Ice Cores from the St. Elias Mountains, Yukon, Canada: Their Significance for Climate, Atmospheric Composition and Volcanism in the North Pacific Region

A major achievement in research supported by the Kluane Lake Research Station was the recovery, in 2001 –02, of a suite of cores from the icefields of the central St. Elias Mountains, Yukon, by teams of researchers from Canada, the United States, and Japan. This project led to the development of parallel, long (103 – 104 year) ice-core records of climate and atmospheric change over an altitudinal range of more than 2 km, from the Eclipse Icefield (3017 m) to the ice-covered plateau of Mt. Logan (5340 m). These efforts built on earlier work recovering single ice cores in this region. Comparison of these records has allowed for variations in climate and atmospheric composition to be linked with changes in the vertical structure and dynamics of the North Pacific atmosphere, providing a unique perspective on these changes over the Holocene. Owing to their privileged location, cores from the St. Elias Icefields also contain a remarkably detailed record of aerosols from various sources around or across the North Pacific. In this paper we review major scientific findings from the study of St. Elias Mountain ice cores, focusing on five main themes: (1) The record of stable water isotopes (δ18O, δD), which has unique characteristics that differ from those of Greenland, other Arctic ice cores, and even among sites in the St. Elias; (2) the snow accumulation history; (3) the record of pollen, biomass burning aerosol, and desert dust deposition; (4) the record of long-range air pollutant deposition (sulphate and lead); and (5) the record of paleo-volcanism. Our discussion draws on studies published since 2000, but based on older ice cores from the St. Elias Mountains obtained in 1980 and 1996

Ice Cores from the St. Elias Mountains, Yukon, Canada: Their Significance for Climate, Atmospheric Composition and Volcanism in the North Pacific Region

A major achievement in research supported by the Kluane Lake Research Station was the recovery, in 2001 –02, of a suite of cores from the icefields of the central St. Elias Mountains, Yukon, by teams of researchers from Canada, the United States, and Japan. This project led to the development of parallel, long (103 – 104 year) ice-core records of climate and atmospheric change over an altitudinal range of more than 2 km, from the Eclipse Icefield (3017 m) to the ice-covered plateau of Mt. Logan (5340 m). These efforts built on earlier work recovering single ice cores in this region. Comparison of these records has allowed for variations in climate and atmospheric composition to be linked with changes in the vertical structure and dynamics of the North Pacific atmosphere, providing a unique perspective on these changes over the Holocene. Owing to their privileged location, cores from the St. Elias Icefields also contain a remarkably detailed record of aerosols from various sources around or across the North Pacific. In this paper we review major scientific findings from the study of St. Elias Mountain ice cores, focusing on five main themes: (1) The record of stable water isotopes (δ18O, δD), which has unique characteristics that differ from those of Greenland, other Arctic ice cores, and even among sites in the St. Elias; (2) the snow accumulation history; (3) the record of pollen, biomass burning aerosol, and desert dust deposition; (4) the record of long-range air pollutant deposition (sulphate and lead); and (5) the record of paleo-volcanism. Our discussion draws on studies published since 2000, but based on older ice cores from the St. Elias Mountains obtained in 1980 and 1996

Dual Suppression of the Cyclin-Dependent Kinase Inhibitors CDKN2C and CDKN1A in Human Melanoma

Resistance to BRAFV600E inhibitors is associated with reactivation of mitogen-activated protein kinase (MAPK) signaling at different levels in melanoma. To identify downstream effectors of MAPK signaling that could be used as potential additional therapeutic targets for BRAFV600E inhibitors, we used hTERT/CDK4R24C/p53DD-immortalized primary human melanocytes genetically modified to ectopically express BRAF V600E or NRAS G12D and observed induction of the AP-1 transcription factor family member c-Jun. Using a dominant negative approach, in vitro cell proliferation assays, western blots, and flow cytometry showed that MAPK signaling via BRAFV600E promotes melanoma cell proliferation at G1 through AP-1-mediated negative regulation of the INK4 family member, cyclin-dependent kinase inhibitor 2C (CDKN2C), and the CIP/KIP family member, cyclin-dependent kinase inhibitor 1A (CDKN1A). These effects were antagonized by pharmacological inhibition of CDKN2C and CDKN1A targets CDK2 and CDK4 in vitro. In contrast to BRAF V600E or NRAS G12D-expressing melanocytes, melanoma cells have an inherent resistance to suppression of AP-1 activity by BRAFV600E- or MEK-inhibitors. Here, CDK2/4 inhibition statistically significantly augmented the effects of BRAFV600E- or MEK-inhibitors on melanoma cell viability in vitro and growth in athymic nude Foxn1 nu mice (P = .03 when mean tumor volume at day 13 was compared for BRAFV600E inhibitor vs BRAFV600E inhibitor plus CDK2/4 inhibition; P = .02 when mean tumor volume was compared for MEK inhibitor vs MEK inhibitor plus CDK2/4 inhibition; P values were calculated by a two-sided Welch t test; n = 4–8 mice per group)

Severe 2010 Cold-Water Event Caused Unprecedented Mortality to Corals of the Florida Reef Tract and Reversed Previous Survivorship Patterns

