An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo.

Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry.

Mycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin.

Lipid biosynthesis in the pathogen Mycobacterium tuberculosis depends on biotin for posttranslational modification of key enzymes. However, the mycobacterial biotin synthetic pathway is not fully understood. Here, we show that rv1590, a gene of previously unknown function, is required by M.

Inhibitors of the Thioesterase Activity of Pks13 Discovered Using DNA-Encoded Chemical Library Screening.

DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme.

Redirecting raltitrexed from cancer cell thymidylate synthase to phosphopantetheinyl transferase.

There is a compelling need to find drugs active against (). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in that has attracted interest as a potential drug target. We optimized a PptT assay, used it to screen 422,740 compounds, and identified raltitrexed, an antineoplastic antimetabolite, as the most potent PptT inhibitor yet reported.

Long-term efficacy of a continuity-of-care treatment model for patients with severe mental illness who transition from in-patient to out-patient services.

Background: Despite its significance, ensuring continuity of care demands substantial resources, which might not be readily accessible in many public healthcare systems. Studies indicate that continuity of care remains uncertain in numerous healthcare systems.

Aims: This study aimed to assess the effectiveness of a continuity-of-care model for patients with severe mental illness (SMI), providing seamless treatment from discharge from a closed ward to subsequent psychiatric, psychological and rehabilitation services.

YisK possesses oxaloacetate decarboxylase activity and exhibits Mbl-dependent localization.

YisK is an uncharacterized protein in previously shown to interact genetically with the elongasome protein Mbl. YisK overexpression leads to cell widening and lysis, phenotypes that are dependent on and suppressed by mutations. In the present work, we characterize YisK's localization, structure, and enzymatic activity.

1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in .

Alternative mode-of-inhibition of clinically validated targets is an effective strategy for circumventing existing clinical drug resistance. Herein, we report 1,3-diarylpyrazolyl-acylsulfonamides as potent inhibitors of HadAB/BC, a 3-hydroxyl-ACP dehydratase complex required to iteratively elongate the meromycolate chain of mycolic acids in (). Mutations in compound -resistant mutants mapped to HadC (Rv0637; K157R), while chemoproteomics confirmed the compound's binding to HadA (Rv0635), HadB (Rv0636), and HadC.

The Impact of a Continuity-of-Care Model From Hospitalization to Outpatient Clinic for Patients With Severe Mental Illness.

The authors sought to assess the impact of a continuity-of-care model on quality-of-care measures among hospitalized patients with severe mental illness in Israel. A "continuity-of-care physician" provided psychiatric care to patients during hospitalization and outpatient care after discharge. In the year after the model's implementation, emergency department visits significantly decreased by 32% and rehospitalization rates of patients discharged within 30 and 90 days decreased by 40% and 29%, respectively.

Anxiety in Patients with Neovascular Age-related Macular Degeneration.

Purpose: The main objective of the study is to investigate the prevalence of anxiety in patients with neovascular age-related macular degeneration (nAMD).

Methods: A retrospective cross-sectional study of 3 304 nAMD patients and 16 515 age- and gender-matched controls. The proportions of patients with anxiety were compared between the groups using univariate analyses and a multivariate logistic regression model.

Structural anatomy of Protein Kinase C C1 domain interactions with diacylglycerol and other agonists.

Diacylglycerol (DAG) is a versatile lipid whose 1,2-sn-stereoisomer serves both as second messenger in signal transduction pathways that control vital cellular processes, and as metabolic precursor for downstream signaling lipids such as phosphatidic acid. Effector proteins translocate to available DAG pools in the membranes by using conserved homology 1 (C1) domains as DAG-sensing modules. Yet, how C1 domains recognize and capture DAG in the complex environment of a biological membrane has remained unresolved for the 40 years since the discovery of Protein Kinase C (PKC) as the first member of the DAG effector cohort.

COVID-19 Booster Vaccination Among Individuals With Schizophrenia in Israel.

Importance: Individuals with schizophrenia are at higher risk for severe COVID-19 illness and mortality. Previous reports have demonstrated vaccination gaps among this high-risk population; however, it is unclear whether these gaps have continued to manifest with the booster dose.

Objective: To assess gaps in first, second, and booster vaccinations among individuals with schizophrenia.

Mechanism-Based Inactivation of Isocitrate Lyase 1 by (2,3)-2-Hydroxy-3-(nitromethyl)succinic acid.

The isocitrate lyase paralogs of (ICL1 and 2) are essential for mycobacterial persistence and constitute targets for the development of antituberculosis agents. We report that (2,3)-2-hydroxy-3-(nitromethyl)succinic acid (5-NIC) undergoes apparent retro-aldol cleavage as catalyzed by ICL1 to produce glyoxylate and 3-nitropropionic acid (3-NP), the latter of which is a covalent-inactivating agent of ICL1. Kinetic analysis of this reaction identified that 5-NIC serves as a robust and efficient mechanism-based inactivator of ICL1 (/ = (1.

