SummaryFragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.

Twitter Irene Torres @lairene1 Acknowledgements The authors are grateful to all people that provided information in our crowdsourcing effort and the Gender and COVID-19 working group for their input and thoughts. Contributors All authors contributed to the design and implementation of the research, to the analysis of the results and to the writing of the manuscript.

Equal doses of veralipride have been given to 12 healthy volunteers by three different administrations--intravenous infusion, oral solution, and oral capsules--in a randomized cross-over design. After the intake of the solution, but not after infusion or capsules, two maximum plasma concentrations have been observed and interpreted, according to a double-site model for drug absorption.

SummaryIn this study, we deep-sequenced the mtDNA of human embryonic and induced pluripotent stem cells (hESCs and hiPSCs) and their source cells and found that the majority of variants pre-existed in the cells used to establish the lines. Early-passage hESCs carried few and low-load heteroplasmic variants, similar to those identified in oocytes and inner cell masses. The number and heteroplasmic loads of these variants increased with prolonged cell culture. The study of 120 individual cells of early- and late-passage hESCs revealed a significant diversity in mtDNA heteroplasmic variants at the single-cell level and that the variants that increase during time in culture are always passenger to the appearance of chromosomal abnormalities. We found that early-passage hiPSCs carry much higher loads of mtDNA variants than hESCs, which single-fibroblast sequencing proved pre-existed in the source cells. Finally, we show that these variants are stably transmitted during short-term differentiation.

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There was significant interpatient and intrapatient variability in the disposition of 9NC and 9AC. 9NC and 9AC undergo primarily nonrenal elimination.

As in many European countries, the Public Health Service (PHS) in Germany has had considerable difficulties in attracting well-qualified personnel for decades. Despite ongoing political and societal debate, limited empirical research on possible causes and explanations is available. To identify areas of action, we explored reasons for the (lack of) interest in working in the PHS by conducting two cross-sectional surveys among 3019 medical students (MS), public health students, and students from other PHS-relevant fields (PH&ONM) in Germany right before (wave 1, 2019/2020) and during the COVID-19 pandemic (wave 2, 2021). While interest in working in the PHS among MS was low, it was considerably higher among PH&ONM. The prevalent underestimation of the importance of public health and low levels of knowledge about the PHS were identified as potential barriers. Although core activities of the PHS were often considered attractive, they were repeatedly not attributed to the PHS. A negative perception of the PHS (e.g., it being too bureaucratic) was prevalent among students with and without PHS interest, indicating that both a negative image and potentially structural deficits need to be overcome to increase attractiveness. Based on the findings, we propose approaches on how to sustainably attract and retain qualified personnel.