SwePub - search: WFRF:(Yang Qiong)

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1.	Klionsky, Daniel J., et al. (author) Guidelines for the use and interpretation of assays for monitoring autophagy 2012 In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544 Research review (peer-reviewed)abstract In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
2.	Yang, Kunpeng, et al. (author) North Atlantic Ocean–Originated Multicentennial Oscillation of the AMOC : A Coupled Model Study 2024 In: Journal of Climate. - 0894-8755 .- 1520-0442. ; 37:9, s. 2789-2807 Journal article (peer-reviewed)abstract Using a CESM1 control simulation, we conduct a follow-up study to advance our earlier theoretical research on the multicentennial oscillation (MCO) of the Atlantic meridional overturning circulation (AMOC). The modeled AMOC MCO primarily arises from internal oceanic processes in the North Atlantic, potentially representing a North Atlantic Ocean–originated mode of AMOC multicentennial variability (MCV) in reality. Specifically, this AMOC MCO is mainly driven by salinity variation in the subpolar upper North Atlantic, which dominates local density variation. Salinity anomaly in the subpolar upper ocean is enhanced by the well-known positive salinity advection feedback that is realized through anomalous advection in the subtropical to subpolar upper ocean. Meanwhile, mean advection moves salinity anomaly in the subtropical intermediate ocean northward, weakening the subpolar upper salinity anomaly and leading to its phase change. The salinity anomalies have a clear three-dimensional life cycle around the North Atlantic. The mechanism and time scale of the modeled AMOC MCO are consistent with our earlier theoretical studies. In the theoretical model, artificially deactivating either the anomalous or mean advection in the AMOC upper branch prevents it from exhibiting AMOC MCO, underscoring the indispensability of both the anomalous and mean advections in this North Atlantic Ocean–originated AMOC MCO. In our coupled model simulation, the South Atlantic and Southern Oceans do not exhibit variabilities synchronous with the AMOC MCO; the Arctic Ocean’s contribution to the subpolar upper salinity anomaly is much weaker than the North Atlantic. Hence, this North Atlantic Ocean–originated AMOC MCO is distinct from the previously proposed Southern Ocean–originated and Arctic Ocean–originated AMOC MCOs.
3.	Li, Cai, et al. (author) Two Antarctic penguin genomes reveal insights into their evolutionary history and molecular changes related to the Antarctic environment 2014 In: GigaScience. - 2047-217X. ; 3 Journal article (peer-reviewed)abstract Background: Penguins are flightless aquatic birds widely distributed in the Southern Hemisphere. The distinctive morphological and physiological features of penguins allow them to live an aquatic life, and some of them have successfully adapted to the hostile environments in Antarctica. To study the phylogenetic and population history of penguins and the molecular basis of their adaptations to Antarctica, we sequenced the genomes of the two Antarctic dwelling penguin species, the Adelie penguin [Pygoscelis adeliae] and emperor penguin [Aptenodytes forsteri]. Results: Phylogenetic dating suggests that early penguins arose similar to 60 million years ago, coinciding with a period of global warming. Analysis of effective population sizes reveals that the two penguin species experienced population expansions from similar to 1 million years ago to similar to 100 thousand years ago, but responded differently to the climatic cooling of the last glacial period. Comparative genomic analyses with other available avian genomes identified molecular changes in genes related to epidermal structure, phototransduction, lipid metabolism, and forelimb morphology. Conclusions: Our sequencing and initial analyses of the first two penguin genomes provide insights into the timing of penguin origin, fluctuations in effective population sizes of the two penguin species over the past 10 million years, and the potential associations between these biological patterns and global climate change. The molecular changes compared with other avian genomes reflect both shared and diverse adaptations of the two penguin species to the Antarctic environment.
