Glucocorticoids improve myogenic differentiation in vitro by suppressing the synthesis of versican, a transitional matrix protein overexpressed in dystrophic skeletal muscles

In Duchenne muscular dystrophy (DMD), a dysregulated extracellular matrix (ECM) directly exacerbates pathology. Glucocorticoids are beneficial therapeutics in DMD, and have pleiotropic effects on the composition and processing of ECM proteins in other biological contexts. The synthesis and remodelling of a transitional versican-rich matrix is necessary for myogenesis; whether glucocorticoids modulate this transitional matrix is not known. Here, versican expression and processing were examined in hindlimb and diaphragm muscles from mdx dystrophin-deficient mice and C57BL/10 wild type mice. V0/V1 versican (Vcan) mRNA transcripts and protein levels were upregulated in dystrophic compared to wild type muscles, especially in the more severely affected mdx diaphragm. Processed versican (versikine) was detected in wild type and dystrophic muscles, and immunoreactivity was highly associated with newly regenerated myofibres. Glucocorticoids enhanced C2C12 myoblast fusion by modulating the expression of genes regulating transitional matrix synthesis and processing. Specifically, Tgfβ1, Vcan and hyaluronan synthase-2 (Has2) mRNA transcripts were decreased by 50% and Adamts1 mRNA transcripts were increased three-fold by glucocorticoid treatment. The addition of exogenous versican impaired myoblast fusion, whilst glucocorticoids alleviated this inhibition in fusion. In dystrophic mdx muscles, versican upregulation correlated with pathology. We propose that versican is a novel and relevant target gene in DMD, given its suppression by glucocorticoids and that in excess it impairs myoblast fusion, a process key for muscle regeneration

A reduction in selenoprotein S amplifies the inflammatory profile of fast-twitch skeletal muscle in the mdx dystrophic mouse

Excessive inflammation is a hallmark of muscle myopathies, including Duchenne muscular dystrophy (DMD). There is interest in characterising novel genes that regulate inflammation due to their potential to modify disease progression. Gene polymorphisms in Selenoprotein S (Seps1) are associated with elevated proinflammatory cytokines, and in vitro SEPS1 is protective against inflammatory stress. Given that SEPS1 is highly expressed in skeletal muscle, we investigated whether the genetic reduction of Seps1 exacerbated inflammation in the mdx mouse. F1 male mdx mice with a heterozygous Seps1 deletion (mdx:Seps1−/+) were generated. The mdx:Seps1−/+ mice had a 50% reduction in SEPS1 protein expression in hindlimb muscles. In the extensor digitorum longus (EDL) muscles, mRNA expression of monocyte chemoattractant protein 1 (Mcp-1) (), macrophage marker F4/80 (), and transforming growth factor-β1 (Tgf-β1) () were increased in mdx:Seps1−/+ mice. This was associated with a reduction in muscle fibre size; however, ex vivo EDL muscle strength and endurance were unaltered. In dystrophic slow twitch soleus muscles, SEPS1 reduction had no effect on the inflammatory profile nor function. In conclusion, the genetic reduction of Seps1 appears to specifically exacerbate the inflammatory profile of fast-twitch muscle fibres, which are typically more vulnerable to degeneration in dystrophy

Understanding maternity waiting home uptake and scale-up within low-income and middle-income countries: a programme theory from a realist review and synthesis

