Transgenic Rescue of the LARGEmyd Mouse: A LARGE Therapeutic Window?

LARGE is a glycosyltransferase involved in glycosylation of α-dystroglycan (α-DG). Absence of this protein in the LARGEmyd mouse results in α-DG hypoglycosylation, and is associated with central nervous system abnormalities and progressive muscular dystrophy. Up-regulation of LARGE has previously been proposed as a therapy for the secondary dystroglycanopathies: overexpression in cells compensates for defects in multiple dystroglycanopathy genes. Counterintuitively, LARGE overexpression in an FKRP-deficient mouse exacerbates pathology, suggesting that modulation of α-DG glycosylation requires further investigation. Here we demonstrate that transgenic expression of human LARGE (LARGE-LV5) in the LARGEmyd mouse restores α-DG glycosylation (with marked hyperglycosylation in muscle) and that this corrects both the muscle pathology and brain architecture. By quantitative analyses of LARGE transcripts we also here show that levels of transgenic and endogenous LARGE in the brains of transgenic animals are comparable, but that the transgene is markedly overexpressed in heart and particularly skeletal muscle (20–100 fold over endogenous). Our data suggest LARGE overexpression may only be deleterious under a forced regenerative context, such as that resulting from a reduction in FKRP: in the absence of such a defect we show that systemic expression of LARGE can indeed act therapeutically, and that even dramatic LARGE overexpression is well-tolerated in heart and skeletal muscle. Moreover, correction of LARGEmyd brain pathology with only moderate, near-physiological LARGE expression suggests a generous therapeutic window

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK)

Background: Risk factors for severe COVID-19 include older age, male sex, obesity, black or Asian ethnicity and underlying medical conditions. Whether these factors also influence susceptibility to developing COVID-19 is uncertain. Methods: We undertook a prospective, population-based cohort study (COVIDENCE UK) from 1 May 2020 to 5 February 2021. Baseline information on potential risk factors was captured by an online questionnaire. Monthly follow-up questionnaires captured incident COVID-19. We used logistic regression models to estimate multivariable-adjusted ORs (aORs) for associations between potential risk factors and odds of COVID-19. Results: We recorded 446 incident cases of COVID-19 in 15 227 participants (2.9%). Increased odds of developing COVID-19 were independently associated with Asian/Asian British versus white ethnicity (aOR 2.28, 95% CI 1.33 to 3.91), household overcrowding (aOR per additional 0.5 people/bedroom 1.26, 1.11 to 1.43), any versus no visits to/from other households in previous week (aOR 1.31, 1.06 to 1.62), number of visits to indoor public places (aOR per extra visit per week 1.05, 1.02 to 1.09), frontline occupation excluding health/social care versus no frontline occupation (aOR 1.49, 1.12 to 1.98) and raised body mass index (BMI) (aOR 1.50 (1.19 to 1.89) for BMI 25.0–30.0 kg/m2 and 1.39 (1.06 to 1.84) for BMI >30.0 kg/m2 versus BMI <25.0 kg/m2). Atopic disease was independently associated with decreased odds (aOR 0.75, 0.59 to 0.97). No independent associations were seen for age, sex, other medical conditions, diet or micronutrient supplement use. Conclusions: After rigorous adjustment for factors influencing exposure to SARS-CoV-2, Asian/Asian British ethnicity and raised BMI were associated with increased odds of developing COVID-19, while atopic disease was associated with decreased odds. Trial registration number: ClinicalTrials.gov Registry (NCT04330599)

The changing carbon cycle of the coastal ocean

The carbon cycle of the coastal ocean is a dynamic component of the global carbon budget. But the diverse sources and sinks of carbon and their complex interactions in these waters remain poorly understood. Here we discuss the sources, exchanges and fates of carbon in the coastal ocean and how anthropogenic activities have altered the carbon cycle. Recent evidence suggests that the coastal ocean may have become a net sink for atmospheric carbon dioxide during post-industrial times. Continued human pressures in coastal zones will probably have an important impact on the future evolution of the coastal ocean's carbon budget