4.	Satizabal, Claudia L., et al. (author) Genetic architecture of subcortical brain structures in 38,851 individuals 2019 In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624- Journal article (peer-reviewed)abstract Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
5.	Yang, Haijun, et al. (author) 多百年际气候变率 : 观测、理论与模拟研究 [Multi-centennial climate variability: Observational, theoretical and modeling studies] 2023 In: Chinese Science Bulletin. - 0023-074X .- 2095-9419. ; 68:16, s. 2037-2045 Journal article (peer-reviewed)abstract Research using long-term proxy data suggests the existence of multi-centennial climate variability in the Earth’s climate system. Its origin and mechanism have been bewildering for climatologists and archaeologists for a long time. Considering that the variation of external forcing of the Earth’ climate was relatively small from the mid-Holocene to the pre-industrial time, it is important to investigate the role of internal natural oscillation of the climate system during this period. The Atlantic meridional overturning circulation (AMOC) is thought to be the first candidate for such multi-centennial timescale variability. It is thus critical to investigate systematically the connection between the AMOC and the Earth climate system at this timescale. From the mid-Holocene to the pre-industrial time, the human civilization experienced rapid development. Historical documents in China suggest that in the past 2000 years, the historical climate in China had a low-frequency variation with 200–300 year period, which might have affected the ancient Chinese civilization. The multi-centennial variability of the AMOC may have played a role in the vax and vane of the human civilization.Currently, there is a lack of in-depth studies on the multi-centennial variability of the AMOC. This is mainly due to the following factors. First, the time period of modern instrumental observations is less than 200 years, which is not long enough to confirm the existence of the multi-centennial climate variability. Second, there is a lack of a well-recognized theory that can account for the multi-centennial variability of the AMOC. Third, it is much easier for a researcher to study the Earth climate change due to external forcing than to study the internal variability of the Earth climate system under a stable external forcing, particularly at this long timescale.Several coupled Earth climate system models have simulated the multi-centennial variability of the AMOC. However, the results from both coupled models and proxy data include comprehensive factors. To fundamentally understand the multi-centennial climate variability, a simple theoretical model is needed. Unfortunately, there is a lack of theoretical studies on the internal multi-centennial variability under the background of stable climate.In this work, we systematically review the current studies on multi-centennial climate variability from observational, theoretical and coupled modeling aspects. We hope that by proposing innovative theory and creative climate modeling approach, we can identify the intrinsic mode of multi-centennial climate variability, picture its spatial pattern, decipher the origin of its timescale, and reveal its internal mechanism. The outcome of these studies will help us understand deeply the wax and wane of the human civilization during the past several thousand years. It will also be of great significance for a better prediction of the long-term trend of future climate change.
6.	Zhang, Zebin, et al. (author) Whole-genome resequencing reveals signatures of selection and timing of duck domestication 2018 In: GigaScience. - : OXFORD UNIV PRESS. - 2047-217X. ; 7:4 Journal article (peer-reviewed)abstract Background: The genetic basis of animal domestication remains poorly understood, and systems with substantial phenotypic differences between wild and domestic populations are useful for elucidating the genetic basis of adaptation to new environments as well as the genetic basis of rapid phenotypic change. Here, we sequenced the whole genome of 78 individual ducks, from two wild and seven domesticated populations, with an average sequencing depth of 6.42X per individual. Results: Our population and demographic analyses indicate a complex history of domestication, with early selection for separate meat and egg lineages. Genomic comparison of wild to domesticated populations suggests that genes that affect brain and neuronal development have undergone strong positive selection during domestication. Our F-ST analysis also indicates that the duck white plumage is the result of selection at the melanogenesis-associated transcription factor locus. Conclusions: Our results advance the understanding of animal domestication and selection for complex phenotypic traits.
