious sites, including lung, peritoneum, bloodstream, catheter, urine, surgical site, and skin/soft tissue.", "RESULTS Among all infections, there was no significant difference in mortality based on gender (men, 11.1% vs women, 14.2%; P = .07).", "After logistic regression analysis, factors independently associated with mortality included higher APACHE (Acute Physiology and Chronic Health Evaluation) II score, older age, malignancy, blood transfusion, and diagnosis of infection more than 7 days after admission, but not gender (female odds ratio [OR] for death, 1.32; 95% confidence interval [CI], 0.90-1.94; P = .16).", "Mortality was higher in women for lung (men, 18% vs women, 34%; P = .002) and soft tissue (men, 2% vs women, 10%; P < or = .05) infection; for other infectious sites, mortality did not differ by gender.", "Factors associated with mortality due to pneumonia by logistic regression included higher APACHE II score, malignancy, diabetes mellitus, diagnosis of infection more than 7 days after admission, older age, transplantation, and female gender (OR for death, 2.25; 95% CI, 1.17-4.32; P = .02).", "CONCLUSIONS Although gender may not be predictive of mortality among all infections, women appear to be at increased risk for death from hospital-acquired pneumonia, even after controlling for other comorbidities." ]

[ 10 ]

[ "BACKGROUND Birth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent.", "We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size-breast cancer association.", "METHODS AND FINDINGS Studies were identified through computer-assisted and manual searches, and personal communication with investigators.", "Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained.", "Random effect models were used, if appropriate, to combine study-specific estimates of effect.", "Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02-1.09) and parental recall when the participants were children (1.02; 95% CI 0.99-1.05), but not in those based on adult self-reports, or maternal recall during the woman's adulthood (0.98; 95% CI 0.95-1.01) (p for heterogeneity between data sources = 0.003).", "Relative to women who weighed 3.000-3.499 kg, the risk was 0.96 (CI 0.80-1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00-1.25) in those who weighed > or = 4.000 kg (p for linear trend = 0.001) in birth record data.", "Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03-1.10] and 1.09 [95% CI 1.03-1.15], respectively).", "Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk.", "The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status.", "The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution.", "CONCLUSIONS This pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood." ]

[ 5, 6 ]

[ "BACKGROUND Emerging evidence suggests an association between female prenatal experience and her subsequent risk of developing breast cancer.", "Potential underlying mechanisms include variation in amounts of maternal endogenous sex hormones and growth hormones, germ-cell mutations, formation of cancer stem-cells, and other genetic or epigenetic events.", "We reviewed and summarised quantitatively the available data on intrauterine exposures and risk of breast cancer.", "METHODS We systematically searched for studies that assessed association between perinatal factors and risk of breast cancer.", "We reviewed separately each of the perinatal factors, including birthweight, birth length, parental age at delivery, gestational age, intrauterine exposure to diethylstilbestrol, twin membership, maternal pre-eclampsia or eclampsia, and other factors.", "FINDINGS We identified 57 studies published between Oct 1, 1980, and June 21, 2007.", "Increased risk of breast cancer was noted with increased birthweight (relative risk [RR] 1.15 [95% CI 1.09-1.21]), birth length (1.28 [1.11-1.48]), higher maternal age (1.13 [1.02-1.25]), and paternal age (1.12 [1.05-1.19]).", "Decreased risk of breast cancer was noted for maternal pre-eclampsia and eclampsia (0.48 [0.30-0.78]) and twin membership (0.93 [0.87-1.00]).", "No association was noted between risk of breast cancer and gestational age at birth (0.95 [0.71-1.26]) or maternal diethylstilbestrol treatment (1.40 [0.86-2.28]).", "INTERPRETATION The intrauterine environment contributes to the predisposition of women to breast cancer in adulthood.", "The in-utero mechanisms responsible for such predisposition need to be elucidated." ]

[ 6 ]

