| 1101. |
- Yagoubov, P., et al.
(författare)
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Wideband 67-116 GHz receiver development for ALMA Band 2
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 634
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Tidskriftsartikel (refereegranskat)abstract
- Context. The Atacama Large Millimeter/submillimeter Array (ALMA) has been in operation since 2011, but it has not yet been populated with the full suite of its planned frequency bands. In particular, ALMA Band 2 (67-90 GHz) is the final band in the original ALMA band definition to be approved for production. Aims. We aim to produce a wideband, tuneable, sideband-separating receiver with 28 GHz of instantaneous bandwidth per polarisation operating in the sky frequency range of 67-116 GHz. Our design anticipates new ALMA requirements following the recommendations of the 2030 ALMA Development Roadmap. Methods. The cryogenic cartridge is designed to be compatible with the ALMA Band 2 cartridge slot, where the coldest components - the feedhorns, orthomode transducers, and cryogenic low noise amplifiers - operate at a temperature of 15 K. We use multiple simulation methods and tools to optimise our designs for both the passive optics and the active components. The cryogenic cartridge is interfaced with a room-temperature (warm) cartridge hosting the local oscillator and the downconverter module. This warm cartridge is largely based on GaAs semiconductor technology and is optimised to match the cryogenic receiver bandwidth with the required instantaneous local oscillator frequency tuning range. Results. Our collaboration has resulted in the design, fabrication, and testing of multiple technical solutions for each of the receiver components, producing a state-of-the-art receiver covering the full ALMA Band 2 and 3 atmospheric window. The receiver is suitable for deployment on ALMA in the coming years and it is capable of dual-polarisation, sideband-separating observations in intermediate frequency bands spanning 4-18 GHz for a total of 28 GHz on-sky bandwidth per polarisation channel. Conclusions. We conclude that the 67-116 GHz wideband implementation for ALMA Band 2 is now feasible and that this receiver provides a compelling instrumental upgrade for ALMA that will enhance observational capabilities and scientific reach.
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| 1102. |
- Yang, Zhijian, et al.
(författare)
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Genetic Landscape of the ACE2 Coronavirus Receptor
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 30:SUPPL 1, s. 36-36
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Tidskriftsartikel (refereegranskat)abstract
- Background: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood.Methods: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data.Results: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-protein quantitative trait loci-based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10-2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; P=0.02). Tissue- and cell type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells.Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.
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| 1103. |
- Yao, Chen, et al.
(författare)
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Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.
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| 1104. |
- Ye, L, et al.
(författare)
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Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.
- 2003
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Ingår i: Journal of Medicinal Chemistry. ; 24;46:9, s. 1580-8
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Tidskriftsartikel (refereegranskat)abstract
- Endogenous thyroid receptor hormones 3,5,3',5'-tetraiodo-l-thyronine (T(4), 1) and 3,5,3'-triiodo-l-thyronine (T(3), 2) exert a significant effects on growth, development, and homeostasis in mammals. They regulate important genes in intestinal, skeletal, and cardiac muscles, the liver, and the central nervous system, influence overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood and overall sense of well being. The literature suggests many or most effects of thyroid hormones on the heart, in particular on the heart rate and rhythm, are mediated through the TRalpha(1) isoform, while most actions of the hormones on the liver and other tissues are mediated more through the TRbeta(1) isoform of the receptor. Some effects of thyroid hormones may be therapeutically useful in nonthyroid disorders if adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, cholesterol lowering for treating hyperlipidemia, amelioration of depression, and stimulation of bone formation in osteoporosis. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and, in particular, cardiovascular toxicity. Consequently, development of thyroid hormone receptor agonists that are selective for the beta-isoform could lead to safe therapies for these common disorders while avoiding cardiotoxicity. We describe here the synthesis and evaluation of a series of novel TR ligands, which are selective for TRbeta(1) over TRalpha(1). These ligands could potentially be useful for treatment of various disorders as outlined above. From a series of homologous R(1)-substituted carboxylic acid derivatives, increasing chain length was found to have a profound effect on affinity and selectivity in a radioreceptor binding assay for the human thyroid hormone receptors alpha(1) and beta(1) (TRalpha(1) and TRbeta(2)) as well as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary cells) stably transfected with hTRalpha(1) or hTRbeta(1) and an alkaline phosphatase reporter-gene downstream thyroid response element (TRAFalpha(1) and TRAFbeta(1)). Affinity increases in the order formic, acetic, and propionic acid, while beta-selectivity is highest when the R(1) position is substituted with acetic acid. Within this series 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were found to reveal the most promising in vitro data based on isoform selectivity and were selected for further in vivo studies. The effect of 2, 11a, and 15 in a cholesterol-fed rat model was monitored including potencies for heart rate (ED(15)), cholesterol (ED(50)), and TSH (ED(50)). Potency for tachycardia was significantly reduced for the TRbeta selective compounds 11a and 15 compared with 2, while both 11a and 15 retained the cholesterol-lowering potency of 2. This left an approximately 10-fold therapeutic window between heart rate and cholesterol, which is consistent with the action of ligands that are approximately 10-fold more selective for TRbeta(1). We also report the X-ray crystallographic structures of the ligand binding domains of TRalpha and TRbeta in complex with 15. These structures reveal that the single amino acid difference in the ligand binding pocket (Ser277 in TRalpha or Asn331 in TRbeta) results in a slightly different hydrogen bonding pattern that may explain the increased beta-selectivity of 15.
