| 1. |
- Ramdas, S., et al.
(author)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Journal article (peer-reviewed)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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| 2. |
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| 3. |
- An, Junghwa, et al.
(author)
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Permanent Genetic Resources added to Molecular Ecology Resources Database 1 October 2009-30 November 2009
- 2010
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In: Molecular Ecology Resources. - : Wiley. - 1755-098X .- 1755-0998. ; 10:2, s. 404-408
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Journal article (peer-reviewed)abstract
- This article documents the addition of 411 microsatellite marker loci and 15 pairs of Single Nucleotide Polymorphism (SNP) sequencing primers to the Molecular Ecology Resources Database. Loci were developed for the following species: Acanthopagrus schlegeli, Anopheles lesteri, Aspergillus clavatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus oryzae, Aspergillus terreus, Branchiostoma japonicum, Branchiostoma belcheri, Colias behrii, Coryphopterus personatus, Cynogolssus semilaevis, Cynoglossus semilaevis, Dendrobium officinale, Dendrobium officinale, Dysoxylum malabaricum, Metrioptera roeselii, Myrmeciza exsul, Ochotona thibetana, Neosartorya fischeri, Nothofagus pumilio, Onychodactylus fischeri, Phoenicopterus roseus, Salvia officinalis L., Scylla paramamosain, Silene latifo, Sula sula, and Vulpes vulpes. These loci were cross-tested on the following species: Aspergillus giganteus, Colias pelidne, Colias interior, Colias meadii, Colias eurytheme, Coryphopterus lipernes, Coryphopterus glaucofrenum, Coryphopterus eidolon, Gnatholepis thompsoni, Elacatinus evelynae, Dendrobium loddigesii Dendrobium devonianum, Dysoxylum binectariferum, Nothofagus antarctica, Nothofagus dombeyii, Nothofagus nervosa, Nothofagus obliqua, Sula nebouxii, and Sula variegata. This article also documents the addition of 39 sequencing primer pairs and 15 allele specific primers or probes for Paralithodes camtschaticus.
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| 9. |
- Sun, XT, et al.
(author)
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Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism
- 2022
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In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 71:1, s. 129-147
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Journal article (peer-reviewed)abstract
- Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy.DesignTwo unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33–ST2–CXCL3–CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models.ResultsIL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33–ST2–MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3–CXCR2 signalling. Type III collagen was identified as the CXCL3–CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis.ConclusionsOur work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.
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| 10. |
- Aartsen, M. G., et al.
(author)
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Multiwavelength follow-up of a rare IceCube neutrino multiplet
- 2017
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In: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 607
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Journal article (peer-reviewed)abstract
- On February 17, 2016, the IceCube real-time neutrino search identified, for the first time, three muon neutrino candidates arriving within 100 s of one another, consistent with coming from the same point in the sky. Such a triplet is expected once every 13.7 years as a random coincidence of background events. However, considering the lifetime of the follow-up program the probability of detecting at least one triplet from atmospheric background is 32%. Follow-up observatories were notified in order to search for an electromagnetic counterpart. Observations were obtained by Swift's X-ray telescope, by ASAS-SN, LCO and MASTER at optical wavelengths, and by VERITAS in the very-high-energy gamma-ray regime. Moreover, the Swift BAT serendipitously observed the location 100 s after the first neutrino was detected, and data from the Fermi LAT and HAWC observatory were analyzed. We present details of the neutrino triplet and the follow-up observations. No likely electromagnetic counterpart was detected, and we discuss the implications of these constraints on candidate neutrino sources such as gamma-ray bursts, core-collapse supernovae and active galactic nucleus flares. This study illustrates the potential of and challenges for future follow-up campaigns.
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| 11. |
- Abeysekara, A. U., et al.
