Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

Ten considerations for effectively managing the COVID-19 transition

Governments around the world have implemented measures to manage the transmission of coronavirus disease 2019 (COVID-19). While the majority of these measures are proving effective, they have a high social and economic cost, and response strategies are being adjusted. The World Health Organization (WHO) recommends that communities should have a voice, be informed and engaged, and participate in this transition phase. We propose ten considerations to support this principle: (1) implement a phased approach to a 'new normal'; (2) balance individual rights with the social good; (3) prioritise people at highest risk of negative consequences; (4) provide special support for healthcare workers and care staff; (5) build, strengthen and maintain trust; (6) enlist existing social norms and foster healthy new norms; (7) increase resilience and self-efficacy; (8) use clear and positive language; (9) anticipate and manage misinformation; and (10) engage with media outlets. The transition phase should also be informed by real-time data according to which governmental responses should be updated

The quest for the solar g modes

Solar gravity modes (or g modes) -- oscillations of the solar interior for which buoyancy acts as the restoring force -- have the potential to provide unprecedented inference on the structure and dynamics of the solar core, inference that is not possible with the well observed acoustic modes (or p modes). The high amplitude of the g-mode eigenfunctions in the core and the evanesence of the modes in the convection zone make the modes particularly sensitive to the physical and dynamical conditions in the core. Owing to the existence of the convection zone, the g modes have very low amplitudes at photospheric levels, which makes the modes extremely hard to detect. In this paper, we review the current state of play regarding attempts to detect g modes. We review the theory of g modes, including theoretical estimation of the g-mode frequencies, amplitudes and damping rates. Then we go on to discuss the techniques that have been used to try to detect g modes. We review results in the literature, and finish by looking to the future, and the potential advances that can be made -- from both data and data-analysis perspectives -- to give unambiguous detections of individual g modes. The review ends by concluding that, at the time of writing, there is indeed a consensus amongst the authors that there is currently no undisputed detection of solar g modes.Comment: 71 pages, 18 figures, accepted by Astronomy and Astrophysics Revie

Global Health Education: a cross-sectional study among German medical students to identify needs, deficits and potential benefits (Part 2 of 2: Knowledge gaps and potential benefits)

<p>Abstract</p> <p>Background</p> <p>In Germany, educational deficits or potential benefits involved in global health education have not been analysed till now.</p> <p>Objective</p> <p>We assess the importance medical students place on learning about social determinants of health (SDH) and assess their knowledge of global health topics in relation to (i) mobility patterns, their education in (ii) tropical medicine or (iii) global health.</p> <p>Methods</p> <p>Cross-sectional study among medical students from all 36 medical schools in Germany using a web-based, semi-structured questionnaire. Participants were recruited via mailing-lists of students' unions, all medical students registered in 2007 were eligible to participate in the study. We captured international mobility patterns, exposure to global health learning opportunities and attitudes to learning about SDH. Both an objective and subjective knowledge assessment were performed.</p> <p>Results</p> <p>1126 online-replies were received and analysed. International health electives in developing countries correlated significantly with a higher importance placed on all provided SDH (p ≤ 0.006). Participation in tropical medicine (p < 0.03) and global health courses (p < 0.02) were significantly associated with a higher rating of 'culture, language and religion' and the 'economic system'. Global health trainings correlated with significantly higher ratings of the 'educational system' (p = 0.007) and the 'health system structure' (p = 0.007), while the item 'politics' was marginally significant (p = 0.053).</p> <p>In the knowledge assessment students achieved an average score of 3.6 (SD 1.5; Mdn 4.0), 75% achieved a score of 4.0 or less (Q₂₅= 3.0; Q₇₅= 4.0) from a maximum achievable score of 8.0. A better performance was associated with international health electives (p = 0.032), participation in tropical medicine (p = 0.038) and global health (p = 0.258) courses.</p> <p>Conclusion</p> <p>The importance medical students in our sample placed on learning about SDH strongly interacts with students' mobility, and participation in tropical medicine and global health courses. The knowledge assessment revealed deficits and outlined needs to further analyse education gaps in global health. Developing concerted educational interventions aimed at fostering students' engagement with SDH could make full use of synergy effects inherent in student mobility, tropical medicine and global health education.</p

Methionine Sulfoxide Reductases Are Essential for Virulence of Salmonella Typhimurium

