Neuregulin signaling regulates neural precursor growth and the generation of oligodendrocytes in vitro

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Return-to-Play Clinical Milestones: Fail-Rate for Those Claiming to Be Fully Symptom Free

Sport-related concussion remains a concerning public health issue. A multifaceted test battery is recommended for clinical judgments, including return-to-play (RTP). Initiation of RTP testing is based on the athletes\u27 honesty with their current symptoms and is confirmed by the multifaceted test battery. PURPOSE: Examine the rates of test failure in NCAA Division I athletes when they present as being symptom free for 24 hours. METHODS: 36 Division I athletes (18 male, 18 female; avg. age=20.1 years) were evaluated at pre-season baselines (BL), within 48 hours of a diagnosed concussion (CON), and when they reported being symptom free (SF) for 24 hours. At each time point, they were evaluated on a symptom severity score (TS), the vestibular/ocular motor screening (VOMS) exam, and tandem gait (TG) under single-task (ST) and dual-task (DT) conditions (serial-7s subtraction). Neurocognitive testing using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) was only performed at BL and again if they were clinically clear on the VOMS and TG. Lastly, the Buffalo Concussion Treadmill Test (BCTT) was administered at CON and SF using the standard recommended procedures. Concussions were diagnosed using the international consensus criteria alongside symptom presentation and a mechanism of injury. The fail rate was determined if they presented with one or more of the following: 1) a TS of \u3e7 or physiological symptoms (i.e. headaches, dizziness) not present at BL, 2) VOMS change score \u3e2, 3) NPC \u3e5.0cm, 4) ST outside of 1.5s of their BL, 5) DT outside of 1.7s of their BL, 6) declined ImPACT test results determined by a trained clinician using minimal detectable change score, and 7) symptom provocation during the BCTT. RESULTS: A total of 67% (n=23/36) successfully cleared all the testing criteria and moved onto an RTP protocol once subjectively considered SF. 67% (n=12/18) of females and 61% (n=11/18) of males successfully cleared all the testing at their respective impressions of being SF. The average time from CON to SF was 16.8±16.91 days with no significant difference (p=.56) between males (18.50±17.72 days) and females (15.11±16.41 days). CONCLUSION: These results suggest that a multifaceted concussion assessment battery is heavily warranted to determine the athletes\u27 concussion status and readiness for RTP

Polymorphisms in the Gene That Encodes the Iron Transport Protein Ferroportin 1 Influence Susceptibility to Tuberculosis

Background: We studied the association between iron intake and polymorphisms in the iron transporter gene, SLC40A1, and the risk of tuberculosis. Methods: We compared iron intake, the frequency of SLC40A1 mutations, and interactions between these variables among 98 TB patients and 125 controls in Kwazulu-Natal, South Africa. Results: Four SLC40A1 SNPs were associated with an increased risk of tuberculosis and one with reduced risk. We also found a gene-environment interaction for four non-exonic SNPs and iron intake. Conclusions: This pilot study demonstrated an association between polymorphisms in SLC40A1 and tuberculosis and provided evidence for an interaction between dietary iron and SLC40A1.Organismic and Evolutionary Biolog

A Functional Role for ADAM10 in Human Immunodeficiency Virus Type-1 Replication

<p>Abstract</p> <p>Background</p> <p>Gene trap insertional mutagenesis was used as a high-throughput approach to discover cellular genes participating in viral infection by screening libraries of cells selected for survival from lytic infection with a variety of viruses. Cells harboring a disrupted <it>ADAM10 </it>(A Disintegrin and Metalloprotease 10) allele survived reovirus infection, and subsequently ADAM10 was shown by RNA interference to be important for replication of HIV-1.</p> <p>Results</p> <p>Silencing ADAM10 expression with small interfering RNA (siRNA) 48 hours before infection significantly inhibited HIV-1 replication in primary human monocyte-derived macrophages and in CD4⁺cell lines. In agreement, ADAM10 over-expression significantly increased HIV-1 replication. ADAM10 down-regulation did not inhibit viral reverse transcription, indicating that viral entry and uncoating are also independent of ADAM10 expression. Integration of HIV-1 cDNA was reduced in ADAM10 down-regulated cells; however, concomitant 2-LTR circle formation was not detected, suggesting that HIV-1 does not enter the nucleus. Further, ADAM10 silencing inhibited downstream reporter gene expression and viral protein translation. Interestingly, we found that while the metalloprotease domain of ADAM10 is not required for HIV-1 replication, ADAM15 and γ-secretase (which proteolytically release the extracellular and intracellular domains of ADAM10 from the plasma membrane, respectively) do support productive infection.</p> <p>Conclusions</p> <p>We propose that ADAM10 facilitates replication at the level of nuclear trafficking. Collectively, our data support a model whereby ADAM10 is cleaved by ADAM15 and γ-secretase and that the ADAM10 intracellular domain directly facilitates HIV-1 nuclear trafficking. Thus, ADAM10 represents a novel cellular target class for development of antiretroviral drugs.</p