(author)
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VERITAS and Fermi-LAT Observations of TeV Gamma-Ray Sources Discovered by HAWC in the 2HWC Catalog
- 2018
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In: Astrophysical Journal. - : Institute of Physics Publishing. - 0004-637X .- 1538-4357. ; 866:1
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Journal article (peer-reviewed)abstract
- The High Altitude Water Cherenkov (HAWC) collaboration recently published their 2HWC catalog, listing 39 very high energy (VHE; >100 GeV) gamma-ray sources based on 507 days of observation. Among these, 19 sources are not associated with previously known teraelectronvolt (TeV) gamma-ray sources. We have studied 14 of these sources without known counterparts with VERITAS and Fermi-LAT. VERITAS detected weak gamma-ray emission in the 1 TeV-30 TeV band in the region of DA 495, a pulsar wind nebula coinciding with 2HWC J1953+294, confirming the discovery of the source by HAWC. We did not find any counterpart for the selected 14 new HAWC sources from our analysis of Fermi-LAT data for energies higher than 10 GeV. During the search, we detected gigaelectronvolt (GeV) gamma-ray emission coincident with a known TeV pulsar wind nebula, SNR G54.1+0.3 (VER J1930+188), and a 2HWC source, 2HWC J1930+188. The fluxes for isolated, steady sources in the 2HWC catalog are generally in good agreement with those measured by imaging atmospheric Cherenkov telescopes. However, the VERITAS fluxes for SNR G54.1+0.3, DA 495, and TeV J2032+4130 are lower than those measured by HAWC, and several new HAWC sources are not detected by VERITAS. This is likely due to a change in spectral shape, source extension, or the influence of diffuse emission in the source region.
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| 12. |
- Abramowski, A., et al.
(author)
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The 2010 very high energy gamma-RAY flare and 10 years of multi-wavelength observations of M 87
- 2012
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 746:2, s. 151-
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Journal article (peer-reviewed)abstract
- The giant radio galaxy M 87 with its proximity (16 Mpc), famous jet, and very massive black hole ((3-6) x 10(9) M-circle dot) provides a unique opportunity to investigate the origin of very high energy (VHE; E > 100 GeV) gamma-ray emission generated in relativistic outflows and the surroundings of supermassive black holes. M 87 has been established as a VHE gamma-ray emitter since 2006. The VHE gamma-ray emission displays strong variability on timescales as short as a day. In this paper, results from a joint VHE monitoring campaign on M 87 by the MAGIC and VERITAS instruments in 2010 are reported. During the campaign, a flare at VHE was detected triggering further observations at VHE (H.E.S.S.), X-rays (Chandra), and radio (43 GHz Very Long Baseline Array, VLBA). The excellent sampling of the VHE gamma-ray light curve enables one to derive a precise temporal characterization of the flare: the single, isolated flare is well described by a two-sided exponential function with significantly different flux rise and decay times of tau(rise)(d) = (1.69 +/- 0.30) days and tau(decay)(d) = (0.611 +/- 0.080) days, respectively. While the overall variability pattern of the 2010 flare appears somewhat different from that of previous VHE flares in 2005 and 2008, they share very similar timescales (similar to day), peak fluxes (Phi(>0.35 TeV) similar or equal to (1-3) x 10(-11) photons cm(-2) s(-1)), and VHE spectra. VLBA radio observations of 43 GHz of the inner jet regions indicate no enhanced flux in 2010 in contrast to observations in 2008, where an increase of the radio flux of the innermost core regions coincided with a VHE flare. On the other hand, Chandra X-ray observations taken similar to 3 days after the peak of the VHE gamma-ray emission reveal an enhanced flux from the core (flux increased by factor similar to 2; variability timescale <2 days). The long-term (2001-2010) multi-wavelength (MWL) light curve of M 87, spanning from radio to VHE and including data from Hubble Space Telescope, Liverpool Telescope, Very Large Array, and European VLBI Network, is used to further investigate the origin of the VHE gamma-ray emission. No unique, common MWL signature of the three VHE flares has been identified. In the outer kiloparsec jet region, in particular in HST-1, no enhanced MWL activity was detected in 2008 and 2010, disfavoring it as the origin of the VHE flares during these years. Shortly after two of the three flares (2008 and 2010), the X-ray core was observed to be at a higher flux level than its characteristic range (determined from more than 60 monitoring observations: 2002-2009). In 2005, the strong flux dominance of HST-1 could have suppressed the detection of such a feature. Published models for VHE gamma-ray emission from M 87 are reviewed in the light of the new data.