[ "INTRODUCTION Various perinatal factors, including birth weight, birth order, maternal age, gestational age, twin status, and parental smoking, have been postulated to affect breast cancer risk in daughters by altering the hormonal environment of the developing fetal mammary glands.", "Despite ample biologic plausibility, epidemiologic studies to date have yielded conflicting results.", "We investigated the associations between perinatal factors and subsequent breast cancer risk through meta-analyses.", "METHODS We reviewed breast cancer studies published from January 1966 to February 2007 that included data on birth weight, birth order, maternal age, gestational age, twin status, and maternal or paternal smoking.", "Meta-analyses using random effect models were employed to summarize the results.", "RESULTS We found that heavier birth weights were associated with increased breast cancer risk, with studies involving five categories of birth weight identifying odds ratios (ORs) of 1.24 (95% confidence interval [CI] 1.04 to 1.48) for 4,000 g or more and 1.15 (95% CI 1.04 to 1.26) for 3,500 g to 3,999 g, relative to a birth weight of 2,500 to 2,599 g. These studies provided no support for a J-shaped relationship of birthweight to risk.", "Support for an association with birthweight was also derived from studies based on three birth weight categories (OR 1.15 [95% CI 1.01 to 1.31] for > or =4,000 g relative to <3,000 g) and two birth weight categories (OR 1.09 [95% CI 1.02 to 1.18] for > or =3,000 g relative to <3,000 g).", "Women born to older mothers and twins were also at some increased risk, but the results were heterogeneous across studies and publication years.", "Birth order, prematurity, and maternal smoking were unrelated to breast cancer risk.", "CONCLUSION Our findings provide some support for the hypothesis that in utero exposures reflective of higher endogenous hormone levels could affect risk for development of breast cancer in adulthood." ]

[ 5 ]

[ "Tissue regeneration requires dynamic cellular adaptation to the wound environment.", "It is currently unclear how this is orchestrated at the cellular level and how cell fate is affected by severe tissue damage.", "Here we dissect cell fate transitions during colonic regeneration in a mouse dextran sulfate sodium (DSS) colitis model, and we demonstrate that the epithelium is transiently reprogrammed into a primitive state.", "This is characterized by de novo expression of fetal markers as well as suppression of markers for adult stem and differentiated cells.", "The fate change is orchestrated by remodeling the extracellular matrix (ECM), increased FAK/Src signaling, and ultimately YAP/TAZ activation.", "In a defined cell culture system recapitulating the extracellular matrix remodeling observed in vivo, we show that a collagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous YAP/TAZ and induce conversion of cell fate.", "This provides a simple model for tissue regeneration, implicating cellular reprogramming as an essential element." ]

[ 4, 5 ]

[ "Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress.", "We show that PKCζ deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose.", "PKCζ represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity.", "Interestingly, the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis.", "Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors.", "Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse and human cancer." ]

[ 3, 5 ]

[ "T cell activation is predicated on the interaction between the T cell receptor and peptide-major histocompatibility (pMHC) ligands.", "The factors that determine the stimulatory potency of a pMHC molecule remain unclear.", "We describe results showing that a peptide exhibiting many hallmarks of a weak agonist stimulates T cells to proliferate more than the wild-type agonist ligand.", "An in silico approach suggested that the inability to form the central supramolecular activation cluster (cSMAC) could underlie the increased proliferation.", "This conclusion was supported by experiments that showed that enhancing cSMAC formation reduced stimulatory capacity of the weak peptide.", "Our studies highlight the fact that a complex interplay of factors determines the quality of a T cell antigen." ]

[ 4 ]

[ "Binding within or nearby target genes involved in cell proliferation and survival enables the p53 tumor suppressor gene to regulate their transcription and cell-cycle progression.", "Using genome-wide chromatin-binding profiles, we describe binding of p53 also to regions located distantly from any known p53 target gene.", "Interestingly, many of these regions possess conserved p53-binding sites and all known hallmarks of enhancer regions.", "We demonstrate that these p53-bound enhancer regions (p53BERs) indeed contain enhancer activity and interact intrachromosomally with multiple neighboring genes to convey long-distance p53-dependent transcription regulation.", "Furthermore, p53BERs produce, in a p53-dependent manner, enhancer RNAs (eRNAs) that are required for efficient transcriptional enhancement of interacting target genes and induction of a p53-dependent cell-cycle arrest.", "Thus, our results ascribe transcription enhancement activity to p53 with the capacity to regulate multiple genes from a single genomic binding site.", "Moreover, eRNA production from p53BERs is required for efficient p53 transcription enhancement." ]

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