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Sökning: WFRF:(Zheng Jie) > (2015-2019)

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  • Föregående 1[2]34Nästa
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11.
  • Doak, Bradley C, et al. (författare)
  • How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets.
  • 2016
  • Ingår i: Journal of Medicinal Chemistry. - 0022-2623 .- 1520-4804. ; 59:6, s. 2312-2327
  • Tidskriftsartikel (refereegranskat)abstract
    • To improve discovery of drugs for difficult targets, the opportunities of chemical space beyond the rule of 5 (bRo5) were examined by retrospective analysis of a comprehensive set of structures for complexes between drugs and clinical candidates and their targets. The analysis illustrates the potential of compounds far beyond rule of 5 space to modulate novel and difficult target classes that have large, flat, and groove-shaped binding sites. However, ligand efficiencies are significantly reduced for flat- and groove-shape binding sites, suggesting that adjustments of how to use such metrics are required. Ligands bRo5 appear to benefit from an appropriate balance between rigidity and flexibility to bind with sufficient affinity to their targets, with macrocycles and nonmacrocycles being found to have similar flexibility. However, macrocycles were more disk- and spherelike, which may contribute to their superior binding to flat sites, while rigidification of nonmacrocycles lead to rodlike ligands that bind well to groove-shaped binding sites. These insights should contribute to altering perceptions of what targets are considered "druggable" and provide support for drug design in beyond rule of 5 space.
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12.
  • Fanidi, Anouar, et al. (författare)
  • Circulating Folate, Vitamin B6, and Methionine in Relation to Lung Cancer Risk in the Lung Cancer Cohort Consortium (LC3)
  • 2018
  • Ingår i: Journal of the National Cancer Institute. - Oxford University Press. - 0027-8874. ; 110:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown.Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models.Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups.Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.
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13.
  • Feitosa, Mary F., et al. (författare)
  • Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
  • 2018
  • Ingår i: PLoS ONE. - Public library science. - 1932-6203. ; 13:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
14.
  • Hattori, Yocefu, et al. (författare)
  • Simultaneous Hot Electron and Hole Injection upon Excitation of Gold Surface Plasmon
  • 2019
  • Ingår i: Journal of Physical Chemistry Letters. - The American Chemical Society (ACS). - 1948-7185. ; 10:11, s. 3140-3146
  • Tidskriftsartikel (refereegranskat)abstract
    • We have successfully investigated the simultaneous injection of hot electrons and holes upon excitation of gold localized surface plasmon resonance (LSPR). The studies were performed on all-solid-state plasmonic system composed of titanium dioxide (TiO2)/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) (PEDOT:PSS) p-n junctions with gold nanoparticles (Au NPs). The study revealed that both charge carriers are transferred within 200 fs to the respective charge acceptors, exhibiting a free carrier transport behavior. We also confirmed that the transfer of charge carriers are accompanied by change in the initial relaxation dynamics of Au NPs.
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15.
  • Huang, Joyce Y., et al. (författare)
  • Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)
  • 2019
  • Ingår i: International Journal of Cancer. - WILEY. - 0020-7136.
  • Tidskriftsartikel (refereegranskat)abstract
    • Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all p(trend) < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.
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16.
  • Jarfors, Anders E.W., 1963-, et al. (författare)
  • Recent advances in commercial application of the rheometal process in China and Europe
  • 2019
  • Ingår i: Semi-Solid of Alloys and Composites. - Trans Tech Publications. - 9783035713732 - 9783035733730 ; s. 405-410
  • Konferensbidrag (refereegranskat)abstract
    • Recent advances in rheocasting have resulted in significant expansion in the types of products currently in full commercial production. The current paper gives an overview of components in production in Europe and in China produced using the RheoMetal™ process, that has taken the lead in a strong drive towards new heavy-duty applications made from aluminium alloys. In China, the dominating applications are found in the telecom industry. The trend in Europe is more towards marine and automotive applications commonly in fatigue loaded applications. The reason for the choice of rheocasting for complicated shape thin-walled electronics components with requirements is dominated by process yield and by the ability to improve thermal conductivity. The heavy-duty truck chassis thick walled components target weight reduction through design and to sustain fatigue load normally requiring forged components. Common in all applications are seen in production yield, reduced tool wear and reduction of die soldering.
