132 research outputs found
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Evaluation of a coastal ocean circulation model for the Columbia River plume in summer 2004
Realistic hindcast of the Columbia River estuarine-plume-shelf circulation in summer
2004 using the Regional Ocean Modeling System nested within the Navy Coastal Ocean
Model (NCOM) is quantitatively evaluated with an extensive set of observations. The
model has about equal skill at tidal and subtidal properties. Tidal circulation and water
properties are best simulated in the estuary, which is strongly forced and damped, but
worst on the shelf. Subtidal currents are again best in the estuary. However, subtidal
temperature and salinity are best simulated in the surface waters on the shelf, even inside
the river plume. A comprehensive skill assessment method is proposed to evaluate the
cross-scale modeling system with a focus on the plume. The model domain is divided into
five dynamical regions: estuary, near- and far-field plume, near surface and deep layers. A
skill score is obtained for each region by averaging the skills of different physical variables,
and an overall skill is obtained by averaging the skills across the five regions. This
weighting metric results in more skill weight per unit volume in the near surface layer where
the plume is trapped and in the estuary. It is also demonstrated, through model/data
comparison and skill assessment, that by nesting within NCOM, some important remote
forcing, e.g., coastal trapped waves, are added to our model; on the other hand, some biases
are also received. With a finer grid and more realistic forcing, our regional model improves
skill over a larger-scale model in modeling the shelf-plume circulation
Accounting for a Quantitative Trait Locus for Plasma Triglyceride Levels: Utilization of Variants in Multiple Genes
For decades, research efforts have tried to uncover the underlying genetic basis of human susceptibility to a variety of diseases. Linkage studies have resulted in highly replicated findings and helped identify quantitative trait loci (QTL) for many complex traits; however identification of specific alleles accounting for linkage remains elusive. The purpose of this study was to determine whether with a sufficient number of variants a linkage signal can be fully explained.We used comprehensive fine-mapping using a dense set of single nucleotide polymorphisms (SNPs) across the entire quantitative trait locus (QTL) on human chromosome 7q36 linked to plasma triglyceride levels. Analyses included measured genotype and combined linkage association analyses.Screening this linkage region, we found an over representation of nominally significant associations in five genes (MLL3, DPP6, PAXIP1, HTR5A, INSIG1). However, no single genetic variant was sufficient to account for the linkage. On the other hand, multiple variants capturing the variation in these five genes did account for the linkage at this locus. Permutation analyses suggested that this reduction in LOD score was unlikely to have occurred by chance (p = 0.008).With recent findings, it has become clear that most complex traits are influenced by a large number of genetic variants each contributing only a small percentage to the overall phenotype. We found that with a sufficient number of variants, the linkage can be fully explained. The results from this analysis suggest that perhaps the failure to identify causal variants for linkage peaks may be due to multiple variants under the linkage peak with small individual effect, rather than a single variant of large effect
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River influences on shelf ecosystems: Introduction and synthesis
River Influences on Shelf Ecosystems (RISE) is the first comprehensive
interdisciplinary study of the rates and dynamics governing the mixing of river and coastal
waters in an eastern boundary current system, as well as the effects of the resultant plume
on phytoplankton standing stocks, growth and grazing rates, and community structure.
The RISE Special Volume presents results deduced from four field studies and two
different numerical model applications, including an ecosystem model, on the buoyant
plume originating from the Columbia River. This introductory paper provides background
information on variability during RISE field efforts as well as a synthesis of results, with
particular attention to the questions and hypotheses that motivated this research. RISE
studies have shown that the maximum mixing of Columbia River and ocean water occurs
primarily near plume liftoff inside the estuary and in the near field of the plume. Most
plume nitrate originates from upwelled shelf water, and plume phytoplankton species are
typically the same as those found in the adjacent coastal ocean. River-supplied nitrate
can help maintain the ecosystem during periods of delayed upwelling. The plume inhibits
iron limitation, but nitrate limitation is observed in aging plumes. The plume also has
significant effects on rates of primary productivity and growth (higher in new plume
water) and microzooplankton grazing (lower in the plume near field and north of the
river mouth); macrozooplankton concentration (enhanced at plume fronts); offshelf
chlorophyll export; as well as the development of a chlorophyll “shadow zone” off
northern Oregon.Keywords: Columbia River plume, freshwater plume, RIS
Simulating rewetting events in intermittent rivers and ephemeral streams: A global analysis of leached nutrients and organic matter
Climate change and human pressures are changing the global distribution and the ex‐
tent of intermittent rivers and ephemeral streams (IRES), which comprise half of the
global river network area. IRES are characterized by periods of flow cessation, during
which channel substrates accumulate and undergo physico‐chemical changes (precon‐
ditioning), and periods of flow resumption, when these substrates are rewetted and
release pulses of dissolved nutrients and organic matter (OM). However, there are no
estimates of the amounts and quality of leached substances, nor is there information
on the underlying environmental constraints operating at the global scale. We experi‐
mentally simulated, under standard laboratory conditions, rewetting of leaves, river‐
bed sediments, and epilithic biofilms collected during the dry phase across 205 IRES
from five major climate zones. We determined the amounts and qualitative character‐
istics of the leached nutrients and OM, and estimated their areal fluxes from riverbeds.
In addition, we evaluated the variance in leachate characteristics in relation to selected
environmental variables and substrate characteristics. We found that sediments, due
to their large quantities within riverbeds, contribute most to the overall flux of dis‐
solved substances during rewetting events (56%–98%), and that flux rates distinctly
differ among climate zones. Dissolved organic carbon, phenolics, and nitrate contrib‐
uted most to the areal fluxes. The largest amounts of leached substances were found
in the continental climate zone, coinciding with the lowest potential bioavailability of
the leached OM. The opposite pattern was found in the arid zone. Environmental vari‐
ables expected to be modified under climate change (i.e. potential evapotranspiration,
aridity, dry period duration, land use) were correlated with the amount of leached sub‐
stances, with the strongest relationship found for sediments. These results show that
the role of IRES should be accounted for in global biogeochemical cycles, especially
because prevalence of IRES will increase due to increasing severity of drying event
The Physics of the B Factories
This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C
Rare and low-frequency coding variants alter human adult height
Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways
Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors
Context
Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).
Objective
To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.
Design
12-year prospective, observational study.
Participants & Setting
We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.
Interventions & Outcome
AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).
Results
Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).
Conclusions
Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD
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