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| 1105. |
- Yoneyama, Sachiko, et al.
(författare)
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Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:9, s. 2498-2510
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Tidskriftsartikel (refereegranskat)abstract
- Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBIs Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 2080 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes 50 000 cosmopolitan tagged SNPs across 2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P 2.4 10(6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR ( SE, 0.048 0.008, P 7.7 10(9)) as was rs7302703-G in HOXC10 ( 0.044 0.008, P 2.9 10(7)) and rs936108-C in PEMT ( 0.035 0.007, P 1.9 10(6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 ( 0.10 0.02, P 1.9 10(6)) and rs1037575-A in ATBDB4 ( 0.046 0.01, P 2.2 10(6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
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| 1106. |
- Younes, George, et al.
(författare)
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X-Ray Burst and Persistent Emission Properties of the Magnetar SGR 1830-0645 in Outburst
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 924:2
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Tidskriftsartikel (refereegranskat)abstract
- We report on NICER X-ray monitoring of the magnetar SGR 1830-0645 covering 223 days following its 2020 October outburst, as well as Chandra and radio observations. We present the most accurate spin ephemerides of the source so far: nu = 0.096008680(2) Hz, = -6.2(1) x 10(-14) Hz s(-1), and significant second and third frequency derivative terms indicative of nonnegligible timing noise. The phase-averaged 0.8-7 keV spectrum is well fit with a double-blackbody (BB) model throughout the campaign. The BB temperatures remain constant at 0.46 and 1.2 keV. The areas and flux of each component decreased by a factor of 6, initially through a steep decay trend lasting about 46 days, followed by a shallow long-term one. The pulse shape in the same energy range is initially complex, exhibiting three distinct peaks, yet with clear continuous evolution throughout the outburst toward a simpler, single-pulse shape. The rms pulsed fraction is high and increases from about 40% to 50%. We find no dependence of pulse shape or fraction on energy. These results suggest that multiple hot spots, possibly possessing temperature gradients, emerged at outburst onset and shrank as the outburst decayed. We detect 84 faint bursts with NICER, having a strong preference for occurring close to the surface emission pulse maximum-the first time this phenomenon is detected in such a large burst sample. This likely implies a very low altitude for the burst emission region and a triggering mechanism connected to the surface active zone. Finally, our radio observations at several epochs and multiple frequencies reveal no evidence of pulsed or burst-like radio emission.
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| 1107. |
- Zewinger, Stephen, et al.
(författare)
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Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : a molecular and genetic association study
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:7, s. 534-543
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.Findings: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies.Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
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| 1108. |
- Zhang, Chen, et al.