Qualified and Unqualified (N-R C) mental health nursing staff - minor differences in sources of stress and burnout. A European multi-centre study

<p>Abstract</p> <p>Background</p> <p>Unqualified/non-registered caregivers (N-R Cs) will continue to play important roles in the mental health services. This study compares levels of burnout and sources of stress among qualified and N-R Cs working in acute mental health care.</p> <p>Methods</p> <p>A total of 196 nursing staff - 124 qualified staff (mainly nurses) and 72 N-R Cs with a variety of different educational backgrounds - working in acute wards or community mental teams from 5 European countries filled out the Maslach Burnout Inventory (MBI), the Mental Health Professional Scale (MHPSS) and the Psychosocial Work Environment and Stress Questionnaire (PWSQ).</p> <p>Results</p> <p>(a) The univariate differences were generally small and restricted to a few variables. Only Social relations (N-R Cs being less satisfied) at Work demands (nurses reporting higher demands) were different at the .05 level. (b) The absolute scores both groups was highest on variables that measured feelings of not being able to influence a work situation characterised by great demands and insufficient resources. Routines and educational programs for dealing with stress should be available on a routine basis. (c) Multivariate analyses identified three extreme groups: (i) a small group dominated by unqualified staff with high depersonalization, (ii) a large group that was low on depersonalisation and high on work demands with a majority of qualified staff, and (iii) a small N-R C-dominated group (low depersonalization, low work demands) with high scores on professional self-doubt. In contrast to (ii) the small and N-R C-dominated groups in (i) and (iii) reflected mainly centre-dependent problems.</p> <p>Conclusion</p> <p>The differences in burnout and sources of stress between the two groups were generally small. With the exception of high work demands the main differences between the two groups appeared to be centre-dependent. High work demands characterized primarily qualified staff. The main implication of the study is that no special measures addressed towards N-R Cs in general with regard to stress and burnout seem necessary. The results also suggest that centre-specific problems may cause more stress among N-R Cs compared to the qualified staff (e.g. professional self-doubt).</p

Addison's disease symptoms - a cross sectional study in urban South Africa

BACKGROUND: Addison's disease is a potentially life-threatening disorder, and prompt diagnosis, and introduction of steroid replacement has resulted in near normal life-expectancy. There are limited data describing the clinical presentation of Addison's disease in South Africa. It is hypothesised that patients may present in advanced state of ill-health, compared to Western countries. Patients A national database of patients was compiled from primary care, referral centres and private practices. 148 patients were enrolled (97 white, 34 mixed ancestry, 5 Asian and 12 black). METHODS: Demographic and clinical data were elicited using questionnaires. Biochemical data were obtained from folder reviews and laboratory archived results. RESULTS: The majority of the cohort was women (62%). The median and inter-quartile age range (IQR) of patients at enrolment was 46.0 (32.0-61.0) years, with a wide range from 2.8-88.0 years. The median and IQR age at initial diagnosis was 34.0 (20.0-45.0) years (range 0.02-77.0) years, indicating that at the time of enrolment, the patients, on average, were diagnosed with Addison's disease 12 years previously. Hyperpigmentation was observed in 76%, nausea and vomiting occurred in more than 40%, and weight loss was noted in 25%. Loss of consciousness as a presenting feature was recorded in 20 %. with a 95% confidence interval [CI] of (14-28%) and shock occurred in 5% CI (1.5-8.5%). Case-finding was recorded at 3.1 per million. CONCLUSIONS: The usual constellation of hyperpigmentation, nausea, vomiting and weight loss suggests Addison's disease, but a significant proportion present with an advanced state of ill-health and Addisonian crises. A lower prevalence rate, compared to Western countries is suggested

Esterase-D and chromosome patterns in Central Amazon piranha (Serrasalmus rhombeus Linnaeus, 1766) from Lake Catalão

