Expression of A Slow Muscle Myosin (β-MyHC) Drives Both Physiological & Pathological Changes In Skeletal Muscle

Skeletal muscle is the most abundant and adaptable tissue in the human body, composed of muscle fibers which have the ability to respond to a variety of physiological and pathological stimuli, acting on the body&rsquo;s needs. Muscle fibers are composed largely of myosin, a highly conserved protein which interacts with actin and other sarcomeric proteins to generate the force needed for muscle contraction. Myosins are highly specialized being specific for varying tissue types and are characterized as slow or fast dependent on their biological properties. To better characterize the role of &beta;-myosin (a slow myosin motor), how it responds to and drives physiological and pathological changes in skeletal muscle, we generated and studied novel animal models. Forced expression of &beta;-myosin (&beta;-MyHC) in fast-type skeletal muscle identified a physiological role for &beta;-MyHC in fiber type specification and plasticity. We showed that &beta;-MyHC transgenic muscle has significantly increased PGC-1&alpha;, exhibits a fast-to-slow fiber type shift, increased oxidative metabolism, increased mitochondrial biogenesis, and resistance to fatigue. By sending a signal downstream, &beta;-MyHC activates physiological and metabolic changes within skeletal muscle. Additionally, we created the first mouse model for a progressive skeletal muscle disease, Laing distal myopathy (MPD1), by expressing the R1500P rod mutation. We observed phenotypes which closely mimic MDP1 in our transgenic animals including muscle-specific functional and structural effects. Furthermore, we observed how this mutation is able to impact contractility parameters which provide new insight into how a rod domain mutation may lead to disease. Changes in myosin isoform expression, specifically &beta;-myosin, are able to drive physiological and pathological responses in skeletal muscle in ways that were previously unidentified. These mouse models can be used in future studies to further elucidate new roles for &beta;-MyHC and its effect/role in skeletal muscle and to act as platforms for testing future therapeutic interventions.</p

The Web of Legal Protections for Participants in Genomic Research

The identification and arrest of the Golden State Killer using DNA uploaded to an ancestry database occurred shortly before recruitment for the National Institutes of Health’s (NIH) All of Us Study commenced, with a goal of enrolling and collecting DNA, health, and lifestyle information from one million Americans. It also highlighted the need to ensure prospective research participants that their confidentiality will be protected and their materials used appropriately. But there are questions about how well current law protects against these privacy risks. This article is the first to consider comprehensively and simultaneously all the federal and state laws offering protections to participants in genomic research. The literature typically focuses on the federal laws in isolation, questioning the strengths of federal legal protections for genomic research participants provided in the Common Rule, the HIPAA Privacy Rule, or the Genetic Information Nondiscrimination Act. Nevertheless, we found significant numbers and surprising variety among state laws that provide greater protections than federal laws, often filling in federal gaps by broadening the applicability of privacy or nondiscrimination standards or by providing important remedies for individuals harmed by breaches. Identifying and explaining the protections these laws provide is significant both to allow prospective participants to accurately weigh the risks of enrolling in these studies and as models for how federal legal protections could be expanded to fill known gaps

Associations of sitting accumulation patterns with cardio-metabolic risk biomarkers in Australian adults

Backgroun

Modeling colorectal cancer: A bio-resource of 50 patient-derived organoid lines

Background and Aim Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. To improve outcomes for these patients, we need to develop new treatment strategies. Personalized cancer medicine, where patients are treated based on the characteristics of their own tumor, has gained significant interest for its promise to improve outcomes and reduce unnecessary side effects. The purpose of this study was to examine the potential utility of patient-derived colorectal cancer organoids (PDCOs) in a personalized cancer medicine setting. Methods Patient-derived colorectal cancer organoids were derived from tissue obtained from treatment-naïve patients undergoing surgical resection for the treatment of CRC. We examined the recapitulation of key histopathological, molecular, and phenotypic characteristics of the primary tumor. Results We created a bio-resource of PDCOs from primary and metastatic CRCs. Key histopathological features were retained in PDCOs when compared with the primary tumor. Additionally, a cohort of 12 PDCOs, and their corresponding primary tumors and normal sample, were characterized through whole exome sequencing and somatic variant calling. These PDCOs exhibited a high level of concordance in key driver mutations when compared with the primary tumor. Conclusions Patient-derived colorectal cancer organoids recapitulate characteristics of the tissue from which they are derived and are a powerful tool for cancer research. Further research will determine their utility for predicting patient outcomes in a personalized cancer medicine setting

