Stress Adaptation

We thank our numerous friends and colleagues for stimulating discussions about stress adaptation. We are also grateful to the following institutions for generously supporting our research. A.J.P.B was funded by the European Research Council (STRIFE, ERC-2009-AdG-249793), the UK Medical Research Council (MR/M026663/1 and MR/N006364/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), and the Wellcome Trust (080088; 097377). L.E.C. is supported by the Canadian Institutes of Health Research Operating Grants (MOP-86452 and MOP-119520), the Natural Sciences and Engineering Research Council (NSERC) of Canada Discovery Grants (06261 and 462167), an NSERC E.W.R. Steacie Memorial Fellowship (477598), a National Institutes of Health R01 Grant (R01AI120958), and a Canada Research Chair in Microbial Genomics and Infectious Disease. Work in the A.D.P. laboratory is funded by grants from the Spanish Ministerio de Innovación y Competitividad (BIO2013-47870-R), the European Commission (Marie Curie ITN FUNGIBRAIN; FP7-PEOPLE-ITN-607963), and the Junta de Andalucia (BIO296). J.Q. is funded by the UK Biotechnology and Biological Research Council (BB/K016939/1) and the Wellcome Trust (097377).Peer reviewedPostprin

The role of H2S bioavailability in endothelial dysfunction

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Endothelial dysfunction (EDF) reflects pathophysiological changes in the phenotype and functions of endothelial cells that result from and/or contribute to a plethora of cardiovascular diseases. We review the role of hydrogen sulfide (H2S) in the pathogenesis of EDF, one of the fastest advancing research topics. Conventionally treated as an environment pollutant, H2S is also produced in endothelial cells and participates in the fine regulation of endothelial integrity and functions. Disturbed H2S bioavailability has been suggested to be a novel indicator of EDF progress and prognosis. EDF manifests in different forms in multiple pathologies, but therapeutics aimed at remedying altered H2S bioavailability may benefit all.This work has been supported by a Discovery Grant from Natural Sciences and Engineering Research council of Canada to RW. CS has been supported by the American Diabetes Association, the National Institutes of Health of USA and the Shriners Hospitals for Children. FI has been supported by the National Institutes of Health of USA. MW has been supported by the Medical Research Council of UK. AA has been supported by programme grants from British Heart Foundation (RG/09/001/25940), Medical Research Council (G0700288), Royal Society and European Union. AP has been supported through an Aristeia grant (1436) that is co-financed by the European Union (ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning”. MW and AP are supported by the COST Action BM1005 (ENOG: European network on gasotransmitters)

Convergent and Biomimetic Enantioselective Total Synthesis of (−)-Communesin F

The first biomimetic enantioselective total synthesis of (-)-communesin F based on a late-stage heterodimerization and aminal exchange is described. Our synthesis features the expedient diazene-directed assembly of two advanced fragments to secure the congested C3a-C3a′ linkage in three steps, followed by a highly efficient biogenetically inspired aminal reorganization to access the heptacyclic communesin core in only two additional steps. Enantioselective syntheses of the two fragments were developed, with highlights including the catalytic asymmetric halocyclization and diastereoselective oxyamination reactions of tryptamine derivatives, a stereoselective sulfinimine allylation, and an efficient cyclotryptamine-C3a-sulfamate synthesis by either a new silver-promoted nucleophilic amination or a rhodium-catalyzed C-H amination protocol. The versatile syntheses of the fragments, their stereocontrolled assembly, and the efficient aminal exchange as supported by in situ monitoring experiments, in addition to the final stage N1′-acylation of the communesin core, provide a highly convergent synthesis of (-)-communesin F.National Institute of General Medical Sciences (U.S.) (GM089732)National Science Foundation (U.S.) (CHE1212527)Ruth L. Kirschstein National Research Service Award ((F32GM097776)Natural Sciences and Engineering Research Council of Canada (PGS D3 Scholarship

Attentional Modulation of Envelope-Following Responses at Lower (93–109 Hz) but Not Higher (217–233 Hz) Modulation Rates

Directing attention to sounds of different frequencies allows listeners to perceive a sound of interest, like a talker, in a mixture. Whether cortically generated frequency-specific attention affects responses as low as the auditory brainstem is currently unclear. Participants attended to either a high- or low-frequency tone stream, which was presented simultaneously and tagged with different amplitude modulation (AM) rates. In a replication design, we showed that envelope-following responses (EFRs) were modulated by attention only when the stimulus AM rate was slow enough for the auditory cortex to track—and not for stimuli with faster AM rates, which are thought to reflect ‘purer’ brainstem sources. Thus, we found no evidence of frequency-specific attentional modulation that can be confidently attributed to brainstem generators. The results demonstrate that different neural populations contribute to EFRs at higher and lower rates, compatible with cortical contributions at lower rates. The results further demonstrate that stimulus AM rate can alter conclusions of EFR studies.This work was supported by funding from the Canadian Institutes of Health Research (CIHR; Operating Grant: MOP 133450) and the Natural Sciences and Engineering Research Council of Canada (NSERC; Discovery Grant: 327429-2012). Authors R.P. Carlyon and H.E. Gockel were supported by intramural funding from the Medical Research Council [SUAG/007 RG91365]

