Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets.

Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases.

Posterior-scleritis: Case report of an uncommon immune-related adverse event in the treatment of advanced endometrial cancer.

As Immune checkpoint inhibitors are being expanded for use in gynecologic malignancies, rare immune-related adverse events are more frequently being reported. Here we describe a 63-year-old with Stage IIIB mismatch repair deficient uterine adenocarcinoma who underwent six cycles of carboplatin and paclitaxel with partial response but persistent disease. She was then started on single agent pembrolizumab.

Living with prostate cancer: a mixed-method evaluation of group therapy intervention to alleviate psychological distress in a Canadian setting.

Purpose: To assess the effects of group therapy focused on the experience of living with prostate cancer (PC) on depression and mental well-being among men with the disease and to explore participant experiences of a guided opportunity to 'speak the unspeakable' as it pertains to living with PC.

Methods: We used a mixed-method convergent design. Participants completed four validated self-report questionnaires at baseline, immediately after the final session, and at three, six, and 12 months follow-up.

The adaptor protein PICK1 targets the sorting receptor SorLA.

SorLA is a member of the Vps10p-domain (Vps10p-D) receptor family of type-I transmembrane proteins conveying neuronal endosomal sorting. The extracellular/luminal moiety of SorLA has a unique mosaic domain composition and interacts with a large number of different and partially unrelated ligands, including the amyloid precursor protein as well as amyloid-β. Several studies support a strong association of SorLA with sporadic and familial forms of Alzheimer's disease (AD).

Converging roles of PSENEN/PEN2 and CLN3 in the autophagy-lysosome system.

PSENEN/PEN2 is the smallest subunit of the γ-secretase complex, an intramembrane protease that cleaves proteins within their transmembrane domains. Mutations in components of the γ-secretase underlie familial Alzheimer disease. In addition to its proteolytic activity, supplementary, γ-secretase independent, functions in the macroautophagy/autophagy-lysosome system have been proposed.

Burnout, compassion fatigue and work-related stressors among organ donation and transplantation coordinators: A qualitative study.

Aim: Organ and Tissue Donation Coordinators (OTDCs) are healthcare professionals who manage deceased organ donation cases. This study investigated the experiences and perceptions of OTDCs, pertaining to compassion fatigue, burnout, and resilience as it relates to their daily work.

Methodology: A qualitative descriptive study was undertaken using semi-structured interviews conducted with a convenience sample of OTDCs.

[Effect of a One-Week Health Program on the Mental Health of Caregiving Parents: A Controlled Panel Study].

Objectives: Parents of children in need of care and home care are a vulnerable group. The aim of this study was to determine the effect of a legally funded, one-week health program of the Social Insurance for Agriculture, Forestry and Horticulture (SVLFG) on the well-being of the participating caregiving. Methods In a controlled panel study (intervention group IG n=23, comparison group n=33, allocation not randomized), the WHO-5 index was collected at several time points of measurement.

Neuronal activity regulates alternative exon usage.

Neuronal activity-regulated gene transcription underlies plasticity-dependent changes in the molecular composition and structure of neurons. A large number of genes regulated by different neuronal plasticity inducing pathways have been identified, but altered gene expression levels represent only part of the complexity of the activity-regulated transcriptional program. Alternative splicing, the differential inclusion and exclusion of exonic sequence in mRNA, is an additional mechanism that is thought to define the activity-dependent transcriptome.

Health literacy and the quality of pharmacist-patient communication among those prescribed anticoagulation therapy.

Background: Adequate counseling from a pharmacist concerning anticoagulation therapy is crucial to the wellbeing of patients. No studies have fully examined the relationship between health literacy, patient-pharmacist communication, and anticoagulation control.

Objective(s): To evaluate the relationship between health literacy and the perceived quality of patient-pharmacist communication among those receiving anticoagulation therapy.

Heavy Episodic Drinking in Early Adulthood: How Parents' Education Contextualizes the Effects of College Status.

Young adults who transition to college are at particular risk of heavy episodic drinking (HED), as they consume more alcohol than their same-aged peers who do not attend college. Yet the link between college attendance and HED during young adulthood may vary depending on social class origins. Building on life course and socio-structural perspectives that suggest that status characteristics give meaning to role transitions in ways that shape young adults' drinking behavior, this study situates the risk of HED within the sociological context of educational attainment, and examines how parents' education conditions the relationship between young adults' college status and HED.

More comprehensively measuring quality of life in life-threatening illness: the McGill Quality of Life Questionnaire - Expanded.

Background: Domains other than those commonly measured (physical, psychological, social, and sometimes existential/spiritual) are important to the quality of life of people with life-threatening illness. The McGill Quality of Life Questionnaire (MQOL) - Revised measures the four common domains. The aim of this study was to create a psychometrically sound instrument, MQOL - Expanded, to comprehensively measure quality of life by adding to MQOL-Revised the domains of cognition, healthcare, environment, (feeling like a) burden, and possibly, finance.