Reported and recorded sleepiness in obesity and depression

Civil war, flight, escape and expulsion are extremely stressful and assert a negative impact on refugees’ mental health. However scientific research about resilience and coping of refugees is scarce. Especially in the recent refugee crisis, calls have been made to consider factors contributing to coping and resilience in this vulnerable population. Therefore, the current research sought to investigate individual differences that could serve as antecedents of coping and contextual factors that might moderate these effects. Specifically, it took into account individual’s self-regulatory differences in terms of regulatory focus (i.e., a promotion focus on nurturance needs, ideals and gains vs. a prevention focus on security needs, oughts and losses). It furthermore explored contextual influences by considering Syrian refugees in Turkey (Sample 1, N = 273) and Germany (Sample 2, N = 169). Compared to Syrian refugees in Turkey, those in Germany had a stronger promotion focus. They also reported more problem-focused and less maladaptive coping, as well as less symptoms. Both promotion and prevention focus were positively related to problem-focused coping. Problem-focused coping, in turn, predicted more symptoms in Turkey but not in Germany. Furthermore, a stronger promotion focus was associated with less symptoms and maladaptive coping was associated with more symptoms in both samples. These results contribute to the coping literature in demonstrating that under certain conditions problem-focused coping can be maladaptive and extend the scarce previous work on self-regulation and coping. Most importantly, they highlight a promotion focus as a clear resilience factor and the role of maladaptive coping in increasing vulnerability. As such, they might inform the design of effective interventions among Syrian refugees and beyond

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women

STUDY QUESTION: Can additional genetic variants for circulating anti-Müllerian hormone (AMH) levels be identified through a genome-wide association study (GWAS) meta-analysis including a large sample of premenopausal women? SUMMARY ANSWER: We identified four loci associated with AMH levels at P < 5 × 10(−8): the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. WHAT IS KNOWN ALREADY: AMH is expressed by antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with disease outcomes. However, the physiological mechanisms underlying these AMH-disease associations are largely unknown. STUDY DESIGN, SIZE, DURATION: We performed a GWAS meta-analysis in which we combined summary statistics of a previous AMH GWAS with GWAS data from 3705 additional women from three different cohorts. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, we included data from 7049 premenopausal female participants of European ancestry. The median age of study participants ranged from 15.3 to 48 years across cohorts. Circulating AMH levels were measured in either serum or plasma samples using different ELISA assays. Study-specific analyses were adjusted for age at blood collection and population stratification, and summary statistics were meta-analysed using a standard error-weighted approach. Subsequently, we functionally annotated GWAS variants that reached genome-wide significance (P < 5 × 10(−8)). We also performed a gene-based GWAS, pathway analysis and linkage disequilibrium score regression and Mendelian randomization (MR) analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We identified four loci associated with AMH levels at P < 5 × 10(−8): the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among single nucleotide polymorphisms for AMH levels and for age at menopause (r(g) = 0.82, FDR = 0.003). Exploratory two-sample MR analyses did not support causal effects of AMH on breast cancer or polycystic ovary syndrome risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. LARGE SCALE DATA: The full AMH GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Whilst this study doubled the sample size of the most recent GWAS, the statistical power is still relatively low. As a result, we may still lack power to identify more genetic variants for AMH and to determine causal effects of AMH on, for example, breast cancer. Also, follow-up studies are needed to investigate whether the signal for the AMH gene is caused by reduced AMH detection by certain assays instead of actual lower circulating AMH levels. WIDER IMPLICATIONS OF THE FINDINGS: Genes mapped to the MCM8, TEX41 and CDCA7 loci are involved in the cell cycle and processes such as DNA replication and apoptosis. The mechanism underlying their associations with AMH may affect the size of the ovarian follicle pool. Altogether, our results provide more insight into the biology of AMH and, accordingly, the biological processes involved in ovarian ageing. STUDY FUNDING/COMPETING INTEREST(S): Nurses’ Health Study and Nurses’ Health Study II were supported by research grants from the National Institutes of Health (CA172726, CA186107, CA50385, CA87969, CA49449, CA67262, CA178949). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the listed authors, who will serve as guarantors for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Funding for the collection of genotype and phenotype data used here was provided by the British Heart Foundation (SP/07/008/24066), Wellcome (WT092830M and WT08806) and UK Medical Research Council (G1001357). M.C.B., A.L.G.S. and D.A.L. work in a unit that is funded by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). M.C.B.’s contribution to this work was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). A.L.G.S. was supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sports of the Netherlands. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Ansh Labs performed the AMH measurements for the Doetinchem Cohort Study free of charge. Ansh Labs was not involved in the data analysis, interpretation or reporting, nor was it financially involved in any aspect of the study. R.M.G.V. was funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (022.005.021). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women’s Health (ORWH) (U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy have grant support from the NIA (U01AG017719). The Generations Study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR). The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent official views of the funders. The Sister Study was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES044005 to D.P.S.); the AMH assays were supported by the Avon Foundation (02-2012-065 to H.B. Nichols and D.P.S.). The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie, de la Science et de l’Innovation du Québec’ through Genome Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al. (Nature, 2017). F.J.M.B. has received fees and grant support from Merck Serono and Ferring BV. D.A.L. has received financial support from several national and international government and charitable funders as well as from Medtronic Ltd and Roche Diagnostics for research that is unrelated to this study. N.S. is scientific consultant for Ansh Laboratories. The other authors declare no competing interests

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.Peer reviewe