7.	Boeger, Carsten A., et al. (author) CUBN Is a Gene Locus for Albuminuria 2011 In: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 22:3, s. 555-570 Journal article (peer-reviewed)abstract Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 x 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
8.	Brierley, Chris M., et al. (author) Large-scale features and evaluation of the PMIP4-CMIP6 midHolocene simulations 2020 In: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 16:5, s. 1847-1872 Journal article (peer-reviewed)abstract The mid-Holocene (6000 years ago) is a standard time period for the evaluation of the simulated response of global climate models using palaeoclimate reconstructions. The latest mid-Holocene simulations are a palaeoclimate entry card for the Palaeoclimate Model Intercomparison Project (PMIP4) component of the current phase of the Coupled Model Intercomparison Project (CMIP6) - hereafter referred to as PMIP4-CMIP6. Here we provide an initial analysis and evaluation of the results of the experiment for the mid-Holocene. We show that state-of-the-art models produce climate changes that are broadly consistent with theory and observations, including increased summer warming of the Northern Hemisphere and associated shifts in tropical rainfall. Many features of the PMIP4-CMIP6 simulations were present in the previous generation (PMIP3-CMIP5) of simulations. The PMIP4-CMIP6 ensemble for the mid-Holocene has a global mean temperature change of -0.3 K, which is -0.2K cooler than the PMIP3-CMIP5 simulations predominantly as a result of the prescription of realistic greenhouse gas concentrations in PMIP4-CMIP6. Biases in the magnitude and the sign of regional responses identified in PMIP3-CMIP5, such as the amplification of the northern African monsoon, precipitation changes over Europe, and simulated aridity in mid-Eurasia, are still present in the PMIP4-CMIP6 simulations. Despite these issues, PMIP4-CMIP6 and the mid-Holocene provide an opportunity both for quantitative evaluation and derivation of emergent constraints on the hydrological cycle, feedback strength, and potentially climate sensitivity.
9.	Cao, Ning, 1987-, et al. (author) The role of internal feedbacks in sustaining multi-centennial variability of the Atlantic Meridional Overturning Circulation revealed by EC-Earth3-LR simulations 2023 In: Earth and Planetary Science Letters. - 0012-821X .- 1385-013X. ; 621 Journal article (peer-reviewed)abstract A significant multi-centennial climate variability with a distinct peak at approximately 200 years is observed in a pre-industrial (PI) control simulation using the EC-Earth3-LR climate model. This oscillation originates predominately from the North Atlantic and displays a strong association with the Atlantic Meridional Overturning Circulation (AMOC). Our study identifies the interplay between salinity advection feedback and vertical mixing in the subpolar North Atlantic as key roles in providing the continues internal energy source to maintain this multi-centennial oscillation. The perturbation flow of mean subtropical-subpolar salinity gradients serves as positive feedback to sustain the AMOC anomaly, while the mean advection of salinity anomalies and the vertical mixing or convection acts as negative feedback, constraining the AMOC anomaly. Notably, this low-frequency variability persists even in a warmer climate with weakened AMOC, emphasizing the robustness of the salinity advection feedback mechanism.
10.	Carraro, Marco, et al. (author) Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI 2017 In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 38:9, s. 1042-1050 Journal article (peer-reviewed)abstract Correct phenotypic interpretation of variants of unknown significance for cancer-associated genes is a diagnostic challenge as genetic screenings gain in popularity in the next-generation sequencing era. The Critical Assessment of Genome Interpretation (CAGI) experiment aims to test and define the state of the art of genotype-phenotype interpretation. Here, we present the assessment of the CAGI p16INK4a challenge. Participants were asked to predict the effect on cellular proliferation of 10 variants for the p16INK4a tumor suppressor, a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene. Twenty-two pathogenicity predictors were assessed with a variety of accuracy measures for reliability in a medical context. Different assessment measures were combined in an overall ranking to provide more robust results. The R scripts used for assessment are publicly available from a GitHub repository for future use in similar assessment exercises. Despite a limited test-set size, our findings show a variety of results, with some methods performing significantly better. Methods combining different strategies frequently outperform simpler approaches. The best predictor, Yang&Zhou lab, uses a machine learning method combining an empirical energy function measuring protein stability with an evolutionary conservation term. The p16INK4a challenge highlights how subtle structural effects can neutralize otherwise deleterious variants.
11.	Chasman, Daniel I., et al. (author) Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function 2012 In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343 Journal article (peer-reviewed)abstract In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
12.	Chen, Qiman, et al. (author) Flexible Service Chain Mapping in Server-Centric Optical Datacenter Networks 2018 In: 2018 ASIA COMMUNICATIONS AND PHOTONICS CONFERENCE (ACP). - : IEEE. - 9781538661581 Conference paper (peer-reviewed)abstract We investigate flexible service chain mapping in server-centric optical terconnects, handling virtual network function (VNF) dependency operly. Blocking probability decreases by a factor of 10 when signing multiple VNFs in the same server is allowed.