(författare)
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Physiological and nutritional constraints on zooplankton productivity due to eutrophication and climate change predicted using a resource-based modeling approach
- 2022
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Ingår i: Canadian Journal of Fisheries and Aquatic Sciences. - : Canadian Science Publishing. - 0706-652X .- 1205-7533. ; 79:3, s. 472-486
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests that zooplankton production is affected by physiological and nutritional constraints due to climate change and eutrophication, which in turn could have broad implications for food-web dynamics and fisheries production. In this study, we developed a resource-based zooplankton production dynamics model that causally links freshwater cladoceran and copepod daily production-to-biomass (P/B) ratios with water temperature, phytoplankton biomass and community composition, and zooplankton feeding selectivity. This model was used to evaluate constraints on zooplankton growth under four hypothetical scenarios: involving natural plankton community seasonal succession; lake fertilization to enhance fisheries production; eutrophication; and climatic warming. Our novel modeling approach predicts zooplankton production is strongly dependent on seasonal variation in resource availability and quality, which results in more complex zooplankton dynamics than predicted by simpler temperature-dependent models. For mesotrophic and hypereutrophic lakes, our study suggests that the ultimate control over zooplankton P/B ratios shifts from physiological control during colder periods to strong resource control during warmer periods. Our resource-based model provides important insights into the nature of biophysical control of zooplankton under a changing climate that has crucial implications for food web energy transfer and fisheries production.
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| 1109. |
- Zhang (张臻), Zhen, et al.
(författare)
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Anthropogenic emission is the main contributor to the rise of atmospheric methane during 1993–2017
- 2022
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Ingår i: National Science Review. - : Oxford University Press (OUP). - 2095-5138 .- 2053-714X. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric methane (CH4) concentrations have shown a puzzling resumption in growth since 2007 following a period of stabilization from 2000 to 2006. Multiple hypotheses have been proposed to explain the temporal variations in CH4 growth, and attribute the rise of atmospheric CH4 either to increases in emissions from fossil fuel activities, agriculture and natural wetlands, or to a decrease in the atmospheric chemical sink. Here, we use a comprehensive ensemble of CH4 source estimates and isotopic δ13C-CH4 source signature data to show that the resumption of CH4 growth is most likely due to increased anthropogenic emissions. Our emission scenarios that have the fewest biases with respect to isotopic composition suggest that the agriculture, landfill and waste sectors were responsible for 53 ± 13% of the renewed growth over the period 2007–2017 compared to 2000–2006; industrial fossil fuel sources explained an additional 34 ± 24%, and wetland sources contributed the least at 13 ± 9%. The hypothesis that a large increase in emissions from natural wetlands drove the decrease in atmospheric δ13C-CH4 values cannot be reconciled with current process-based wetland CH4 models. This finding suggests the need for increased wetland measurements to better understand the contemporary and future role of wetlands in the rise of atmospheric methane and climate feedback. Our findings highlight the predominant role of anthropogenic activities in driving the growth of atmospheric CH4 concentrations.
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| 1110. |
- Zhu, Yongda, et al.
(författare)
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Probing Ultralate Reionization: Direct Measurements of the Mean Free Path over 5 z
- 2023
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Ingår i: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 955:2
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Tidskriftsartikel (refereegranskat)abstract
- The mean free path of ionizing photons, lambda(mfp), is a critical parameter for modeling the intergalactic medium (IGM) both during and after reionization. We present direct measurements of lambda(mfp) from QSO spectra over the redshift range 5 < z < 6, including the first measurements at z similar or equal to 5.3 and 5.6. Our sample includes data from the XQR-30 VLT large program, as well as new Keck/ESI observations of QSOs near z similar to 5.5, for which we also acquire new [C II] 158 mu m redshifts with ALMA. By measuring the Lyman continuum transmission profile in stacked QSO spectra, we find lambda(mfp) = 9.33(-1.80)(+2.06), 5.40(-1.40)(+1.47), 3.31(-1.34)(+2.74), and 0.81(-0.48)(+0.73) pMpc at z = 5.08, 5.31, 5.65, and 5.93, respectively. Our results demonstrate that lambda(mfp) increases steadily and rapidly with time over 5 < z < 6. Notably, we find that lambda(mfp) deviates significantly from predictions based on a fully ionized and relaxed IGM as late as z = 5.3. By comparing our results to model predictions and indirect lambda(mfp) constraints based on IGM Ly alpha opacity, we find that the evolution of lambda(mfp) is consistent with scenarios wherein the IGM is still undergoing reionization and/or retains large fluctuations in the ionizing UV background well below redshift 6.
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