The Positive and Negative Influence of Search Results on People's Decisions about the Efficacy of Medical Treatments

© Frances A. Pogacar, Amira Ghenai, Mark D. Smucker, and Charles L. A. Clarke, 2017. This is the author's version of the work. It is posted here for your personal use. Not for redistribution. The definitive version was published in the Proceedings of the 3rd ACM International Conference on the Theory of Information Retrieval (ICTIR'17), ACM. , https://doi.org/10.1145/10.1145/3121050.3121074People regularly use web search engines to investigate the efficacy of medical treatments. Search results can contain documents that present incorrect information that contradicts current established medical understanding on whether a treatment is helpful or not for a health issue. If people are influenced by the incorrect information found in search results, they can make harmful decisions about the appropriate treatment. To determine the extent to which people can be influenced by search engine results, we conducted a controlled laboratory study that biased search results towards correct or incorrect information for 10 different medical treatments. We found that search engine results can significantly influence people both positively and negatively. Importantly, study participants made more incorrect decisions when they interacted with search results biased towards incorrect information than when they had no interaction with search results at all. For search domains such as health information, search engine designers and researchers must recognize that not all non-relevant information is the same. Some non-relevant information is incorrect and potentially harmful when people use it to make decisions that may negatively impact their lives.Natural Sciences and Engineering Research Council of Canada||CRDPJ 468812-14, Natural Sciences and Engineering Research Council of Canada||RGPIN-2014-03642, Google, Qatar Foundation for Education, Science and Community Development, University of Waterlo

Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis

Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study in 142,487 individuals from the UK Biobank to identify loci associated with BMD estimated by quantitative ultrasound of the heel (“eBMD”). We identified 307 conditionally independent SNPs attaining genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 novel loci, and several rare variants with large effect sizes. To investigate underlying mechanisms we undertook: 1) bioinformatic, functional genomic annotation and human osteoblast expression studies; 2) gene function prediction; 3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and 4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. These studies strongly implicate GPC6 as a novel determinant of BMD and also identify abnormal skeletal phenotypes in knockout mice for a further 100 prioritized genes.This part of the work was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). This work was supported by the Medical Research Council (Programme Grant MC_UU_12013/4 to D.M.E.), the Wellcome Trust (Strategic Award grant number 101123; project grant 094134; to G.R.W., J.H.D.B. and P.I.C.), the Netherlands Organization for Health Research and Development ZonMw VIDI 016.136.367 (funding to F.R., C.M.-G. and K.T.), the mobility stimuli plan of the European Union Erasmus Mundus Action 2: ERAWEB (programme funding to K.T.), NIAMS, NIH (AR060981 and AR060234 to C.L.A.-B.), the National Health and Medical Research Council (Early Career Fellowship APP1104818 to N.M.W.), the Swedish Research Council (funding to E.G.), the Réseau de Médecine Génétique Appliquée (RMGA; J.A.M.), the Fonds de Recherche du Québec–Santé (FRQS; J.A.M. and J.B.R.), the Natural Sciences and Engineering Research Council of Canada (C.M.T.G.), the J. Gibson and the Ernest Heine Family Foundation (P.I.C.), Arthritis Research UK (ref. 20000; to C.L.G.), the Canadian Institutes of Health Research (J.B.R.), the Jewish General Hospital (J.B.R.), and the Australian Research Council (Future Fellowship FT130101709 to D.M.E.). This research was conducted using the UK Biobank Resource (application number 12703). Access to the UK Biobank study data was funded by the University of Queensland (Early Career Researcher Grant 2014002959 to N.M.W.)

RNAi-Microsponges Form through Self-Assembly of the Organic and Inorganic Products of Transcription

Inorganic nanostructures have been used extensively to package nucleic acids into forms useful for therapeutic applications. Here we report that the two products of transcription, RNA and inorganic pyrophosphate, can self-assemble to form composite microsponge structures composed of nanocrystalline magnesium pyrophosphate sheets (Mg[subscript 2]P[subscript 2]O[subscript 7]•3.5H[subscript 2]O) with RNA adsorbed to their surfaces. The microsponge particles contain high loadings of RNA (15–21 wt.%) that are protected from degradation and can be obtained through a rolling circle mechanism as large concatemers capable of mediating RNAi. The morphology of the RNAi microsponges is influenced by the time-course of the transcription reaction and interactions between RNA and the inorganic phase. Previous work demonstrated that polycations can be used to condense RNAi microsponges into nanoparticles capable of efficient transfection with low toxicity. Our new findings suggest that the formation of these nanoparticles is mediated by the gradual dissolution of magnesium pyrophosphate that occurs in the presence of polycations. The simple one-pot approach for assembling RNAi microsponges along with their unique properties could make them useful for RNA-based therapeutics.National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)National Cancer Institute (U.S.) (Center for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02)Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)National Health and Medical Research Council (Australia) (CJ Martin Fellowship)National Science Foundation (U.S.). Graduate Research Fellowshi