13.	de Vries, Paul S., et al. (author) Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study 2017 In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:1 Journal article (peer-reviewed)abstract An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5x10(-8) is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5x10(-8)), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.
14.	Debette, Stephanie, et al. (author) Identification of cis- and trans-Acting Genetic Variants Explaining Up to Half the Variation in Circulating Vascular Endothelial Growth Factor Levels 2011 In: Circulation Research. - 0009-7330 .- 1524-4571. ; 109:5, s. 554-563 Journal article (peer-reviewed)abstract Rationale: Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings. Objective: Our aim was to identify genetic variants associated with circulating VEGF levels, using an unbiased genome-wide approach, and to explore their functional significance with gene expression and pathway analysis. Methods and Results: We undertook a genome-wide association study of serum VEGF levels in 3527 participants of the Framingham Heart Study, with preplanned replication in 1727 participants from 2 independent samples, the STANISLAS Family Study and the Prospective Investigation of the Vasculature in Uppsala Seniors study. One hundred forty single nucleotide polymorphism (SNPs) reached genome-wide significance (P<5x10(-8)). We found evidence of replication for the most significant associations in both replication datasets. In a conditional genome-wide association study, 4 SNPs mapping to 3 chromosomal regions were independently associated with circulating VEGF levels: rs6921438 and rs4416670 (6p21.1, P=6.11x10(-506) and P=1.47x10(-12)), rs6993770 (8q23.1, P=2.50x10(-16)), and rs10738760 (9p24.2, P=1.96x10(-34)). A genetic score including these 4 SNPs explained 48% of the heritability of serum VEGF levels. Six of the SNPs that reached genome-wide significance in the genome-wide association study were significantly associated with VEGF messenger RNA levels in peripheral blood mononuclear cells. Ingenuity pathway analyses showed found plausible biological links between VEGF and 2 novel genes in these loci (ZFPM2 and VLDLR). Conclusions: Genetic variants explaining up to half the heritability of serum VEGF levels were identified. These new insights provide important clues to the pathways regulating circulating VEGF levels.
15.	Delling, Francesca N, et al. (author) Heritability of Mitral Regurgitation : Observations From the Framingham Heart Study and Swedish Population 2017 In: Circulation: Cardiovascular Genetics. - 1942-325X. ; 10:5 Journal article (peer-reviewed)
16.	Ding, Yang, et al. (author) Artificial intelligence-assisted point-of-care testing system for ultrafast and quantitative detection of drug-resistant bacteria 2023 In: SMARTMAT. - : WILEY. - 2766-8525. Journal article (peer-reviewed)abstract As one of the major causes of antimicrobial resistance, beta-lactamase develops rapidly among bacteria. Detection of beta-lactamase in an efficient and low-cost point-of-care testing (POCT) way is urgently needed. However, due to the volatile environmental factors, the quantitative measurement of current POCT is often inaccurate. Herein, we demonstrate an artificial intelligence (AI)-assisted mobile health system that consists of a paper-based beta-lactamase fluorogenic probe analytical device and a smartphone-based AI cloud. An ultrafast broad-spectrum fluorogenic probe (B1) that could respond to beta-lactamase within 20 s was first synthesized, and the detection limit was determined to be 0.13 nmol/L. Meanwhile, a three-dimensional microfluidic paper-based analytical device was fabricated for integration of B1. Also, a smartphone-based AI cloud was developed to correct errors automatically and output results intelligently. This smart system could calibrate the temperature and pH in the beta-lactamase level detection in complex samples and mice infected with various bacteria, which shows the problem-solving ability in interdisciplinary research, and demonstrates potential clinical benefits.
