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S The high percentage of centers using digital records is encouraging. RG-7112 However, routine adjudication of clinical events in NMOSD seems highly heterogeneous. MRI is the mainstay in the majority of queried centers, but its immediate availability is limited. Only a minority of centers are equipped for trial-grade classification of attacks, if this is not solely clinically based. Thus, standard and feasible guidelines for attack adjudication are urgently needed to standardize routine care, optimize future clinical trials and allow studying long-term safety and efficacy of newly approved drugs in phase IV trials. INTRODUCTION In Multiple Sclerosis (MS), withdrawal from employment is a critical problem. This study explores relationships between disease characteristics, work difficulties, health-related quality of life, depression, and stigma and how these factors affect employment status. METHODS A multicenter, non-interventional, cross-sectional study was conducted in adults with relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). Patient-reported questionnaires included 23-item Multiple Sclerosis Work Difficulties Questionnaire, 29-item Multiple Sclerosis Impact Scale, Stigma Scale for Chronic Illness, and Beck Depression Inventory-Fast Screen. RESULTS A total of 199 individuals (mean age = 43.9 ± 10.5 years, 60.8% female, 86.4% with RRMS) participated in the study. Mean time from diagnosis was 9.6 ± 7.2 years and median Expanded Disability Status Scale score was 2.0 (interquartile range 1.0-3.5). Employment rate was 47.2% (n = 94). Mean physical and psychological MSIS-29 impact sub-scores were 40.38 ± 17.1 and 20.24 ± 7.8, respectively. Forty patients (19.9%) had at least one SSCI-8 item with a score of 4 or 5, suggesting the presence of stigma often or always. Eighty-one patients (40.7%) were depressed and 25 (12.6%) had moderate-to-severe depression. Work difficulties were higher in those with worse functional status, a diagnosis of PPMS, and lower educational levels. Employed participants had lower perceptions of stigma and depressive symptoms than those not employed. Higher perceptions of stigma were also strongly linked to higher physical and psychological impact on health-related quality of life and greater work difficulties. Depressive symptoms were also strongly related to work-related problems. CONCLUSIONS Work difficulties, stigma and poor quality of life are common in MS patients, even in a population with low physical disability. Evaluation of these dimensions in clinical practice would allow the development of targeted rehabilitation and specific work plans for MS employers. Defining the pathways that control cardiac development facilitates understanding the pathogenesis of congenital heart disease. Herein, we identify enrichment of a Cullin5 Ub ligase key subunit, Asb2, in myocardial progenitors and differentiated cardiomyocytes. Using two conditional murine knockouts, Nkx+/Cre.Asb2fl/fl and AHF-Cre.Asb2fl/fl, and tissue clarifying technique, we reveal Asb2 requirement for embryonic survival and complete heart looping. Deletion of Asb2 results in upregulation of its target Filamin A (Flna), and concurrent Flna deletion partially rescues embryonic lethality. Conditional AHF-Cre.Asb2 knockouts harboring one Flna allele have double outlet right ventricle (DORV), which is rescued by biallelic Flna excision. Transcriptomic and immunofluorescence analyses identify Tgfβ/Smad as downstream targets of Asb2/Flna. Finally, using CRISPR/Cas9 genome editing, we demonstrate Asb2 requirement for human cardiomyocyte differentiation suggesting a conserved mechanism between mice and humans. Collectively, our study provides deeper mechanistic understanding of the role of the ubiquitin proteasome system in cardiac development and suggests a previously unidentified murine model for DORV. Compared with other mammals, bats harbor more zoonotic viruses per species and do not demonstrate signs of disease on infection with these viruses. To counteract infections with viruses, bats have evolved enhanced mechanisms to limit virus replication and immunopathology. However, molecular and cellular drivers of antiviral responses in bats largely remain an enigma. In this study, we demonstrate that a serine residue in IRF3 is positively selected for in multiple bat species. IRF3 is a central regulator of innate antiviral responses in mammals. Replacing the serine residue in bat IRF3 with the human leucine residue decreased antiviral protection in bat cells, whereas the addition of this serine residue in human IRF3 significantly enhanced antiviral protection in human cells. Our study provides genetic and functional evidence for enhanced IRF3-mediated antiviral responses in bats and adds support to speculations that bats have positively selected for multiple adaptations in their antiviral immune responses. The SUSD4 (Sushi domain-containing protein 4) gene encodes a complement inhibitor that is frequently deleted in 1q41q42 microdeletion syndrome, a multisystem congenital disorder that includes neurodevelopmental abnormalities. To understand SUSD4's role in the mammalian nervous system, we analyzed Susd4 knockout (KO) mice. Susd4 KO mice exhibited significant defects in motor performance and significantly higher levels of anxiety-like behaviors. Susd4 KO brain had abnormal "hairy" basket cells surrounding Purkinje neurons within the cerebellum and significantly reduced dendritic spine density in hippocampal pyramidal neurons. Neurons and oligodendrocyte lineage cells of wild-type mice were found to express Susd4 mRNA. Protein expression of the complement component C1q was increased in the brains of Susd4 KO mice. Our data indicate that SUSD4 plays an important role in neuronal functions, possibly via the complement pathway, and that SUSD4 deletion may contribute to the nervous system abnormalities in patients with 1q41q42 deletions. Published by Elsevier Inc.The maintenance of the intestinal epithelium is ensured by the controlled proliferation of intestinal stem cells (ISCs) and differentiation of their progeny into various cell types, including enterocytes (ECs) that both mediate nutrient absorption and provide a barrier against pathogens. The signals that regulate transition of proliferative ISCs into differentiated ECs are not fully understood. IRBIT is an evolutionarily conserved protein that regulates ribonucleotide reductase (RNR), an enzyme critical for the generation of DNA precursors. Here, we show that IRBIT expression in ISC progeny within the Drosophila midgut epithelium cells regulates their differentiation via suppression of RNR activity. Disruption of this IRBIT-RNR regulatory circuit causes a premature loss of intestinal tissue integrity. Furthermore, age-related dysplasia can be reversed by suppression of RNR activity in ISC progeny. Collectively, our findings demonstrate a role of the IRBIT-RNR pathway in gut homeostasis. Published by Elsevier Inc.