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| 13. |
- Aliu, E., et al.
(author)
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Multiwavelength Observations of the Previously Unidentified Blazar RX J0648.7+1516
- 2011
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 742:2
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Journal article (peer-reviewed)abstract
- We report on the VERITAS discovery of very high energy (VHE) gamma-ray emission above 200 GeV from the high-frequency-peaked BL Lac (HBL) object RX J0648.7+1516 (GB J0648+1516), associated with 1FGL J0648.8+1516. The photon spectrum above 200 GeV is fitted by a power law dN/dE = F 0(E/E 0)–Γ with a photon index Γ of 4.4 ± 0.8stat ± 0.3syst and a flux normalization F 0 of (2.3 ± 0.5stat ± 1.2sys) × 10–11 TeV–1 cm–2 s–1 with E 0 = 300 GeV. No VHE variability is detected during VERITAS observations of RX J0648.7+1516 between 2010 March 4 and April 15. Following the VHE discovery, the optical identification and spectroscopic redshift were obtained using the Shane 3 m Telescope at the Lick Observatory, showing the unidentified object to be a BL Lac type with a redshift of z = 0.179. Broadband multiwavelength observations contemporaneous with the VERITAS exposure period can be used to subclassify the blazar as an HBL object, including data from the MDM observatory, Swift-UVOT, and X-Ray Telescope, and continuous monitoring at photon energies above 1 GeV from the FermiLarge Area Telescope (LAT). We find that in the absence of undetected, high-energy rapid variability, the one-zone synchrotron self-Compton (SSC) model overproduces the high-energy gamma-ray emission measured by the Fermi-LAT over 2.3 years. The spectral energy distribution can be parameterized satisfactorily with an external-Compton or lepto-hadronic model, which have two and six additional free parameters, respectively, compared to the one-zone SSC model.
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| 14. |
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| 15. |
- Artigas Soler, María, et al.
(author)
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
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Journal article (peer-reviewed)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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| 16. |
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| 17. |
- Graff, M., et al.
(author)
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Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
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In: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Journal article (peer-reviewed)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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| 18. |
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| 19. |
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| 20. |
- He, J., et al.
(author)
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Development and Evaluation of an Ensemble-Based Data Assimilation System for Regional Reanalysis Over the Tibetan Plateau and Surrounding Regions
- 2019
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In: Journal of Advances in Modeling Earth Systems. - 1942-2466. ; 11:8, s. 2503-2522
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Journal article (peer-reviewed)abstract
- The Tibetan Plateau is regarded as the Earth's Third Pole, which is the source region of several major rivers that impact more 20% the world population. This high‐altitude region is reported to have been undergoing much greater rate of weather changes under global warming, but the existing reanalysis products are inadequate for depicting the state of the atmosphere, particularly with regard to the amount of precipitation and its diurnal cycle. An ensemble Kalman filter (EnKF) data assimilation system based on the limited‐area Weather Research and Forecasting (WRF) model was evaluated for use in developing a regional reanalysis over the Tibetan Plateau and the surrounding regions. A 3‐month prototype reanalysis over the summer months (June−August) of 2015 using WRF‐EnKF at a 30‐km grid spacing to assimilate nonradiance observations from the Global Telecommunications System was developed and evaluated against independent sounding and satellite observations in comparison to the ERA‐Interim and fifth European Centre for Medium‐Range Weather Forecasts Reanalysis (ERA5) global reanalysis. Results showed that both the posterior analysis and the subsequent 6‐ to 12‐hr WRF forecasts of the prototype regional reanalysis compared favorably with independent sounding observations, satellite‐based precipitation versus those from ERA‐Interim and ERA5 during the same period. In particular, the prototype regional reanalysis had clear advantages over the global reanalyses of ERA‐Interim and ERA5 in the analysis accuracy of atmospheric humidity, as well as in the subsequent downscale‐simulated precipitation intensity, spatial distribution, diurnal evolution, and extreme occurrence.