17.	Djoussé, Luc, et al. (author) Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. 2004 In: Neurogenetics. - : Springer Science and Business Media LLC. - 1364-6745 .- 1364-6753. ; 5:2, s. 109-14 Journal article (peer-reviewed)abstract Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests that one modifier may reside in the region close to the HD gene itself. We used data from 535 HD participants of the New England Huntington cohort and the HD MAPS cohort to assess whether AO was influenced by any of the three markers in the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo box 7, HOX7), Delta2642 (within the HD coding sequence), and BJ56 ( D4S127). Suggestive evidence for an association was seen between MSX1 alleles and AO, after adjustment for normal CAG repeat, expanded repeat, and their product term (model P value 0.079). Of the variance of AO that was not accounted for by HD and normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals with MSX1 genotype 3/3 tended to have younger AO. No association was found between Delta2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous studies suggesting that there may be a significant genetic modifier for AO in HD in the 4p16 region. Furthermore, the modifier may be present on both HD and normal chromosomes bearing the 3 allele of the MSX1 marker.
18.	Döscher, Ralf, et al. (author) The EC-Earth3 Earth system model for the Coupled Model Intercomparison Project 6 2022 In: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 15:7, s. 2973-3020 Journal article (peer-reviewed)abstract The Earth system model EC-Earth3 for contributions to CMIP6 is documented here, with its flexible coupling framework, major model configurations, a methodology for ensuring the simulations are comparable across different high-performance computing (HPC) systems, and with the physical performance of base configurations over the historical period. The variety of possible configurations and sub-models reflects the broad interests in the EC-Earth community. EC-Earth3 key performance metrics demonstrate physical behavior and biases well within the frame known from recent CMIP models. With improved physical and dynamic features, new Earth system model (ESM) components, community tools, and largely improved physical performance compared to the CMIP5 version, EC-Earth3 represents a clear step forward for the only European community ESM. We demonstrate here that EC-Earth3 is suited for a range of tasks in CMIP6 and beyond.
19.	Gorski, Mathias, et al. (author) 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function. 2017 In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7 Journal article (peer-reviewed)abstract HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
20.	Gorski, Mathias, et al. (author) Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies 2022 In: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639 Journal article (peer-reviewed)abstract Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
21.	Gorski, Mathias, et al. (author) Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline 2021 In: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939 Journal article (peer-reviewed)abstract Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
22.	Gravgaard Askjær, Thomas, et al. (author) Multi-centennial Holocene climate variability in proxy records and transient model simulations 2022 In: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 296 Journal article (peer-reviewed)abstract Variability on centennial to multi-centennial timescales is mentioned as a feature in reconstructions of the Holocene climate. As more long transient model simulations with complex climate models become available and efforts have been made to compile large proxy databases, there is now a unique opportunity to study multi-centennial variability with greater detail and a large amount of data than earlier. This paper presents a spectral analysis of transient Holocene simulations from 9 models and 120 proxy records to find the common signals related to oscillation periods and geographic dependencies and discuss the implications for the potential driving mechanisms. Multi-centennial variability is significant in most proxy records, with the dominant oscillation periods around 120–130 years and an average of 240 years. Spectra of model-based global mean temperature (GMT) agree well with proxy evidence with significant multi-centennial variability in all simulations with the dominant oscillation periods around 120–150 years. It indicates a comparatively good agreement between model and proxy data. A lack of latitudinal dependencies in terms of oscillation period is found in both the model and proxy data. However, all model simulations have the highest spectral density distributed over the Northern hemisphere high latitudes, which could indicate a particular variability sensitivity or potential driving mechanisms in this region. Five models also have differentiated forcings simulations with various combinations of forcing agents. Significant multi-centennial variability with oscillation periods between 100 and 200 years is found in all forcing scenarios, including those with only orbital forcing. The different forcings induce some variability in the system. Yet, none appear to be the predominant driver based on the spectral analysis. Solar irradiance has long been hypothesized to be a primary driver of multi-centennial variability. However, all the simulations without this forcing have shown significant multi-centennial variability. The results then indicate that internal mechanisms operate on multi-centennial timescales, and the North Atlantic-Arctic is a region of interest for this aspect.