Disturbed Prefrontal Cortex Activity in the Absence of Schizophrenia-Like Behavioral Dysfunction in Deficient Mice.

, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditional knock-out (KO) mice to investigate the causal relationship between deletion and schizophrenia-linked neurophysiological and behavioral phenotypes.

Amyloidosis causes downregulation of SorLA, SorCS1 and SorCS3 expression in mice.

Accumulation of β-amyloid peptide (Aβ) is regarded as a primary cause of Alzheimer's disease (AD). Aβ is derived by sequential cleavage of the amyloid precursor protein (APP). Alterations in the subcellular targeting of APP are thought to affect the degree of Aβ production.

Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice.

In humans, genetic variants of DLGAP1-4 have been linked with neuropsychiatric conditions, including autism spectrum disorder (ASD). While these findings implicate the encoded postsynaptic proteins, SAPAP1-4, in the etiology of neuropsychiatric conditions, underlying neurobiological mechanisms are unknown. To assess the contribution of SAPAP4 to these disorders, we characterized SAPAP4-deficient mice.

Cut to the Quick: The Consequences of Youth Violent Victimization for the Timing of Dating Debut and First Union Formation.

Concentrated in adolescence, violent victimization is developmentally disruptive. It undermines physical, mental, and socioemotional well-being and compromises youths' transitions into and progression through key life course tasks. Youth violent victimization (YVV) has been linked to precocious exits from adolescence and premature entries into adulthood.

Arc/Arg3.1 mediates a critical period for spatial learning and hippocampal networks.

During early postnatal development, sensory regions of the brain undergo periods of heightened plasticity which sculpt neural networks and lay the foundation for adult sensory perception. Such critical periods were also postulated for learning and memory but remain elusive and poorly understood. Here, we present evidence that the activity-regulated and memory-linked gene Arc/Arg3.

Structural Properties of Synaptic Transmission and Temporal Dynamics at Excitatory Layer 5B Synapses in the Adult Rat Somatosensory Cortex.

Cortical computations rely on functionally diverse and highly dynamic synapses. How their structural composition affects synaptic transmission and plasticity and whether they support functional diversity remains rather unclear. Here, synaptic boutons on layer 5B (L5B) pyramidal neurons in the adult rat barrel cortex were investigated.

SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling.

Medial vascular calcification, associated with enhanced mortality in chronic kidney disease (CKD), is fostered by osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Here, we describe that serum- and glucocorticoid-inducible kinase 1 (SGK1) was upregulated in VSMCs under calcifying conditions. In primary human aortic VSMCs, overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation.

Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation.

Skin-migratory dendritic cells (migDCs) are pivotal antigen-presenting cells that continuously transport antigens to draining lymph nodes and regulate immune responses. However, identification of migDCs is complicated by the lack of distinguishing markers, and it remains unclear which molecules determine their migratory capacity during inflammation. We show that, in the skin, the neuronal plasticity molecule activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.

Neuronal activity-regulated alternative mRNA splicing.

Activity-regulated gene transcription underlies plasticity-dependent changes in the molecular composition and structure of neurons. Numerous genes whose expression is induced by different neuronal plasticity inducing pathways have been identified, but the alteration of gene expression levels represents only part of the complexity of the activity-regulated transcriptional program. Alternative splicing of precursor mRNA is an additional mechanism that modulates the activity-dependent transcriptional signature.

Profiling the MAPK/ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus in vivo.

Activity-dependent alteration of the transcriptional program is central for shaping neuronal connectivity. Constitutively expressed transcription factors orchestrate the initial response to neuronal stimulation and serve as substrates for second messenger-regulated kinase signalling cascades. The mitogen-activated protein kinase ERK conveys signalling from the synapse to the nucleus but its genetic signature following neuronal activity has not been revealed.

Parenthood Residency Status and Criminal Desistance across Neighborhood Contexts.

Research on desistance and parenthood has yielded mixed results bringing into question whether, and for whom, parenthood matters. Scholarship has not fully explored the importance of residency status or patterns of desistance across a full range of neighborhood contexts, nor examined distinctions between temporary and long-term desistance. Our study uses data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to examine the association between parenthood residence and criminal desistance across levels of adolescent neighborhood poverty.

Race, Adolescent Binge Drinking, and the Context of Neighborhood Exposure.

Drawing on theories of social structure and normative exposure, we examine how the neighborhood context of socioeconomic advantage and racial composition affects race/ethnic differences in youth binge drinking. Using data from Waves 1 and 2 of the National Longitudinal Study of Adolescent to Adult Health, logistic regressions reveal significant racial differences, with whites having higher odds of binge drinking than other groups. We also find that neighborhood advantage and racial composition have moderating effects on binge drinking; black youths' odds of binge drinking are significantly lower than whites' odds in highly advantaged neighborhoods, and Hispanics living in racially integrated neighborhoods have significantly lower odds of binge drinking than Hispanics living in white neighborhoods.