Production of reactive oxygen species represents a fundamental innate defense against microbes in a diversity of host organisms. Oxidative stress, amongst others, converts peptidyl and free methionine to a mixture of methionine-S- (Met-S-SO) and methionine-R-sulfoxides (Met-R-SO). To cope with such oxidative damage, methionine sulfoxide reductases MsrA and MsrB are known to reduce MetSOs, the former being specific for the S-form and the latter being specific for the R-form. However, at present the role of methionine sulfoxide reductases in the pathogenesis of intracellular bacterial pathogens has not been fully detailed. Here we show that deletion of msrA in the facultative intracellular pathogen Salmonella (S.) enterica serovar Typhimurium increased susceptibility to exogenous H2O2, and reduced bacterial replication inside activated macrophages, and in mice. In contrast, a ΔmsrB mutant showed the wild type phenotype. Recombinant MsrA was active against free and peptidyl Met-S-SO, whereas recombinant MsrB was only weakly active and specific for peptidyl Met-R-SO. This raised the question of whether an additional Met-R-SO reductase could play a role in the oxidative stress response of S. Typhimurium. MsrC is a methionine sulfoxide reductase previously shown to be specific for free Met-R-SO in Escherichia (E.) coli. We tested a ΔmsrC single mutant and a ΔmsrBΔmsrC double mutant under various stress conditions, and found that MsrC is essential for survival of S. Typhimurium following exposure to H2O2, as well as for growth in macrophages, and in mice. Hence, this study demonstrates that all three methionine sulfoxide reductases, MsrA, MsrB and MsrC, facilitate growth of a canonical intracellular pathogen during infection. Interestingly MsrC is specific for the repair of free methionine sulfoxide, pointing to an important role of this pathway in the oxidative stress response of Salmonella Typhimurium

Temporal and Spatial Profiling of Root Growth Revealed Novel Response of Maize Roots under Various Nitrogen Supplies in the Field

A challenge for Chinese agriculture is to limit the overapplication of nitrogen (N) without reducing grain yield. Roots take up N and participate in N assimilation, facilitating dry matter accumulation in grains. However, little is known about how the root system in soil profile responds to various N supplies. In the present study, N uptake, temporal and spatial distributions of maize roots, and soil mineral N (Nmin) were thoroughly studied under field conditions in three consecutive years. The results showed that in spite of transient stimulation of growth of early initiated nodal roots, N deficiency completely suppressed growth of the later-initiated nodal roots and accelerated root death, causing an early decrease in the total root length at the rapid vegetative growth stage of maize plants. Early N excess, deficiency, or delayed N topdressing reduced plant N content, resulting in a significant decrease in dry matter accumulation and grain yield. Notably, N overapplication led to N leaching that stimulated root growth in the 40–50 cm soil layer. It was concluded that the temporal and spatial growth patterns of maize roots were controlled by shoot growth and local soil Nmin, respectively. Improving N management involves not only controlling the total amount of chemical N fertilizer applied, but also synchronizing crop N demand and soil N supply by split N applications

Excretion patterns of coccidian oocysts and nematode eggs during the reproductive season in Northern Bald Ibis (Geronticus eremita)

Individual reproductive success largely depends on the ability to optimize behaviour, immune function and the physiological stress response. We have investigated correlations between behaviour, faecal steroid metabolites, immune parameters, parasite excretion patterns and reproductive output in a critically endangered avian species, the Northern Bald Ibis (Geronticus eremita). In particular, we related haematocrit, heterophil/lymphocyte ratio, excreted immune-reactive corticosterone metabolites and social behaviour with parasite excretion and two individual fitness parameters, namely, number of eggs laid and number of fledglings. We found that the frequency of excretion of parasites’ oocysts and eggs tended to increase with ambient temperature. Paired individuals excreted significantly more samples containing nematode eggs than unpaired ones. The excretion of nematode eggs was also significantly more frequent in females than in males. Individuals with a high proportion of droppings containing coccidian oocysts were more often preened by their partners than individuals with lower excretion rates. We observed that the more eggs an individual incubated and the fewer offspring fledged, the higher the rates of excreted samples containing coccidian oocysts. Our results confirm that social behaviour, physiology and parasite burden are linked in a complex and context-dependent manner. They also contribute background information supporting future conservation programmes dealing with this critically endangered species