Native Mass Spectrometry Reveals Binding Interactions of SARS-CoV-2 PLpro with Inhibitors and Cellular Targets.

Here we used native mass spectrometry (native MS) to probe a SARS-CoV protease, PLpro, which plays critical roles in coronavirus disease by affecting viral protein production and antagonizing host antiviral responses. Ultraviolet photodissociation (UVPD) and variable temperature electrospray ionization (vT ESI) were used to localize binding sites of PLpro inhibitors and revealed the stabilizing effects of inhibitors on protein tertiary structure. We compared PLpro from SARS-CoV-1 and SARS-CoV-2 in terms of inhibitor and ISG15 interactions to discern possible differences in protease function.

Upregulated solute-carrier family genes in the hippocampus of schizophrenia can be rescued by antipsychotic medications.

Background And Hypothesis: Our previous studies have found that functional changes in the hippocampal circuit from dentate gyrus (DG) to cornu ammonis 3 and 1 (CA3, CA1) are highly associated with schizophrenia (SZ). However, no studies have explored the genetic expression across the three and two human hippocampal subfields (DG-CA3-CA1 and CA3-CA1) between subjects with SZ and healthy controls (CT).

Study Design: We matched cohorts between CT (n = 13) and SZ (n = 13).

Cellular targets and lysine selectivity of the HERC5 ISG15 ligase.

ISG15 is a type I interferon-induced ubiquitin-like modifier that functions in innate immune responses. The major human ISG15 ligase is hHERC5, a ribosome-associated HECT E3 that broadly ISGylates proteins cotranslationally. Here, we characterized the hHERC5-dependent ISGylome and identified over 2,000 modified lysines in over 1,100 proteins in IFN-β-stimulated cells.

Hippocampal subfield transcriptome analysis in schizophrenia psychosis.

We have previously demonstrated functional and molecular changes in hippocampal subfields in individuals with schizophrenia (SZ) psychosis associated with hippocampal excitability. In this study, we use RNA-seq and assess global transcriptome changes in the hippocampal subfields, DG, CA3, and CA1 from individuals with SZ psychosis and controls to elucidate subfield-relevant molecular changes. We also examine changes in gene expression due to antipsychotic medication in the hippocampal subfields from our SZ ON- and OFF-antipsychotic medication cohort.

ACCESS Open Minds at the University of Alberta: Transforming student mental health services in a large Canadian post-secondary educational institution.

Aim: Demands for mental health services in post-secondary institutions are increasing. This paper describes key features of a response to these needs: ACCESS Open Minds University of Alberta (ACCESS OM UA) is focused on improving mental health services for first-year students, as youth transition to university and adulthood.

Methods: The core transformation activities at ACCESS OM UA are described, including early case identification, rapid access, appropriate and timely connections to follow-up care and engagement of students and families/carers.

Molecular alterations in the medial temporal lobe in schizophrenia.

The medial temporal lobe (MTL) and its individual structures have been extensively implicated in schizophrenia pathophysiology, with considerable efforts aimed at identifying structural and functional differences in this brain region. The major structures of the MTL for which prominent differences have been revealed include the hippocampus, the amygdala and the superior temporal gyrus (STG). The different functions of each of these regions have been comprehensively characterized, and likely contribute differently to schizophrenia.

Phosphorylation of the E3 ubiquitin protein ligase ITCH diminishes binding to its cognate E2 ubiquitin ligase.

Heightened and extended inflammation underlies the pathogenesis of many disorders, including inflammatory bowel disease, sepsis, and inflammatory arthritis. Ubiquitin networks help dictate the strength and duration of inflammatory signaling. In innate immunity, the itchy E3 ubiquitin protein ligase (ITCH)-A20 ubiquitin-editing complex inhibits receptor-interacting Ser/Thr kinase (RIPK) activation by removing Lys-63-linked polyubiquitinated chains from key proteins in the nuclear factor kappa B (NF-κB) signaling pathway.

An IκB Kinase-Regulated Feedforward Circuit Prolongs Inflammation.

Loss of NF-κB signaling causes immunodeficiency, whereas inhibition of NF-κB can be efficacious in treating chronic inflammatory disease. Inflammatory NF-κB signaling must therefore be tightly regulated, and although many mechanisms to downregulate NF-κB have been elucidated, there have only been limited studies demonstrating positive feedforward regulation of NF-κB signaling. In this work, we use a bioinformatic and proteomic approach to discover that the IKK family of proteins can phosphorylate the E3 ubiquitin ligase ITCH, a critical downregulator of TNF-mediated NF-κB activation.

Variants in the LEPR gene are nominally associated with higher BMI and lower 24-h energy expenditure in Pima Indians.

Genome-wide association studies (GWASs) have been used to search for susceptibility genes for type 2 diabetes and obesity in the Pima Indians, a population with a high prevalence of both diseases. In these studies, a variant (rs2025804) in the LEPR gene was nominally associated with BMI in 1,082 subjects (P = 0.03 adjusted for age, sex, birth year, and family membership).

Evaluation of A2BP1 as an obesity gene.

Objective: A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity.

Research Design And Methods: Variants spanning A2BP1 were genotyped in a population-based sample of 3,234 full-heritage Pima Indians, 2,843 of whom were not part of the initial GWAS study and therefore could serve as a sample to assess replication.