Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease.

Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood.

Three-year trajectories and associated factors of fear of cancer recurrence in newly diagnosed head and neck cancer patients: a longitudinal study.

Purpose: Limited data exists on the long-term course of fear of cancer recurrence (FCR) in head and neck cancer (HNC) patients. One in five patients was found to experience persistent high FCR in the first months after diagnosis. This study assessed the 3-year trajectories and associated factors of FCR in newly diagnosed HNC patients.

Cross-species single-cell RNA-seq analysis reveals disparate and conserved cardiac and extracardiac inflammatory responses upon heart injury.

The immune system coordinates the response to cardiac injury and controls regenerative and fibrotic scar outcomes in the heart and subsequent chronic low-grade inflammation associated with heart failure. Adult mice and humans lack the ability to fully recover while adult zebrafish spontaneously regenerate after heart injury. Here we profile the inflammatory response to heart cryoinjury in zebrafish and coronary artery ligation in mouse using single cell transcriptomics.

Precision-cut liver slices as an ex vivo model to assess impaired hepatic glucose production.

Fasting hypoglycemia is a severe and incompletely understood symptom of various inborn errors of metabolism (IEM). Precision-cut liver slices (PCLS) represent a promising model for studying glucose production ex vivo. This study quantified the net glucose production of human and murine PCLS in the presence of different gluconeogenic precursors.

Expect the unexpected: fulminant myocardial cytotoxic Injury from Trabectedin.

Background: Trabectedin (Tbt) is an alkylating agent prescribed for soft tissue sarcomas after treatment failure of first line agents. While cardiomyopathy can occur with Tbt treatment after anthracycline exposure, Tbt-induced fulminant myocardial cytotoxic injury in the setting of other systemic cytotoxicity associated with Tbt has not been reported.

Case Presentation: 51-year-old female with hypertension, hyperlipidemia, metastatic leiomyosarcoma with progression of disease despite several lines of chemotherapy including doxorubicin-based therapy was started on Trabectedin (Tbt) 5 days prior to presentation with symptoms of fever, myalgias, arthralgias, and palpitations.

GPCR Function in Autophagy Control: A Systematic Approach of Chemical Intervention.

Autophagy facilitates the degradation of cellular content via the lysosome and is involved in cellular homeostasis and stress response pathways. As such, malfunction of autophagy is linked to a variety of diseases ranging from organ-specific illnesses like cardiomyopathy to systemic illnesses such as cancer or metabolic syndromes. Given the variety of autophagic functions within a cell and tissue, regulation of autophagy is complex and contains numerous positive and negative feedback loops.

The Effects of Lithium Chloride Exposure on the Reproduction of .

( are model organisms that share similar anatomical structures to humans. By exploring the effects of lithium chloride (LiCl) on we can collect crucial data regarding the compound's impact on patients taking psychiatric medications containing LiCl. Here we performed an egg retention assay on nematode populations to explore how LiCl can influence reproduction.

Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1 via a comprehensive screening funnel.

SAMHD1 is a dNTP triphosphohydrolase governing nucleotide pool homeostasis and can detoxify chemotherapy metabolites controlling their clinical responses. To understand SAMHD1 biology and investigate the potential of targeting SAMHD1 as neoadjuvant to current chemotherapies, we set out to discover selective small-molecule inhibitors. Here, we report a discovery pipeline encompassing a biochemical screening campaign and a set of complementary biochemical, biophysical, and cell-based readouts for rigorous characterization of the screen output.

Adipose Signals Regulating Distal Organ Health and Disease.

Excessive adiposity in obesity is a significant risk factor for development of type 2 diabetes (T2D), nonalcoholic fatty liver disease, and other cardiometabolic diseases. An unhealthy expansion of adipose tissue (AT) results in reduced adipogenesis, increased adipocyte hypertrophy, adipocyte hypoxia, chronic low-grade inflammation, increased macrophage infiltration, and insulin resistance. This ultimately culminates in AT dysfunction characterized by decreased secretion of antidiabetic adipokines such as adiponectin and adipsin and increased secretion of proinflammatory prodiabetic adipokines including RBP4 and resistin.

PSW-Designer: An Open-Source Computational Platform for the Design and Virtual Screening of Photopharmacological Ligands.