Undervaccination and severe COVID-19 outcomes : meta-analysis of national cohort studies in England, Northern Ireland, Scotland, and Wales

Background: Undervaccination (receiving fewer than the recommended number of SARS-CoV-2 vaccine doses) could be associated with increased risk of severe COVID-19 outcomes—ie, COVID-19 hospitalisation or death—compared with full vaccination (receiving the recommended number of SARS-CoV-2 vaccine doses). We sought to determine the factors associated with undervaccination, and to investigate the risk of severe COVID-19 outcomes in people who were undervaccinated in each UK nation and across the UK. Methods: We used anonymised, harmonised electronic health record data with whole population coverage to carry out cohort studies in England, Northern Ireland, Scotland, and Wales. Participants were required to be at least 5 years of age to be included in the cohorts. We estimated adjusted odds ratios for undervaccination as of June 1, 2022. We also estimated adjusted hazard ratios (aHRs) for severe COVID-19 outcomes during the period June 1 to Sept 30, 2022, with undervaccination as a time-dependent exposure. We combined results from nation-specific analyses in a UK-wide fixed-effect meta-analysis. We estimated the reduction in severe COVID-19 outcomes associated with a counterfactual scenario in which everyone in the UK was fully vaccinated on June 1, 2022. Findings: The numbers of people undervaccinated on June 1, 2022 were 26 985 570 (45·8%) of 58 967 360 in England, 938 420 (49·8%) of 1 885 670 in Northern Ireland, 1 709 786 (34·2%) of 4 992 498 in Scotland, and 773 850 (32·8%) of 2 358 740 in Wales. People who were younger, from more deprived backgrounds, of non-White ethnicity, or had a lower number of comorbidities were less likely to be fully vaccinated. There was a total of 40 393 severe COVID-19 outcomes in the cohorts, with 14 156 of these in undervaccinated participants. We estimated the reduction in severe COVID-19 outcomes in the UK over 4 months of follow-up associated with a counterfactual scenario in which everyone was fully vaccinated on June 1, 2022 as 210 (95% CI 94–326) in the 5–15 years age group, 1544 (1399–1689) in those aged 16–74 years, and 5426 (5340–5512) in those aged 75 years or older. aHRs for severe COVID-19 outcomes in the meta-analysis for the age group of 75 years or older were 2·70 (2·61–2·78) for one dose fewer than recommended, 3·13 (2·93–3·34) for two fewer, 3·61 (3·13–4·17) for three fewer, and 3·08 (2·89–3·29) for four fewer. Interpretation: Rates of undervaccination against COVID-19 ranged from 32·8% to 49·8% across the four UK nations in summer, 2022. Undervaccination was associated with an elevated risk of severe COVID-19 outcomes. Funding: UK Research and Innovation National Core Studies: Data and Connectivity

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

The importance of balanced canonical Wnt signalling and analysis of its pathway components in spermatogenesis