COVID-19 vaccination among individuals with autism spectrum disorder: A population-based study.

Background: Individuals with autistic spectrum disorder (ASD) are more susceptible to COVID-19 morbidity and should therefore be prioritized for vaccination. Although individuals with neurodevelopmental disabilities are given some priority in Israel, it is unclear to what extent individuals with ASD are being vaccinated relative to that of the general population. This study was aimed to assess vaccination prevalence among individuals with ASD.

COVID-19 Morbidity Among Individuals with Autistic Spectrum Disorder: A Matched Controlled Population-Based Study.

In this study we aimed to assess whether individuals with ASD are prone to higher infection rates, or to severe COVID-19 illness. Individuals with ASD and age- and gender-matched controlled counterparts (total n = 32,812) were assessed for COVID-19 infection rates and hospitalizations. Results indicated higher infection rates among individuals with ASD, with the largest effect among individuals aged 40-60 (OR = 2.

Blood transcriptional response to treatment-resistant depression during electroconvulsive therapy.

Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line antidepressant drug treatment for major depressive disorder (MDD). Treatment-resistant depression (TRD), defined as failure to achieve remission despite adequate treatment, affects ~30% of persons with MDD. The current recommended treatment for TRD is electroconvulsive therapy (ECT), while ketamine is an experimentally suggested treatment.

The co-occurrence of autistic spectrum disorder and schizophrenia: A nationwide population-based study.

Although the co-occurrence of autistic spectrum disorder (ASD) and schizophrenia have been previously reported, the scope and magnitude of this comorbidity across large samples have not been sufficiently established. This study was aimed to assess the co-occurrence between schizophrenia and ASD in a large dataset, and to examine its predominance across different age and sex groups. Schizophrenia patients and age and sex frequency controls (n = 49,334) were assessed for the prevalence of autism spectrum disorder.

Covalent Inactivation of Isocitrate Lyase by -2,3-Epoxy-Succinic Acid.

The isocitrate lyases (ICL1/2) are essential enzymes of (), the causative agent of tuberculosis. At present, no ICL1/2 inhibitors have progressed to clinical evaluation, despite extensive drug discovery efforts. Herein, we surveyed succinate analogs against ICL1 and found that dicarboxylic acids constrained in their conformations, such as maleic acid, comprise uncompetitive inhibitors of ICL1 and inhibit more potently than their -isomers.

COVID-19 Prevalence and Mortality Among Schizophrenia Patients: A Large-Scale Retrospective Cohort Study.

Objective: Individuals with schizophrenia may be at an increased risk for COVID-19 morbidity due to the disease characteristics. In this study, we aimed to explore the odds of significant COVID-19 morbidity and mortality among schizophrenia patients while controlling for potential sociodemographic and medical confounders.

Methods: Schizophrenia patients and age-and-sex matched controls (total n = 51 078) were assessed for frequency of COVID-19 positivity, hospitalizations, and mortality.

Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.

The approval of bedaquiline (BDQ) for the treatment of tuberculosis has generated substantial interest in inhibiting energy metabolism as a therapeutic paradigm. However, it is not known precisely how BDQ triggers cell death in Mycobacterium tuberculosis (Mtb). Using C isotopomer analysis, we show that BDQ-treated Mtb redirects central carbon metabolism to induce a metabolically vulnerable state susceptible to genetic disruption of glycolysis and gluconeogenesis.

Open-Label placebo for the treatment of unipolar depression: Results from a randomized controlled trial.

Background: The response to placebo is robust in studies of various antidepressant treatments. The strong placebo response, combined with the absence of side-effects, has prompted suggestions to use the ethically sound open-label placebo (OLP) as a treatment for depression. The aim of the present study was to assess the efficacy of OLP as an adjunct to treatment as usual (TAU) in the setting of a randomized controlled trial for the treatment of unipolar depression.

A Sec14-like phosphatidylinositol transfer protein paralog defines a novel class of heme-binding proteins.

Yeast Sfh5 is an unusual member of the Sec14-like phosphatidylinositol transfer protein (PITP) family. Whereas PITPs are defined by their abilities to transfer phosphatidylinositol between membranes in vitro, and to stimulate phosphoinositide signaling in vivo, Sfh5 does not exhibit these activities. Rather, Sfh5 is a redox-active penta-coordinate high spin Fe hemoprotein with an unusual heme-binding arrangement that involves a co-axial tyrosine/histidine coordination strategy and a complex electronic structure connecting the open shell iron -orbitals with three aromatic ring systems.