Photoswitchable (PSW) molecules offer an attractive opportunity for the optical control of biological processes. However, the successful design of such compounds remains a challenging multioptimization endeavor, resulting in several biological target classes still relatively poorly explored by photoswitchable ligands, as is the case for G protein-coupled receptors (GPCRs). Here, we present the PSW-Designer, a fully open-source computational platform, implemented in the KNIME Analytics Platform, to design and virtually screen novel photoswitchable ligands for photopharmacological applications based on privileged scaffolds.

Target 2035 - an update on private sector contributions.

Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging 'open' principles to develop a pharmacological tool for every human protein. These tools are important reagents for scientists studying human health and disease and will facilitate the development of new medicines. It is therefore not surprising that pharmaceutical companies are joining Target 2035, contributing both knowledge and reagents to study novel proteins.

Evaluation of "Test to Return" after COVID-19 Diagnosis in a Massachusetts Public School District.

Background: Per Centers for Disease Control and Prevention guidance, students with COVID-19 may end isolation after 5 days if symptoms are improving; some individuals may still be contagious. Rapid antigen testing identifies possibly infectious virus. We report on a test-to-return (TTR) program in a Massachusetts school district to inform policy decisions about return to school after COVID-19.

Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

Cancer alters the function of multiple organs beyond those targeted by metastasis. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a.

Determinants of tumor immune evasion: the role of T cell exposed motif frequency and mutant amino acid exposure.

Few neoepitopes detected in tumor biopsies are immunogenic. Tumor-specific T cell responses require both the presentation of an epitope that differs from wildtype and the presence of T cells with neoepitope-cognate receptors. We show that mutations detected in tumor biopsies result in an increased frequency of rare amino acid combinations compared to the human proteome and gastrointestinal microorganisms.

Recombinant Bacillus Calmette-Guérin Expressing SARS-CoV-2 Chimeric Protein Protects K18-hACE2 Mice against Viral Challenge.

COVID-19 has accounted for more than 6 million deaths worldwide. Bacillus Calmette-Guérin (BCG), the existing tuberculosis vaccine, is known to induce heterologous effects over other infections due to trained immunity and has been proposed to be a potential strategy against SARS-CoV-2 infection. In this report, we constructed a recombinant BCG (rBCG) expressing domains of the SARS-CoV-2 nucleocapsid and spike proteins (termed rBCG-ChD6), recognized as major candidates for vaccine development.

Cross-species single-cell comparison of systemic and cardiac inflammatory responses after cardiac injury.

The immune system coordinates the response to cardiac injury and is known to control regenerative and fibrotic scar outcomes in the heart and subsequent chronic low-grade inflammation associated with heart failure. Here we profiled the inflammatory response to heart injury using single cell transcriptomics to compare and contrast two experimental models with disparate outcomes. We used adult mice, which like humans lack the ability to fully recover and zebrafish which spontaneously regenerate after heart injury.

Impact of acute TTE-evidenced cardiac dysfunction on in-hospital and outpatient mortality: A multicenter NYC COVID-19 registry study.

Background: COVID-19 is associated with cardiac dysfunction. This study tested the relative prognostic role of left (LV), right and bi- (BiV) ventricular dysfunction on mortality in a large multicenter cohort of patients during and after acute COVID-19 hospitalization.

Methods/results: All hospitalized COVID-19 patients who underwent clinically indicated transthoracic echocardiography within 30 days of admission at four NYC hospitals between March 2020 and January 2021 were studied.

A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes.

The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibits higher mitochondrial respiration compared with CD63 beta cells.

Optimization of N-Piperidinyl-Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8-Oxo-Guanine DNA Glycosylase 1.

8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8-oxoG could lead to G : C→T : A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated levels of reactive oxygen species this dependency is further increased.

Butyrate oxidation attenuates the butyrate-induced improvement of insulin sensitivity in myotubes.

Skeletal muscle insulin resistance is a key pathophysiological process that precedes the development of type 2 diabetes. Whereas an overload of long-chain fatty acids can induce muscle insulin resistance, butyrate, a short-chain fatty acid (SCFA) produced from dietary fibre fermentation, prevents it. This preventive role of butyrate has been attributed to histone deacetylase (HDAC)-mediated transcription regulation and activation of mitochondrial fatty-acid oxidation.

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure.