SUMMARY Notch is a conserved signaling pathway that is essential for metazoan development and homeostasis; dysregulated signaling underlies the pathophysiology of numerous human diseases. Receptor-ligand interactions result in gene expression changes, which are regulated by the transcription factor RBPJ. RBPJ forms a complex with the intracellular domain of the Notch receptor and the coactivator Mastermind to activate transcription, but it can also function as a repressor by interacting with corepressor proteins. Here, we determine the structure of RBPJ bound to the corepressor SHARP and DNA, revealing its mode of binding to RBPJ. We tested structure-based mutants in biophysical and biochemical-cellular as-says to characterize the role of RBPJ as a repressor, clearly demonstrating that RBPJ mutants deficient for SHARP binding are incapable of repressing transcription of genes responsive to Notch signaling in cells. Altogether, our structure-function studies provide significant insights into the repressor function of RBPJ.

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The implementation and continued expansion of telehealth services assists a variety of health care organizations in the delivery of care during the current COVID-19 global pandemic. However, limited research has been conducted on recent, rapid telehealth implementation and expansion initiatives regarding facilitators and barriers surrounding the provision of quality patient care. Our rapid review evaluated the literature specific to rapid telehealth implementation during the current COVID-19 pandemic from three research databases between January 2020 and May 2020 and reported using preferred reporting items for systematic reviews and meta-analyses (PRISMA). The results indicate the rapid implementation and enhanced use of telehealth during the COVID-19 pandemic in the United States surrounding the facilitators and barriers to the provision of patient care, which are categorized into three identified themes: (1) descriptive process-oriented implementations, (2) the interpretation and infusion of the CARES Act of 2020 telehealth exemptions related to the relaxation of patient privacy and security (HIPAA) protocols, and (3) the standard of care protocols and experiences addressing organizational liability and the standard of care. While the study limitation of sample size exists (n = 21), an identification of rapid telehealth implementation advancements and challenges during the current pandemic may assist health care organizations in the delivery of ongoing quality care during the COVID-19 pandemic.

Our data suggests that there may be a role for preadmission beta-blockers in reducing sepsis-related mortality.

Notch signalling activity governs cellular differentiation in higher metazoa, where Notch signals are transduced by the transcription factor CSL, called Suppressor of Hairless [Su(H)] in Drosophila. Su(H) operates as molecular switch on Notch target genes: within activator complexes, including intracellular Notch, or within repressor complexes, including the antagonist Hairless. Mass spectrometry identified phosphorylation on Serine 269 in Su(H), potentially serving as a point of cross-regulation by other signalling pathways. To address the biological significance, we generated phospho-deficient [Su(H)S269A] and phospho-mimetic [Su(H)S269D] variants: the latter displayed reduced transcriptional activity despite unaltered protein interactions with co-activators and -repressors. Based on the Su(H) structure, Ser269 phosphorylation may interfere with DNA-binding, which we confirmed by electro-mobility shift assay and isothermal titration calorimetry. Overexpression of Su(H)S269D during fly development demonstrated reduced transcriptional regulatory activity, similar to the previously reported DNA-binding defective mutant Su(H)R266H. As both are able to bind Hairless and Notch proteins, Su(H)S269D and Su(H)R266H provoked dominant negative effects upon overexpression. Our data imply that Ser269 phosphorylation impacts Notch signalling activity by inhibiting DNA-binding of Su(H), potentially affecting both activation and repression. Ser269 is highly conserved in vertebrate CSL homologues, opening the possibility of a general and novel mechanism of modulating Notch signalling activity.