From BMJ via Jisc Publications RouterHistory: received 2022-05-13, ppub 2022-09, accepted 2022-09-01, epub 2022-09-30Peer reviewed: TrueAcknowledgements: We gratefully acknowledge members of the advisory group including Anayda Portela, Denise Kouri, Jessie Forsyth, João Paulo Souza and Tami Waldron. We also extend sincere thanks to the 12 MWH implementers and policy makers who were interviewed during the PT refinement process, including, Abebe Mamo G/tsadik, Bwalya Misheck, Chipo Chimamise, Cristalina Mahumane, Esther Ngaru, Faith Akovi Cooper, Fernanda Andre, Gebeyehu Bulcha and Thandiwe Ngoma.Publication status: PublishedFunder: University of Saskatchewan; FundRef: http://dx.doi.org/10.13039/100008920Funder: Mozambique-Canada Maternal Health Project; Grant(s): D-002085Introduction: Maternity waiting homes (MWHs) link pregnant women to skilled birth attendance at health facilities. Research suggests that some MWH-facility birth interventions are more success at meeting the needs and expectations of their intended users than others. We aimed to develop theory regarding what resources work to support uptake and scale-up of MHW-facility birth interventions, how, for whom, in what contexts and why. Methods: A four-step realist review was conducted which included development of an initial programme theory; searches for evidence; selection, appraisal and extraction of data; and analysis and data synthesis. Results: A programme theory was developed from 106 secondary sources and 12 primary interviews with MWH implementers. The theory demonstrated that uptake and scale-up of the MWH-facility birth intervention depends on complex interactions between three adopter groups: health system stakeholders, community gatekeepers and pregnant women and their families. It describes relationships between 19 contexts, 11 mechanisms and 31 outcomes accross nine context-mechanism-outcome configurations (CMOCs) which were grouped into 3 themes: (1) Engaging stakeholders to develop, integrate, and sustain MWH-facility birth interventions, (2) Promoting and enabling MWH-facility birth utilisation and (3) Creating positive and memorable MWH-facility birth user experiences. Belief, trust, empowerment, health literacy and perceptions of safety, comfort and dignity were mechanisms that supported diffusion and adoption of the intervention within communities and health systems. Examples of resources provided by implementers to trigger mechanisms associated with each CMOC were identified. Conclusions: Implementers of MWHs cannot merely assume that communities will collectively value an MWH-facility birth experience over delivery at home. We posit that MWH-facility birth interventions become vulnerable to under-utilisation when implementers fail to: (1) remove barriers that hinder women’s access to MWH and (2) ensure that conditions and interactions experienced within the MWH and its affiliated health facility support women to feel treated with compassion, dignity and respect. PROSPERO registration number: CRD42020173595

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases). INTERPRETATION: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes. FUNDING: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre

‘Multi-Epitope-Targeted’ Immune-Specific Therapy for a Multiple Sclerosis-Like Disease via Engineered Multi-Epitope Protein Is Superior to Peptides

Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS) yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and “epitope spread”, have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such “multi-epitope-targeting” approach in murine experimental autoimmune encephalomyelitis (EAE) associated with a single (“classical”) or multiple (“complex”) anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc) encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as “multi-epitope-targeting” agents. Y-MSPc was superior to peptide(s) in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells). Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of “classical” or “complex EAE” or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a “multi-epitope-targeting” strategy is required for effective immune-specific therapy of organ-specific autoimmune diseases associated with complex and dynamic pathogenic autoimmunity, such as MS; our data further demonstrate that the “multi-epitope-targeting” approach to therapy is optimized through specifically designed multi-epitope-proteins, rather than myelin peptide cocktails, as “multi-epitope-targeting” agents. Such artificial multi-epitope proteins can be tailored to other organ-specific autoimmune diseases

GW170817: Measurements of Neutron Star Radii and Equation of State

On 17 August 2017, the LIGO and Virgo observatories made the first direct detection of gravitational waves from the coalescence of a neutron star binary system. The detection of this gravitational-wave signal, GW170817, offers a novel opportunity to directly probe the properties of matter at the extreme conditions found in the interior of these stars. The initial, minimal-assumption analysis of the LIGO and Virgo data placed constraints on the tidal effects of the coalescing bodies, which were then translated to constraints on neutron star radii. Here, we expand upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars. Our analysis employs two methods: the use of equation-of-state-insensitive relations between various macroscopic properties of the neutron stars and the use of an efficient parametrization of the defining function p(rho) of the equation of state itself. From the LIGO and Virgo data alone and the first method, we measure the two neutron star radii as R-1 = 10.8(-1.7)(+2.0) km for the heavier star and R-2 = 10.7(-1.5)(+2.1) km for the lighter star at the 90% credible level. If we additionally require that the equation of state supports neutron stars with masses larger than 1.97 M-circle dot as required from electromagnetic observations and employ the equation-of-state parametrization, we further constrain R-1 = 11.9(-1.4)(+1.4) km and R-2 = 11.9(-1.4)(+1.4) km at the 90% credible level. Finally, we obtain constraints on p(rho) at supranuclear densities, with pressure at twice nuclear saturation density measured at 3.5(-1.7)(+2.7) x 10(34) dyn cm(-2) at the 90% level.The authors gratefully acknowledge the support of the U.S. National Science Foundation (NSF) for the construction and operation of the LIGO Laboratory and Advanced LIGO as well as the Science and Technology Facilities Council (STFC) of the United Kingdom, the Max-PlanckSociety (MPS), and the State of Niedersachsen/Germany for support of the construction of Advanced LIGO and construction and operation of the GEO600 detector. Additional support for Advanced LIGO was provided by the Australian Research Council. The authors gratefully acknowledge the Italian Istituto Nazionale di Fisica Nucleare (INFN), the French Centre National de la Recherche Scientifique (CNRS) and the Foundation for Fundamental Research on Matter supported by the Netherlands Organisation for Scientific Research, for the construction and operation of the Virgo detector and the creation and support of the EGO consortium. The authors also gratefully acknowledge research support from these agencies as well as by the Council of Scientific and Industrial Research of India, the Department of Science and Technology, India, the Science & Engineering Research Board (SERB), India, the Ministry of Human Resource Development, India, the Spanish Agencia Estatal de Investigación, the Vicepresid`encia i Conselleria d’Innovació, Recerca i Turisme and the Conselleria d’Educació i Universitat del Govern de les Illes Balears, the Conselleria d’Educació, Investigació, Cultura i Esport de la Generalitat Valenciana, the National Science Centre of Poland, the Swiss National Science Foundation (SNSF), the Russian Foundation for Basic Research, the Russian Science Foundation, the European Commission, the European Regional Development Funds (ERDF), the Royal Society, the Scottish Funding Council, the Scottish Universities Physics Alliance, the Hungarian Scientific Research Fund (OTKA), the Lyon Institute of Origins (LIO), the Paris Île-de-France Region, the National Research, Development and Innovation Office Hungary (NKFI), the National Research Foundation of Korea, Industry Canada and the Province of Ontario through the Ministry of Economic Development and Innovation, the Natural Science and Engineering Research Council Canada, the Canadian Institute for Advanced Research, the Brazilian Ministry of Science, Technology, Innovations, and Communications, the International Center for Theoretical Physics South American Institute for Fundamental Research (ICTP-SAIFR), the Research Grants Council of Hong Kong, the National Natural Science Foundation of China (NSFC), the Leverhulme Trust, the Research Corporation, the Ministry of Science and Technology (MOST), Taiwan and the Kavli Foundation. The authors gratefully acknowledge the support of the NSF, STFC, MPS, INFN, CNRS and the State of Niedersachsen/Germany for provision of computational resources