Understanding fundamental reproductive biology is essential for generating improved contraceptive options, resolving fertility problems, and preserving fertility in individuals choosing to reproduce later in life. Disruptions in the development of male germ cells and their supporting somatic cells are considered to underpin many cases of idiopathic disease. Wnt signalling is a highly conserved pathway that plays essential roles in many tissue types and organs. Reports of Wnt signalling in the testis demonstrating that it is functionally important are limited, so further research is required to understand the contribution of this pathway to male fertility. Wnt signalling is tightly controlled in normal development. This thesis investigates the importance of appropriate levels of Wnt signalling for spermatogenic development. These studies employed AhCre mouse models with acute testis-wide perturbations in β-catenin and the negative regulator, Adenomatous Polyposis Coli, to examine outcomes of down- and up-regulation of Wnt signalling respectively. Both mutant models displayed germ cell loss, increased levels of TUNEL-positive cells, maintained PLZF-positive spermatogonia numbers, displayed normal Sertoli cell SOX9 expression, abnormal localisation of the blood-testis-barrier marker CNX43, and increased levels of immature Sertoli cell marker AMH. These results demonstrated that balanced levels of Wnt signalling are essential for normal adult spermatogenesis. Sites of active Wnt signalling were determined in the postnatal and adult mouse testis using several detection methods. The first demonstration of Wnt signalling activation in spermatogonia in vivo was presented through Axin2 expression, whilst active Wnt signalling in post-mitotic germ cells was confirmed though BATGAL expression and nuclear β-catenin localisation. In addition, Wnt signalling activation was identified in early postnatal Sertoli cells, but terminates once they terminally differentiate at puberty. Transcriptome analysis and protein localisation studies identified sites of several Wnt ligands, receptors, and other components that may mediate Wnt signalling in the testis. These data have demonstrated that while Wnt signalling is active in both mitotic and post-mitotic germ cells, each spermatogenic cell type has different signalling component expression profiles and Wnt signalling outcomes are driven by distinct transcription factors. To investigate the requirement of Wnt signalling within spermatogenic cells, VasaCre Ctnnb1fl/fl mice were employed. This demonstrated that β-catenin signalling controls the speed of the first wave of spermatogenesis, and is required for the maintenance of spermatogonia in adults. Transcriptome analysis identified several potential Wnt signalling downstream targets in the adult testis. Additionally, characterisation of the novel application of the AhCre mouse line for use in acute genetic recombination studies in the testis was demonstrated. Recombination efficiency differences between distinct floxed β-catenin alleles and the complexities of using different Cre drivers to examine gene function in the context of the testis have also been highlighted. Data presented in this thesis and by others have demonstrated that tight regulation of Wnt signalling, controlled by compartmentalised expression of different Wnt ligands, receptors, antagonists and enhancers is essential for normal spermatogenesis. These findings may contribute to a better understanding of fertility issues in men

Lessons for improved COVID-19 surveillance from the scale-up of malaria testing strategies

Abstract Effective control of infectious diseases is facilitated by informed decisions that require accurate and timely diagnosis of disease. For malaria, improved access to malaria diagnostics has revolutionized malaria control and elimination programmes. However, for COVID-19, diagnosis currently remains largely centralized and puts many low- and middle-income countries (LMICs) at a disadvantage. Malaria and COVID-19 are infectious diseases that share overlapping symptoms. While the strategic responses to disease control for malaria and COVID-19 are dependent on the disease ecologies of each disease, the fundamental need for accurate and timely testing remains paramount to inform accurate responses. This review highlights how the roll-out of rapid diagnostic tests has been fundamental in the fight against malaria, primarily within the Asia Pacific and along the Greater Mekong Subregion. By learning from the successful elements of malaria control programmes, it is clear that improving access to point-of-care testing strategies for COVID-19 will provide a suitable framework for COVID-19 diagnosis in not only the Asia Pacific, but all malarious countries. In malaria-endemic countries, an integrated approach to point-of-care testing for COVID-19 and malaria would provide bi-directional benefits for COVID-19 and malaria control, particularly due to their paralleled likeness of symptoms, infection control strategies and at-risk individuals. This is especially important, as previous disease pandemics have disrupted malaria control infrastructure, resulting in malaria re-emergence and halting elimination progress. Understanding and combining strategies may help to both limit disruptions to malaria control and support COVID-19 control