Background Coral reefs are facing increasing pressure from natural and anthropogenic stressors that have already caused significant worldwide declines. In January 2010, coral reefs of Florida, United States, were impacted by an extreme cold-water anomaly that exposed corals to temperatures well below their reported thresholds (16°C), causing rapid coral mortality unprecedented in spatial extent and severity. Methodology/Principal Findings Reef surveys were conducted from Martin County to the Lower Florida Keys within weeks of the anomaly. The impacts recorded were catastrophic and exceeded those of any previous disturbances in the region. Coral mortality patterns were directly correlated to in-situ and satellite-derived cold-temperature metrics. These impacts rival, in spatial extent and intensity, the impacts of the well-publicized warm-water bleaching events around the globe. The mean percent coral mortality recorded for all species and subregions was 11.5% in the 2010 winter, compared to 0.5% recorded in the previous five summers, including years like 2005 where warm-water bleaching was prevalent. Highest mean mortality (15%–39%) was documented for inshore habitats where temperatures were \u3c11°C for prolonged periods. Increases in mortality from previous years were significant for 21 of 25 coral species, and were 1–2 orders of magnitude higher for most species. Conclusions/Significance The cold-water anomaly of January 2010 caused the worst coral mortality on record for the Florida Reef Tract, highlighting the potential catastrophic impacts that unusual but extreme climatic events can have on the persistence of coral reefs. Moreover, habitats and species most severely affected were those found in high-coral cover, inshore, shallow reef habitats previously considered the “oases” of the region, having escaped declining patterns observed for more offshore habitats. Thus, the 2010 cold-water anomaly not only caused widespread coral mortality but also reversed prior resistance and resilience patterns that will take decades to recover

Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 x 10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84 x 10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at similar to 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults

Ice Cores from the St. Elias Mountains, Yukon, Canada: Their Significance for Climate, Atmospheric Composition and Volcanism in the North Pacific Region

A major achievement in research supported by the Kluane Lake Research Station was the recovery, in 2001–02, of a suite of cores from the icefields of the central St. Elias Mountains, Yukon, by teams of researchers from Canada, the United States, and Japan. This project led to the development of parallel, long (10³–10⁴ year) ice-core records of climate and atmospheric change over an altitudinal range of more than 2 km, from the Eclipse Icefield (3017 m) to the ice-covered plateau of Mt. Logan (5340 m). These efforts built on earlier work recovering single ice cores in this region. Comparison of these records has allowed for variations in climate and atmospheric composition to be linked with changes in the vertical structure and dynamics of the North Pacific atmosphere, providing a unique perspective on these changes over the Holocene. Owing to their privileged location, cores from the St. Elias Icefields also contain a remarkably detailed record of aerosols from various sources around or across the North Pacific. In this paper we review major scientific findings from the study of St. Elias Mountain ice cores, focusing on five main themes: (1) The record of stable water isotopes (δ¹⁸O, δD), which has unique characteristics that differ from those of Greenland, other Arctic ice cores, and even among sites in the St. Elias; (2) the snow accumulation history; (3) the record of pollen, biomass burning aerosol, and desert dust deposition; (4) the record of long-range air pollutant deposition (sulphate and lead); and (5) the record of paleo-volcanism. Our discussion draws on studies published since 2000, but based on older ice cores from the St. Elias Mountains obtained in 1980 and 1996.This is the publisher’s final pdf. The published article is copyrighted by the Arctic Institute of North America and can be found at: http://arctic.journalhosting.ucalgary.ca/arctic/index.php/arctic/index.Keywords: Air pollution, Aerosols, Volcanism, North Pacific, Ice cores, Holocene, Climate chang

Statistical techniques to construct assays for identifying likely responders to a treatment under evaluation from cell line genomic data

<p>Abstract</p> <p>Background</p> <p>Developing the right drugs for the right patients has become a mantra of drug development. In practice, it is very difficult to identify subsets of patients who will respond to a drug under evaluation. Most of the time, no single diagnostic will be available, and more complex decision rules will be required to define a sensitive population, using, for instance, mRNA expression, protein expression or DNA copy number. Moreover, diagnostic development will often begin with in-vitro cell-line data and a high-dimensional exploratory platform, only later to be transferred to a diagnostic assay for use with patient samples. In this manuscript, we present a novel approach to developing robust genomic predictors that are not only capable of generalizing from in-vitro to patient, but are also amenable to clinically validated assays such as qRT-PCR.</p> <p>Methods</p> <p>Using our approach, we constructed a predictor of sensitivity to dacetuzumab, an investigational drug for CD40-expressing malignancies such as lymphoma using genomic measurements of cell lines treated with dacetuzumab. Additionally, we evaluated several state-of-the-art prediction methods by independently pairing the feature selection and classification components of the predictor. In this way, we constructed several predictors that we validated on an independent DLBCL patient dataset. Similar analyses were performed on genomic measurements of breast cancer cell lines and patients to construct a predictor of estrogen receptor (ER) status.</p> <p>Results</p> <p>The best dacetuzumab sensitivity predictors involved ten or fewer genes and accurately classified lymphoma patients by their survival and known prognostic subtypes. The best ER status classifiers involved one or two genes and led to accurate ER status predictions more than 85% of the time. The novel method we proposed performed as well or better than other methods evaluated.</p> <p>Conclusions</p> <p>We demonstrated the feasibility of combining feature selection techniques with classification methods to develop assays using cell line genomic measurements that performed well in patient data. In both case studies, we constructed parsimonious models that generalized well from cell lines to patients.</p

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far