Limited data exist on the reproductive hormone dynamics that govern the transition from menarche to the establishment of the mature ovulatory cycles of a fertile young woman. It is also unclear how ...environmental and lifestyle factors could modulate this transition in contemporary girls. Here, we introduce A Girl's First Period Study, an ambitious longitudinal study aimed at charting the early post-menarchal course of a cohort of healthy girls in the Triangle region of North Carolina.
A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to ...afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.
A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These ...discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
Here we show that the inhibitor is not specific for the H3K27me3/me2-demethylase subfamily in vitro and in tissue culture assays. Thus, the inhibitor cannot be used alone for drawing conclusions ...regarding the specific role of H3K27me3/me2-demethylase activity in biological processes or disease.
Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies ...have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10-6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10-8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10-8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10-8; RREB1: p = 5.7×10-8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
Once ice-bound, difficult to access, and largely ignored by the rest of the world, the Arctic is now front and center in the midst of many important questions facing the world today. Our daily ...weather, what we eat, and coastal flooding are all interconnected with the future of the Arctic. The year 2012 was an astounding year for Arctic change. The summer sea ice volume smashed previous records, losing approximately 75 percent of its value since 1980 and half of its areal coverage. Multiple records were also broken when 97 percent of Greenland's surface experienced melt conditions in 2012, the largest melt extent in the satellite era. Receding ice caps in Arctic Canada are now exposing land surfaces that have been continuously ice covered for more than 40,000 years.
What happens in the Arctic has far-reaching implications around the world. Loss of snow and ice exacerbates climate change and is the largest contributor to expected global sea level rise during the next century. Ten percent of the world's fish catches comes from Arctic and sub-Arctic waters. The U.S. Geological Survey estimated that up to 13 percent of the world's remaining oil reserves are in the Arctic. The geologic history of the Arctic may hold vital clues about massive volcanic eruptions and the consequent release of massive amount of coal fly ash that is thought to have caused mass extinctions in the distant past. How will these changes affect the rest of Earth? What research should we invest in to best understand this previously hidden land, manage impacts of change on Arctic communities, and cooperate with researchers from other nations?
The Arctic in the Anthropocene reviews research questions previously identified by Arctic researchers, and then highlights the new questions that have emerged in the wake of and expectation of further rapid Arctic change, as well as new capabilities to address them. This report is meant to guide future directions in U.S. Arctic research so that research is targeted on critical scientific and societal questions and conducted as effectively as possible. The Arctic in the Anthropocene identifies both a disciplinary and a cross-cutting research strategy for the next 10 to 20 years, and evaluates infrastructure needs and collaboration opportunities. The climate, biology, and society in the Arctic are changing in rapid, complex, and interactive ways. Understanding the Arctic system has never been more critical; thus, Arctic research has never been more important. This report will be a resource for institutions, funders, policy makers, and students. Written in an engaging style, The Arctic in the Anthropocene paints a picture of one of the last unknown places on this planet, and communicates the excitement and importance of the discoveries and challenges that lie ahead.
Once ice-bound, difficult to access, and largely ignored by the rest of the world, the Arctic is now front and center in the midst of many important questions facing the world today. Our daily ...weather, what we eat, and coastal flooding are all interconnected with the future of the Arctic. The year 2012 was an astounding year for Arctic change. The summer sea ice volume smashed previous records, losing approximately 75 percent of its value since 1980 and half of its areal coverage. Multiple records were also broken when 97 percent of Greenland's surface experienced melt conditions in 2012, the largest melt extent in the satellite era. Receding ice caps in Arctic Canada are now exposing land surfaces that have been continuously ice covered for more than 40,000 years.
What happens in the Arctic has far-reaching implications around the world. Loss of snow and ice exacerbates climate change and is the largest contributor to expected global sea level rise during the next century. Ten percent of the world's fish catches comes from Arctic and sub-Arctic waters. The U.S. Geological Survey estimated that up to 13 percent of the world's remaining oil reserves are in the Arctic. The geologic history of the Arctic may hold vital clues about massive volcanic eruptions and the consequent release of massive amount of coal fly ash that is thought to have caused mass extinctions in the distant past. How will these changes affect the rest of Earth? What research should we invest in to best understand this previously hidden land, manage impacts of change on Arctic communities, and cooperate with researchers from other nations?
The Arctic in the Anthropocene reviews research questions previously identified by Arctic researchers, and then highlights the new questions that have emerged in the wake of and expectation of further rapid Arctic change, as well as new capabilities to address them. This report is meant to guide future directions in U.S. Arctic research so that research is targeted on critical scientific and societal questions and conducted as effectively as possible. The Arctic in the Anthropocene identifies both a disciplinary and a cross-cutting research strategy for the next 10 to 20 years, and evaluates infrastructure needs and collaboration opportunities. The climate, biology, and society in the Arctic are changing in rapid, complex, and interactive ways. Understanding the Arctic system has never been more critical; thus, Arctic research has never been more important. This report will be a resource for institutions, funders, policy makers, and students. Written in an engaging style, The Arctic in the Anthropocene paints a picture of one of the last unknown places on this planet, and communicates the excitement and importance of the discoveries and challenges that lie ahead.
Once ice-bound, difficult to access, and largely ignored by the rest of the world, the Arctic is now front and center in the midst of many important questions facing the world today. Our daily ...weather, what we eat, and coastal flooding are all interconnected with the future of the Arctic. The year 2012 was an astounding year for Arctic change. The summer sea ice volume smashed previous records, losing approximately 75 percent of its value since 1980 and half of its areal coverage. Multiple records were also broken when 97 percent of Greenland's surface experienced melt conditions in 2012, the largest melt extent in the satellite era. Receding ice caps in Arctic Canada are now exposing land surfaces that have been continuously ice covered for more than 40,000 years.
What happens in the Arctic has far-reaching implications around the world. Loss of snow and ice exacerbates climate change and is the largest contributor to expected global sea level rise during the next century. Ten percent of the world's fish catches comes from Arctic and sub-Arctic waters. The U.S. Geological Survey estimated that up to 13 percent of the world's remaining oil reserves are in the Arctic. The geologic history of the Arctic may hold vital clues about massive volcanic eruptions and the consequent release of massive amount of coal fly ash that is thought to have caused mass extinctions in the distant past. How will these changes affect the rest of Earth? What research should we invest in to best understand this previously hidden land, manage impacts of change on Arctic communities, and cooperate with researchers from other nations?
The Arctic in the Anthropocene reviews research questions previously identified by Arctic researchers, and then highlights the new questions that have emerged in the wake of and expectation of further rapid Arctic change, as well as new capabilities to address them. This report is meant to guide future directions in U.S. Arctic research so that research is targeted on critical scientific and societal questions and conducted as effectively as possible. The Arctic in the Anthropocene identifies both a disciplinary and a cross-cutting research strategy for the next 10 to 20 years, and evaluates infrastructure needs and collaboration opportunities. The climate, biology, and society in the Arctic are changing in rapid, complex, and interactive ways. Understanding the Arctic system has never been more critical; thus, Arctic research has never been more important. This report will be a resource for institutions, funders, policy makers, and students. Written in an engaging style, The Arctic in the Anthropocene paints a picture of one of the last unknown places on this planet, and communicates the excitement and importance of the discoveries and challenges that lie ahead.
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