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| 21. |
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| 22. |
- Lee, Sang Hwui, et al.
(author)
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Fine keyed alignment and bonding for wafer-level 3D ICs
- 2006
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In: MATERIALS RESEARCH SOCIETY SYMPOSIUM PROCEEDINGS. - WARRENDALE, PA : MATERIALS RESEARCH SOCIETY. ; , s. 433-438
-
Conference paper (peer-reviewed)abstract
- Precise wafer-to-wafer alignment accuracy is crucial to interconnecting circuits on different wafers in three dimensional integrated circuits. We discuss the use of fabricated structures on wafer surfaces to mechanically achieve higher alignment accuracy than can be achieved with our existing (baseline) alignment protocol. The keyed alignment structures rely on structures with tapered side-walls that can slide into each after two wafers are "pre-aligned" using our baseline alignment protocol. Results indicate that alignment accuracy is about a quarter micron, well below the one micron alignment accuracy obtained in our baseline alignment procedure using commercial state-of-the-art wafer alignment equipment. In addition to improving alignment, the alignment structures also hinder undesirable bonding-induced misalignment. The keyed alignment structures are also promising for nano-imprint lithography.
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| 23. |
- Leong, D. P., et al.
(author)
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Reference ranges of handgrip strength from 125,462 healthy adults in 21 countries: a prospective urban rural epidemiologic (PURE) study
- 2016
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In: Journal of cachexia, sarcopenia and muscle. - : Wiley. - 2190-5991 .- 2190-5991. ; 7:5, s. 535-546
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Journal article (peer-reviewed)abstract
- BACKGROUND: The measurement of handgrip strength (HGS) has prognostic value with respect to all-cause mortality, cardiovascular mortality and cardiovascular disease, and is an important part of the evaluation of frailty. Published reference ranges for HGS are mostly derived from Caucasian populations in high-income countries. There is a paucity of information on normative HGS values in non-Caucasian populations from low- or middle-income countries. The objective of this study was to develop reference HGS ranges for healthy adults from a broad range of ethnicities and socioeconomically diverse geographic regions. METHODS: HGS was measured using a Jamar dynamometer in 125,462 healthy adults aged 35-70 years from 21 countries in the Prospective Urban Rural Epidemiology (PURE) study. RESULTS: HGS values differed among individuals from different geographic regions. HGS values were highest among those from Europe/North America, lowest among those from South Asia, South East Asia and Africa, and intermediate among those from China, South America, and the Middle East. Reference ranges stratified by geographic region, age, and sex are presented. These ranges varied from a median (25th-75th percentile) 50 kg (43-56 kg) in men <40 years from Europe/North America to 18 kg (14-20 kg) in women >60 years from South East Asia. Reference ranges by ethnicity and body-mass index are also reported. CONCLUSIONS: Individual HGS measurements should be interpreted using region/ethnic-specific reference ranges.
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| 26. |
- Lin, Q., et al.
