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Abstract Background Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin. Results From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans. Conclusions These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.

We present a combined experimental and theoretical study of the two-dimensional electron states at the iridium-silicide surface of the antiferromagnet GdIr2Si2 above and below the Néel temperature. Using angle-resolved photoemission spectroscopy (ARPES) we find a significant spin-orbit splitting of the surface states in the paramagnetic phase. By means of ab initio density-functional-theory (DFT) calculations we establish that the surface electron states that reside in the projected band gap around the ¯¯¯¯M point exhibit very different spin structures which are governed by the conventional and the cubic Rashba effect. The latter is reflected in a triple spin winding, i.e., the surface electron spin reveals three complete rotations upon moving once around the constant energy contours. Below the Néel temperature, our ARPES measurements show an intricate photoemission intensity picture characteristic of a complex magnetic domain structure. The orientation of the domains, however, can be clarified from a comparative analysis of the ARPES data and their DFT modeling. To characterize a single magnetic domain picture, we resort to the calculations and scrutinize the interplay of the Rashba spin-orbit coupling field with the in-plane exchange field, provided by the ferromagnetically ordered 4f moments of the near-surface Gd layer. ; This work was supported by the German Research Foundation (DFG) through Grants No. KR3831/5-1, No. LA655/20-1, No. GRK1621, No. SFB1143 (Project No. 247310070). We acknowledge support from the Russian Foundation for Basic Research (Grant No. 20-32-70127) and Saint Petersburg State University (Grant No. ID 51126254). M.M.O. acknowledges the support by Spanish Ministerio de Ciencia e Innovación (Grant No. PID2019-103910GB-I00). A.Yu.V. acknowledges the support by RFBR, Project No. 19-32-90251. D.V.V. acknowledges financial support from the Spanish Ministry of Economy (MAT-2017-88374-P). We acknowledge MAX IV Laboratory for time on the Bloch Beamline under Proposal 20190824. Research conducted at MAX IV, a Swedish national user facility, is supported by the Swedish Research council under contract 2018-07152, the Swedish Governmental Agency for Innovation Systems under contract 2018-04969, and Formas under contract 2019-02496. The authors gratefully acknowledge the GWK support for funding this work by providing computing time through the Center for Information Services and HPC (ZIH) at TU Dresden. ; Peer reviewed

Early protection with a high potency (>6PD50) foot-and-mouth disease (FMD) O1 Manisa (Middle-EastSouth Asia lineage) vaccine against challenge with O/VIT/2010 (O Mya98 lineage) was tested in pigs. Only two pigs that were vaccinated seven days prior to challenge had any demonstrable antibodies as a result of vaccination at the time of challenge. However, 80% and 60% of pigs that were vaccinated seven and four days prior to coronary band challenge were protected. Vaccination significantly reduced the amount of virus excreted in nasal swabs, saliva and faeces compared to unvaccinated and infected controls. Virus and viral RNA could be detected in some pigs until termination of the experiment 14 days after challenge.Antibodies to the non-structural proteins (NSP) were detected in only one pig that was challenged four days post vaccination (dpv) and transiently in two pigs that were challenged seven dpv at only one timepoint. For each vaccine and control group, a group of unvaccinated pigs were kept in the same room but with no direct contact with the infected pigs to determine whether vaccination prevented transmission. Despite the presence of live virus and viral RNA in these indirect contact pigs, the groups in contact with the vaccinated and infected pigs did not develop clinical signs nor did they sero-convert. Contact pigs in the same room as unvaccinated challenged controls did show signs of disease and virus infection that resulted in sero-conversion to the NSP. A breach of the wall that separated the two groups at nine days post challenge might have contributed to this finding. This study showed that high potency vaccine can provide protection to pigs soon after vaccination and that aerosol transmission within rooms is a rare event. ; Funding was provided in part by the livestock industries in Australia through Animal Health Australia. The AHA funds are matched through the Meat and Livestock Australia Donor Company by the Australian Government under MLA Project P.PSH 0652. ...

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-642-17711-8_22. ; This paper evaluates the performance of face and speaker verification techniques in the context of a mobile environment. The mobile environment was chosen as it provides a realistic and challenging test-bed for biometric person verification techniques to operate. For instance the audio environment is quite noisy and there is limited control over the illumination conditions and the pose of the subject for the video. To conduct this evaluation, a part of a database captured during the "Mobile Biometry" (MOBIO) European Project was used. In total there were nine participants to the evaluation who submitted a face verification system and five participants who submitted speaker verification systems. The results have shown that the best performing face and speaker verification systems obtained the same level of performance, respectively 10.9% and 10.6% of HTER. ; This work has been performed by the MOBIO project 7th Framework Research Programme of the European Union (EU), grant agreement number: 214324. The authors would like to thank the EU for the financial support and the partners within the consortium for a fruitful collaboration. For more information about the MOBIO consortium please visit http://www.mobioproject.org. NICTA is funded by the Australian Government as represented by the Department of Broadband, Communications and the Digital Economy as well as the Australian Research Council through the ICT Centre of Excellence program. ; Marcel, S.; Mccool, C.; Matejka, P.; Ahonen, T.; Cernocky, J.; Chakraborty, S.; Balasubramanian, V. (2010). On the Results of the First Mobile Biometry (MOBIO) Face and Speaker Verification Evaluation. En Recognizing Patterns in Signals, Speech, Images and Videos: ICPR 2010 Contests, Istanbul, Turkey, August 23-26, 2010, Contest Reports. Springer Verlag (Germany). 210-225. https://doi.org/10.1007/978-3-642-17711-8_22 ; S ; 210 ; 225 ; Visidon ltd., http://www.visidon.fi ; Ahonen, ...

AbstractPrevious genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016). ; This work was supported by the Canadian Breast Cancer Foundation BC/Yukon, BC Cancer Foundation, Stand Up to Cancer Canada (SU2C-AACR-DT-18-15), TFRI Grant 1021, CCSRI Grant 701584, CIHR Grant MOP-126119, Canada Foundation for Innovation and Cancer Research UK. Grant Brown lab is supported by CCSRI Impact Grant 702310 (to G.W.B.) and Ontario Government Scholarship (to B.H.). S.A. is supported by a Canada Research Chair in Molecular Oncology. The Balasubramanian lab is supported by a programme grant (C14303/A17197) and core funding (C14303/A17197) from Cancer Research UK.

Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes. © 2021, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. ; National Institutes of Health ; https://doi.org/10.1038/s41467-021-23470-9

Background: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. Methods: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. Results: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: −1.1 days, 95% CI −9.5 to 7.3, P =.79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. Conclusions: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. Trial registration: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.