Hunter-Gatherer Olfaction Is Special

People struggle to name odors [1-4]. This has been attributed to a diminution of olfaction in trade-off to vision [5-10]. This presumption has been challenged recently by data from the hunter-gatherer Jahai who, unlike English speakers, find odors as easy to name as colors [4]. Is the superior olfactory performance among the Jahai because of their ecology (tropical rainforest), their language family (Aslian), or because of their subsistence (they are hunter-gatherers)? We provide novel evidence from the hunter-gatherer Semaq Beri and the non-hunter-gatherer (swidden-horticulturalist) Semelai that subsistence is the critical factor. Semaq Beri and Semelai speakers-who speak closely related languages and live in the tropical rainforest of the Malay Peninsula-took part in a controlled odor- and color-naming experiment. The swidden-horticulturalist Semelai found odors much more difficult to name than colors, replicating the typical Western finding. But for the hunter-gatherer Semaq Beri odor naming was as easy as color naming, suggesting that hunter-gatherer olfactory cognition is special

Towards Sustainable Environmental Quality : Priority Research Questions for the Australasian Region of Oceania

Environmental challenges persist across the world, including the Australasian region of Oceania, where biodiversity hotspots and unique ecosystems such as the Great Barrier Reef are common. These systems are routinely affected by multiple stressors from anthropogenic activities, and increasingly influenced by global megatrends (e.g., the food-energy-water nexus, demographic transitions to cities) and climate change. Here we report priority research questions from the Global Horizon Scanning Project, which aimed to identify, prioritize, and advance environmental quality research needs from an Australasian perspective, within a global context. We employed a transparent and inclusive process of soliciting key questions from Australasian members of the Society of Environmental Toxicology and Chemistry. Following submission of 78 questions, 20 priority research questions were identified during an expert workshop in Nelson, New Zealand. These research questions covered a range of issues of global relevance, including research needed to more closely integrate ecotoxicology and ecology for the protection of ecosystems, increase flexibility for prioritizing chemical substances currently in commerce, understand the impacts of complex mixtures and multiple stressors, and define environmental quality and ecosystem integrity of temporary waters. Some questions have specific relevance to Australasia, particularly the uncertainties associated with using toxicity data from exotic species to protect unique indigenous species. Several related priority questions deal with the theme of how widely international ecotoxicological data and databases can be applied to regional ecosystems. Other timely questions, which focus on improving predictive chemistry and toxicology tools and techniques, will be important to answer several of the priority questions identified here. Another important question raised was how to protect local cultural and social values and maintain indigenous engagement during problem formulation and identification of ecosystem protection goals. Addressing these questions will be challenging, but doing so promises to advance environmental sustainability in Oceania and globally