23.	Haycock, Philip C., et al. (author) Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study 2017 In: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651 Journal article (peer-reviewed)abstract IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
24.	Helsen, Michiel M., et al. (author) On the importance of the albedo parameterization for the mass balance of the Greenland ice sheet in EC-Earth 2017 In: The Cryosphere. - : Copernicus GmbH. - 1994-0416 .- 1994-0424. ; 11:4, s. 1949-1965 Journal article (peer-reviewed)abstract The albedo of the surface of ice sheets changes as a function of time due to the effects of deposition of new snow, ageing of dry snow, bare ice exposure, melting and run-off. Currently, the calculation of the albedo of ice sheets is highly parameterized within the earth system model EC-Earth by taking a constant value for areas with thick perennial snow cover. This is an important reason why the surface mass balance (SMB) of the Greenland ice sheet (GrIS) is poorly resolved in the model. The purpose of this study is to improve the SMB forcing of the GrIS by evaluating different parameter settings within a snow albedo scheme. By allowing ice-sheet albedo to vary as a function of wet and dry conditions, the spatial distribution of albedo and melt rate improves. Nevertheless, the spatial distribution of SMB in EC-Earth is not significantly improved. As a reason for this, we identify omissions in the current snow albedo scheme, such as separate treatment of snow and ice and the effect of refreezing. The resulting SMB is downscaled from the lower-resolution global climate model topography to the higher-resolution ice-sheet topography of the GrIS, such that the influence of these different SMB climatologies on the long-term evolution of the GrIS is tested by ice-sheet model simulations. From these ice-sheet simulations we conclude that an albedo scheme with a short response time of decaying albedo during wet conditions performs best with respect to long-term simulated ice-sheet volume. This results in an optimized albedo parameterization that can be used in future EC-Earth simulations with an interactive ice-sheet component.
25.	Kang, Nai-xin, et al. (author) Anemoside B4 inhibits enterovirus 71 propagation in mice through upregulating 14-3-3 expression and type I interferon responses 2022 In: Acta Pharmacologica Sinica. - : Springer Nature. - 1671-4083 .- 1745-7254. ; 43, s. 977-991 Journal article (peer-reviewed)abstract Enterovirus 71 (EV71) is the major pathogens of human hand, foot, and mouth disease (HFMD). EV71 efficiently escapes innate immunity responses of the host to cause infection. At present, no effective antiviral drugs for EV71 are available. Anemoside B4 (B4) is a natural saponin isolated from the roots of Pulsatilla chinensis (Bunge) Regel. P. chinensis extracts that shows a wide variety of biological activities. In this study, we investigated the antiviral activities of B4 against EV71 both in cell culture and in suckling mice. We showed that B4 (12.5-200 mu M) dose dependently increased the viability of EV71-infected RD cells with an IC50 value of 24.95 +/- 0.05 mu M against EV71. The antiviral activity of B4 was associated with enhanced interferon (IFN)-beta response, since knockdown of IFN-beta abolished its antiviral activity. We also confirmed that the enhanced IFN response was mediated via activation of retinoic acid-inducible gene I (RIG-I) like receptors (RLRs) pathway, and it was executed by upregulation of 14-3-3 protein, which disrupted the interaction between yes-associated protein (YAP) and interferon regulatory factor 3 (IRF3). By using amino acids in cell culture (SILAC)-based proteomics profiling, we identified the Hippo pathway as the top-ranking functional cluster in B4-treated EV71-infected cells. In vivo experiments were conducted in suckling mice (2-day-old) infected with EV71 and subsequently B4 (200 mg center dot kg(-1) center dot d(-1), i.p.) was administered for 16 days. We showed that B4 administration effectively suppressed EV71 replication and improved muscle inflammation and limb activity. Meanwhile, B4 administration regulated the expressions of HFMD biomarkers IL-10 and IFN-gamma, attenuating complications of EV71 infection. Collectively, our results suggest that B4 could enhance the antiviral effect of IFN-beta by orchestrating Hippo and RLRs pathway, and B4 would be a potential lead compound for developing an anti-EV71 drug.

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