(author)
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Performance of the WRF Model at the Convection-Permitting Scale in Simulating Snowfall and Lake-Effect Snow Over the Tibetan Plateau
- 2023
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In: Journal of Geophysical Research-Atmospheres. - 2169-897X. ; 128:16
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Journal article (peer-reviewed)abstract
- This study investigated the performance of the Weather Research Forecasting (WRF) model at 4-km horizontal grid spacing in simulating precipitation, 2 m air temperature (T2), snowfall, and lake-effect snow (October 4-8, 2018) over the Tibetan Plateau (TP). Multiple simulations with different physical parameterization schemes (PPSs), including two planetary boundary layer schemes (Yonsei University and Mellor-Yamada-Janjic), no cumulus and multi-scale Kain-Fritsch, two land surface models (Noah and Noah-MP), and two microphysics schemes (Thompson and Milbrandt), were conducted and compared. Compared with gauge observations, all PPSs simulate mean daily precipitation with mean relative errors (MREs) of 27.7%-53.6%. Besides, spatial correlation coefficients (SCCs) between simulated and observed mean daily precipitation range from 0.56 to 0.71. For simulations of T2, all PPSs perform similarly well, even though the mean cold biases are up to about 3 degrees C. Meanwhile, all PPSs exhibit acceptable performance in simulating spatial distributions of snow depth, snow cover, and snowfall amount, with SCCs of 0.37-0.65 between simulations and observations. However, the WRF simulations significantly overestimate snow depth (similar to 0.4 cm mean error) and snowfall amount (MREs >372%). The Milbrandt scheme slightly outperforms the other PPSs in simulating snow-related variable magnitudes. Due to their inaccurate temperature and airflow modeling over the lake surface and its surroundings, none of the WRF simulations well reproduce the characteristics that more snow occurs over the lake and downwind area. Overall, this study provides a useful reference for future convection-permitting climate modeling of snow or other extreme events when using the WRF model in the TP and other alpine regions. Plain Language Summary Snow falls frequently in cold seasons, especially in alpine regions. When there is a lake, a very interesting snowfall phenomenon named lake-effect snow may happen, that is, more snow occurred over the lake and downwind areas. However, the lake-effect snow caused by large lakes over the Tibetan Plateau (TP) may induce snow disaster events. Thus, conducting reliable simulations of lake-effect snow events are essential for understanding the mechanism of these particular events over the TP. This study investigated the performance of the numerical model in simulating precipitation, 2 m air temperature (T2), snowfall, and lake-effect snow (October 4-8, 2018) over the TP. The results show that the simulated precipitation and T2 perform reasonably well, although wet and cold biases are observed. However, the investigated numerical model fails to reproduce the characteristics of this event well, which may be due to the inaccurate temperature and airflow modeling over the lake surface and its surroundings. Continued improvement is needed for future modeling. Hence, this study provides some suggestions for future numerical modeling of lake-effect snow or other snow events over the TP and other alpine regions.
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| 27. |
- Luo, Ning, et al.
(author)
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Band-inverted gaps in InAs/GaSb and GaSb/InAs core-shell nanowires
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- The [111]-oriented InAs/GaSb and GaSb/InAs core-shell nanowires have been studied by the 8 × 8 Luttinger-Kohn "Equation missing" Hamiltonian to search for non-vanishing fundamental gaps between inverted electron and hole bands. We focus on the variations of the band-inverted fundamental gap, the hybridization gap, and the effective gap with the core radius and shell thickness of the nanowires. The evolutions of all the energy gaps with the structural parameters are shown to be dominantly governed by the effect of quantum confinement. With a fixed core radius, a band-inverted fundamental gap exists only at intermediate shell thicknesses. The maximum band-inverted gap found is ~4.4 meV for GaSb/InAs and ~3.5 meV for InAs/GaSb core-shell nanowires, and for the GaSb/InAs core-shell nanowires the gap persists over a wider range of geometrical parameters. The intrinsic reason for these differences between the two types of nanowires is that in the shell the electron-like states of InAs is more delocalized than the hole-like state of GaSb, while in the core the hole-like state of GaSb is more delocalized than the electron-like state of InAs, and both favor a stronger electron-hole hybridization.
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| 31. |
- Rubens-Augustson, Taylor, et al.