This study presents additional genetic data on piranha (Serrasalmus rhombeus Linnaeus, 1766) complex previously diagnosed due to the presence of distinct cytotypes 2n = 58 and 2n = 60. Three esterase-D enzyme loci (Est-D1, Est-D2 and Est-D3) were examined and complemented with chromosomal data from 66 piranha specimens collected from Lake Catalão. For all specimens the Est-D1 and Est-D2 loci were monomorphic. In contrast, the Est-D3 locus was polymorphic with genotypes and alleles being differentially distributed in the previously described cytotypes and served as the basis for detecting a new cytotype (2n = 60 B). In cytotype 2n = 58 the Est-D3 locus was also polymorphic and presented Mendelian allelic segregation with four genotypes (Est-D311, Est-D312, Est-D322 and Est-D333) out of six theoretically possible genotypes, presumably encoded by alleles Est-D31 (frequency = 0.237), EsT-D32 (0.710) and Est-D33 (0.053). A Chi-squared (χ2) test for Hardy-Weinberg equilibrium was applied to the Est-D3locus and revealed a genetic unbalance in cytotype 2n = 58, indicating the probable existence in the surveyed area of different stocks for that karyotypic structure. A silent null allele (Est-D30 with a high frequency (0.959) occurred exclusively in the 2n = 60 cytotype. On the other hand, the new cytotype 2n = 60 B described here for the first time was monomorphic for the presumably fixed Est-D33 allele. The data as a whole should contribute to the better understanding the rhombeus complex taxonomic status definitíon in the Central Amazon. © 2006 Sociedade Brasileira de Genética

Perspectives and Integration in SOLAS Science

Why a chapter on Perspectives and Integration in SOLAS Science in this book? SOLAS science by its nature deals with interactions that occur: across a wide spectrum of time and space scales, involve gases and particles, between the ocean and the atmosphere, across many disciplines including chemistry, biology, optics, physics, mathematics, computing, socio-economics and consequently interactions between many different scientists and across scientific generations. This chapter provides a guide through the remarkable diversity of cross-cutting approaches and tools in the gigantic puzzle of the SOLAS realm. Here we overview the existing prime components of atmospheric and oceanic observing systems, with the acquisition of ocean–atmosphere observables either from in situ or from satellites, the rich hierarchy of models to test our knowledge of Earth System functioning, and the tremendous efforts accomplished over the last decade within the COST Action 735 and SOLAS Integration project frameworks to understand, as best we can, the current physical and biogeochemical state of the atmosphere and ocean commons. A few SOLAS integrative studies illustrate the full meaning of interactions, paving the way for even tighter connections between thematic fields. Ultimately, SOLAS research will also develop with an enhanced consideration of societal demand while preserving fundamental research coherency. The exchange of energy, gases and particles across the air-sea interface is controlled by a variety of biological, chemical and physical processes that operate across broad spatial and temporal scales. These processes influence the composition, biogeochemical and chemical properties of both the oceanic and atmospheric boundary layers and ultimately shape the Earth system response to climate and environmental change, as detailed in the previous four chapters. In this cross-cutting chapter we present some of the SOLAS achievements over the last decade in terms of integration, upscaling observational information from process-oriented studies and expeditionary research with key tools such as remote sensing and modelling. Here we do not pretend to encompass the entire legacy of SOLAS efforts but rather offer a selective view of some of the major integrative SOLAS studies that combined available pieces of the immense jigsaw puzzle. These include, for instance, COST efforts to build up global climatologies of SOLAS relevant parameters such as dimethyl sulphide, interconnection between volcanic ash and ecosystem response in the eastern subarctic North Pacific, optimal strategy to derive basin-scale CO2 uptake with good precision, or significant reduction of the uncertainties in sea-salt aerosol source functions. Predicting the future trajectory of Earth’s climate and habitability is the main task ahead. Some possible routes for the SOLAS scientific community to reach this overarching goal conclude the chapter