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17.
  • Justice, Anne E, et al. (författare)
  • Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
  • 2019
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036. ; 51:3, s. 452-469
  • Tidskriftsartikel (refereegranskat)abstract
    • Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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18.
  • Kilpeläinen, Tuomas O, et al. (författare)
  • Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
  • 2019
  • Ingår i: Nature Communications. - London : Nature Publishing Group. - 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol- increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
19.
  • Larose, Tricia L, et al. (författare)
  • Circulating cotinine concentrations and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)
  • 2018
  • Ingår i: International Journal of Epidemiology. - Oxford University Press. - 0300-5771. ; 47:6, s. 1760-1771
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine—a nicotine metabolite and biomarker of recent tobacco exposure—provides additional information on lung cancer risk.Methods: The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnostic serum cotinine concentrations were measured in one laboratory on 5364 lung cancer cases and 5364 individually matched controls. We used conditional logistic regression to evaluate the association between circulating cotinine and lung cancer, and assessed if cotinine provided additional risk-discriminative information compared with self-reported smoking (smoking status, smoking intensity, smoking duration), using receiver-operating characteristic (ROC) curve analysis.Results: We observed a strong positive association between cotinine and lung cancer risk for current smokers [odds ratio (OR ) per 500 nmol/L increase in cotinine (OR500): 1.39, 95% confidence interval (CI): 1.32–1.47]. Cotinine concentrations consistent with active smoking (≥115 nmol/L) were common in former smokers (cases: 14.6%; controls: 9.2%) and rare in never smokers (cases: 2.7%; controls: 0.8%). Former and never smokers with cotinine concentrations indicative of active smoking (≥115 nmol/L) also showed increased lung cancer risk. For current smokers, the risk-discriminative performance of cotinine combined with self-reported smoking (AUCintegrated: 0.69, 95% CI: 0.68–0.71) yielded a small improvement over self-reported smoking alone (AUCsmoke: 0.66, 95% CI: 0.64–0.68) (P = 1.5x10–9).Conclusions: Circulating cotinine concentrations are consistently associated with lung cancer risk for current smokers and provide additional risk-discriminative information compared with self-report smoking alone.
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20.
  • Li, Cong, et al. (författare)
  • Impacts of conservation and human development policy across stakeholders and scales
  • 2015
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424. ; 112:24, s. 7396-7401
  • Tidskriftsartikel (refereegranskat)abstract
    • Ideally, both ecosystem service and human development policies should improve human well-being through the conservation of ecosystems that provide valuable services. However, program costs and benefits to multiple stakeholders, and how they change through time, are rarely carefully analyzed. We examine one of China's new ecosystem service protection and human development policies: the Relocation and Settlement Program of Southern Shaanxi Province (RSP), which pays households who opt voluntarily to resettle from mountainous areas. The RSP aims to reduce disaster risk, restore important ecosystem services, and improve human well-being. We use household surveys and biophysical data in an integrated economic cost-benefit analysis for multiple stakeholders. We project that the RSP will result in positive net benefits to the municipal government, and to cross-region and global beneficiaries over the long run along with environment improvement, including improved water quality, soil erosion control, and carbon sequestration. However, there are significant short-run relocation costs for local residents so that poor households may have difficulty participating because they lack the resources to pay the initial costs of relocation. Greater subsidies and subsequent supports after relocation are necessary to reduce the payback period of resettled households in the long run. Compensation from downstream beneficiaries for improved water and from carbon trades could be channeled into reducing relocation costs for the poor and sharing the burden of RSP implementation. The effectiveness of the RSP could also be greatly strengthened by early investment in developing human capital and environment-friendly jobs and establishing long-term mechanisms for securing program goals. These challenges and potential solutions pervade ecosystem service efforts globally.
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