(author)
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Healthcare provider perspectives on the uptake of the human papillomavirus vaccine among newcomers to Canada : a qualitative study
- 2019
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In: Human Vaccines and Immunotherapeutics. - : Informa UK Limited. - 2164-5515 .- 2164-554X. ; 15:7-8, s. 1697-1707
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Journal article (peer-reviewed)abstract
- Human papillomavirus is among the most common sexually transmitted infections in the world. Newcomers, defined in Canada as foreign-born individuals who are either immigrants or refugees, but may also include students and undocumented migrants, face numerous barriers to HPV vaccination. This study sought to understand, from the perspective of healthcare providers, barriers and facilitators to HPV vaccination, and recommendations to improve HPV vaccine uptake among newcomers. Semi-structured interviews were conducted with 10 healthcare providers between March and April 2018. Data were analyzed at the manifest level using a Qualitative Content Analysis approach. Categories of barriers to vaccination included: access, communication, knowledge, culture, and provider-related factors. Facilitators included targeted health promotion; understanding the relevance of HPV vaccination; trusting the healthcare system; and cultural sensitivity. Two overarching recommendations were to publicly fund the HPV vaccine, and enhance language- and culturally-appropriate health promotion activities. Further research should explore informational desires and needs from the perspective of newcomers to inform strategies to promote equitable HPV vaccine coverage.
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| 32. |
- Wang, Z., et al.
(author)
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Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
- 2022
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 54:9, s. 1332-1344
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Journal article (peer-reviewed)abstract
- Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention. Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.
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| 33. |
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| 34. |
- Wu, Q, et al.
(author)
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IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms
- 2021
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In: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 9:6
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Journal article (peer-reviewed)abstract
- Pharmacological autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds on a robotized fluorescence microscopy platform to identify novel autophagy inducers.ResultsHere, we report the discovery of picropodophyllin (PPP) as a potent inducer of autophagic flux that acts on-target, as an inhibitor of the tyrosine kinase activity of the insulin-like growth factor-1 receptor (IGF1R). Thus, PPP lost its autophagy-stimulatory activity in cells engineered to lack IGF1R or to express a constitutively active AKT serine/threonine kinase 1 (AKT1) mutant. When administered to cancer-bearing mice, PPP improved the therapeutic efficacy of chemoimmunotherapy with a combination of immunogenic cytotoxicants and programmed cell death 1 (PDCD1, better known as PD-1) blockade. These PPP effects were lost when tumors were rendered PPP-insensitive or autophagy-incompetent. In combination with chemotherapy, PPP enhanced the infiltration of tumors by cytotoxic T lymphocytes, while reducing regulatory T cells. In human triple-negative breast cancer patients, the activating phosphorylation of IGF1R correlated with inhibited autophagy, an unfavorable local immune profile, and poor prognosis.ConclusionAltogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of cancer in conjunction with chemoimmunotherapies.
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| 35. |
- Wuttke, Matthias, et al.
(author)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 36. |
- Zhou, Y., et al.
(author)
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Roles of miRNAs in microcystin-LR-induced Sertoli cell toxicity
- 2015
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In: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 287:1, s. 1-8
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Journal article (peer-reviewed)abstract
- Microcystin (MC)-LR, a cyclic heptapeptide, is a potent reproductive system toxin. To understand the molecular mechanisms of MC-induced reproductive system cytotoxicity, we evaluated global changes of miRNA and mRNA expression in mouse Sertoli cells following MC-LR treatment. Our results revealed that the exposure to MC-LR resulted in an altered miRNA expression profile that might be responsible for the modulation of mRNA expression. Bio-functional analysis indicated that the altered genes were involved in specific cellular processes, including cell death and proliferation. Target gene analysis suggested that junction injury in Sertoli cells exposed to MC-LR might be mediated by miRNAs through the regulation of the Sertoli cell-Sertoli cell pathway. Collectively, these findings may enhance our understanding on the modes of action of MC-LR on mouse Sertoli cells as well as the molecular mechanisms underlying the toxicity of MC-LR on the male reproductive system. (C) 2015 Elsevier Inc. All rights reserved.
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