| 1. |
- Wessel, Jennifer, et al.
(author)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Journal article (peer-reviewed)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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| 2. |
- Bozek, Katarzyna, et al.
(author)
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Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness.
- 2014
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In: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885. ; 12:5
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Journal article (peer-reviewed)abstract
- Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys.
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| 3. |
- Hu, Yuning, et al.
(author)
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Cooking methods affect the intake of per- and polyfluoroalkyl substances (PFASs) from grass carp
- 2020
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In: Ecotoxicology and Environmental Safety. - : Academia Press. - 0147-6513 .- 1090-2414. ; 203
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Journal article (peer-reviewed)abstract
- Consumption of fish is one of the predominant sources of human exposure to per- and polyfluoroalkyl substances (PFASs). In this study, the effect of various cooking methods (boiling, steaming, grilling and frying) on the levels of PFASs in fish muscle and the intake of PFASs was explored by using grass carp collected from Tangxun Lake, Wuhan, China. Perfluorooctane sulfonate (PFOS) was the predominant PFASs in raw fish fillets, with the concentrations ranging from 59.6 to 136 ng/g ww, followed by perfluorobutane sulfonate (PFBS) (7.73-51.9 ng/g ww). The concentrations of long-chain PFASs in fish increased after cooking, while those of short-chain PFASs decreased. The amounts of PFASs in the cooked fish fillets decreased except PFOS. Short-chain PFASs, including PFBS and perfluoroheptanoic acid (PFHpA), were dominant in cooking juice. The highest amounts of PFBS in the juices were observed after boiling and frying, even higher than those in cooked fish fillets, suggesting that the release of short-chain PFASs to the cooking juices could not be neglected. Based on these results, the intake of short-chain PFASs amount through cooked fish fillets slightly decreased, but the intake of PFOS amount increased. However, consumption of cooking juice (fish soup) could increase the exposure risk of PFBS. Comprehensively considering the increase of PFOS and decrease of total PFASs, boiling may be the relatively better method to cook fish. As PFASs are ubiquitous and inevitable in aquatic food, it is thus important to choose appropriate cooking processes and dietary habits for reducing the intake of different PFASs from fish.
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| 4. |
- Jiang, Xiangyi, et al.
(author)
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Molecular design opportunities presented by solvent-exposed regions of target proteins
- 2019
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In: Medicinal research reviews (Print). - : John Wiley & Sons. - 0198-6325 .- 1098-1128. ; 39:6, s. 2194-2238
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Research review (peer-reviewed)abstract
- Solvent-exposed regions, or solvent-filled pockets, within or adjacent to the ligand-binding sites of drug-target proteins provide opportunities for substantial modifications of existing small-molecular drug molecules without serious loss of activity. In this review, we present recent selected examples of exploitation of solvent-exposed regions of proteins in drug design and development from the recent medicinal-chemistry literature.
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| 5. |
- Joshi, Peter K, et al.
(author)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Journal article (peer-reviewed)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 6. |
- Liu, Lizheng, et al.
(author)
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A FPGA-based Hardware Accelerator for Bayesian Confidence Propagation Neural Network
- 2020
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In: 2020 IEEE Nordic Circuits and Systems Conference, NORCAS 2020 - Proceedings. - : Institute of Electrical and Electronics Engineers (IEEE).
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Conference paper (peer-reviewed)abstract
- The Bayesian Confidence Propagation Neural Network (BCPNN) has been applied in higher level of cognitive intelligence (e.g. working memory, associative memory). However, in the spike-based version of this learning rule the pre-, postsynaptic and coincident activity is traced in three low-passfiltering stages, the calculation processes of weight update are very computationally intensive. In this paper, a hardware architecture of the updating process for lazy update mode is proposed for updating 8 local synaptic state variables. The parallelism by decomposing the calculation steps of formulas based on the inherent data dependencies is optimized. The FPGA-based hardware accelerator of BCPNN is designed and implemented. The experimental results show the updating process on FPGA can be accomplished within 110 ns with a clock frequency of 200 MHz, the updating speed is greatly enhanced compared with the CPU test. The trade-off between performance, accuracy and resources on dedicated hardware is evaluated, and the impact of the module reuse on resource consumption and computing performance is evaluated.
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| 7. |
- Ouyang, Yuezhen, et al.
(author)
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Cancer-fighting potentials of algal polysaccharides as nutraceuticals
- 2021
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In: Food Research International. - : Elsevier. - 0963-9969 .- 1873-7145. ; 147
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Journal article (peer-reviewed)abstract
- Cancer has been listed as one of the world's five incurable diseases by the World Health Organization and causes tens of thousands of deaths every year. Unfortunately, anticancer agents either show limited efficacy or show serious side effects. The algae possess high nutritional value and their polysaccharides have a variety of biological activities, especially anti-cancer and immunomodulatory properties. Algal polysaccharides exert anticancer effects by inducing apoptosis, cell cycle arrest, anti-angiogenesis, and regulating intestinal flora and immune function. Algal polysaccharides can be combined with nanoparticles and other drugs to reduce the side effects caused by chemotherapy and increase the anticancer effects. This review shows the signal pathways related to the anti-cancer mechanisms of algal polysaccharides, including their influence on intestinal flora and immune regulation, the application of nanoparticles, and the effects on combination therapy and clinical trials of cancer treatments.
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| 8. |
- Scott, Robert A., et al.
(author)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
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Journal article (peer-reviewed)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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| 9. |
- Wu, Gaochan, et al.
(author)
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Overview of Recent Strategic Advances in Medicinal Chemistry
- 2019
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 62:21, s. 9375-9414
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Journal article (peer-reviewed)abstract
- Introducing novel strategies, concepts, and technologies that speed up drug discovery and the drug development cycle is of great importance both in the highly competitive pharmaceutical industry as well as in academia. This Perspective aims to present a "big-picture" overview of recent strategic innovations in medicinal chemistry and drug discovery.
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| 10. |
- Xiong, Shaobing, et al.
(author)
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Additive-Induced Synergies of Defect Passivation and Energetic Modification toward Highly Efficient Perovskite Solar Cells
- 2021
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In: Advanced Energy Materials. - : WILEY-V C H VERLAG GMBH. - 1614-6832 .- 1614-6840. ; 11:29
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Journal article (peer-reviewed)abstract
- Defect passivation via additive and energetic modification via interface engineering are two effective strategies for achieving high-performance perovskite solar cells (PSCs). Here, the synergies of pentafluorophenyl acrylate when used as additive, in which it not only passivates surface defect states but also simultaneously modifies the energetics at the perovskite/Spiro-OMeTAD interface to promote charge transport, are shown. The additive-induced synergy effect significantly suppresses both defect-assisted recombination and interface carrier recombination, resulting in a device efficiency of 22.42% and an open-circuit voltage of 1.193 V with excellent device stability. The two photovoltaic parameters are among the highest values for polycrystalline CsFormamidinium/Methylammonium (FAMA)/FAMA based n-i-p structural PSCs using low-cost silver electrodes reported to date. The findings provide a promising approach by choosing the dual functional additive to enhance efficiency and stability of PSCs.
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