Biological characterization of AB-343, a novel and potent SARS-CoV-2 M inhibitor with pan-coronavirus activity.

Since the SARS-CoV-2 outbreak, there have been ongoing efforts to identify antiviral molecules with broad coronavirus activity to combat COVID-19. SARS-CoV-2's main protease (M) is responsible for processing the viral polypeptide into non-structural proteins essential for replication. Here, we present the biological characterization of AB-343, a covalent small-molecule inhibitor of SARS-CoV-2 M with potent activity in both cell-based (EC = 0.

Sandwich immunoassay for adrenomedullin precursor and its practical application.

Adrenomedullin (ADM) is a multifaceted peptide hormone involved in numerous physiological processes, including vascular stability, vasodilation, angiogenesis, and anti-inflammatory responses. The processing of ADM results in several fragments, including midregional proadrenomedullin (MR-proADM), and glycine-extended ADM (ADM-Gly) and bioactive ADM (bio-ADM). MR-proADM, the stable ADM fragment, and bio-ADM, the active form of ADM with a short half-life, have been shown to be potent biomarkers in a variety of pathologies.

Caspases promote cell proliferation after necrosis.

An enzyme known as caspase, which initiates apoptosis, has a central role in the regeneration of cells and repair of tissue that can occur after necrosis.

Unraveling the intricate link between cell death and neuroinflammation using as a model.

Protein aggregation is a common pathological occurrence in neurodegenerative diseases. This often leads to neuroinflammation, which exacerbates the aggregation and progression of diseases like Parkinson's and Alzheimer's. Here, we focus on immune responses and neurotoxicity in a Parkinson's disease model in .

The Initiator Caspase Dronc Drives Compensatory Proliferation of Apoptosis-Resistant Cells During Epithelial Tissue Regeneration After Ionizing Radiation.

Caspases, well-known for their role in executing apoptosis, also participate in various non-apoptotic processes. Despite this, their involvement in promoting compensatory proliferation - a key aspect of tissue regeneration following extensive cell death - has been a subject of ongoing ambiguity. In our study, we investigate compensatory proliferation in the wing imaginal disc following ionizing radiation, a model epithelial tissue that has been a pioneering system for studying this regenerative response.

Proenkephalin improves cardio-renal risk prediction in acute coronary syndromes: the KID-ACS score.

Background And Aims: Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndrome (ACS).

Methods: Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n = 4787) and in validation cohorts from the UK (n = 1141), Czechia (n = 927), and Germany (n = 220).

Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus.

Context: Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides.

Objective: To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA).

Design: We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012).

An epidemiological and clinicopathological study of type 1 vs. type 2 morphological subtypes of papillary renal cell carcinoma- results from a nation-wide study covering 50 years in Iceland.

Introduction: Papillary renal cell carcinoma (pRCC) is the second most common histology of renal cell carcinoma (RCC), accounting for 10-15% of cases. Traditionally, pRCC is divided into type 1 and type 2, although this division is currently debated as a prognostic factor of survival. Our aim was to investigate the epidemiology and survival of the pRCC subtypes in a whole nation cohort of patients during a 50-year period.

Low Levels of Selenoprotein P Are Associated With Cognitive Impairment in Patients Hospitalized for Heart Failure.

Background: Selenoprotein P (SELENOP) is a transporter for selenium and has been shown to protect selenium-status maintenance in the brain against deficiency and to support neuronal development, neurogenesis and neurocognitive function. Selenium deficiency has previously been associated with cognitive impairment in various populations, but no studies have been carried out in subjects with heart failure (HF).

Purpose: To explore whether SELENOP deficiency in subjects with acute HF is associated with cognitive impairment.

Association between low selenoprotein P concentrations and anaemia in hospitalized heart failure patients.

Aims: Heart failure (HF) patients with anaemia tend to have a worse outcome, with increased hospitalization rates, decreased exercise tolerance, and higher mortality compared to those without anaemia. Limited research exists on the association between selenium deficiency and anaemia specifically in HF patients, despite previous findings of a correlation in different populations. The BIOSTAT-CHF study demonstrated that higher selenium levels in HF patients were associated to a lower risk of anaemia and iron deficiency.

Peptidylglycine α-amidating monooxygenase and adrenomedullin measurement in patients with hepatic cirrhosis.

Peptidylglycine α-amidating monooxygenase (PAM) is an enzyme involved in the maturation of regulatory peptides. Here we examined PAM activity and adrenomedullin (bio-ADM) concentrations in patients with hepatic cirrhosis and determined net changes across the liver, kidneys and leg. A total of 48 patients with hepatic cirrhosis and 16 control subjects were included.

Dipeptidyl peptidase 3 plasma levels predict cardiogenic shock and mortality in acute coronary syndromes.

Background And Aims: Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left ventricular function. This study examined the relationship of circulating DPP3 (cDPP3) with cardiogenic shock (CS) and mortality in patients presenting with acute coronary syndromes (ACS).

Methods: Plasma cDPP3 levels were assessed at baseline and 12-24 h after presentation in patients with ACS prospectively enrolled into the multi-centre SPUM-ACS study (n = 4787).

Selenoprotein P deficiency is associated with higher risk of incident heart failure.

Introduction: Selenium deficiency has been associated with mortality, cardiovascular disease and worsened prognosis in heart failure (HF). In a recent population-based study, high selenium levels were shown to be associated with reduced mortality and reduced incidence of HF, but only in non-smokers. Here, we aimed to examine if selenoprotein P (SELENOP), a main selenium carrier protein, is associated with incident HF.

Immunoassay-based quantification of full-length peptidylglycine alpha-amidating monooxygenase in human plasma.

A one-step sandwich chemiluminescence immunometric assay (LIA) was developed for the quantification of bifunctional peptidylglycine-α-amidating monooxygenase (PAM) in human plasma (PAM-LIA). PAM is responsible for the activation of more than half of known peptide hormones through C-terminal α-amidation. The assay employed antibodies targeting specific catalytic PAM-subunits, peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL), to ensure detection of full-length PAM.

Something new under the sun: caspases promote cell survival under moderate heat stress.

Since the discovery of caspases in 1993 (Yuan et al, 1993), they have largely been regarded as essential Cys proteases in apoptosis. However, more recently, it has become evident that caspases also have non-apoptotic functions in the so-called caspase-dependent non-lethal processes (CDPs) including cell proliferation and cell differentiation (Aram et al, 2017). While most of the non-apoptotic functions were characterized under normal developmental conditions, a new study by Galasso et al took this examination a step further-to the analysis of moderate stress conditions.

Prognostic Value for Mortality of Plasma Bioactive Adrenomedullin in Patients with Pulmonary Arterial Hypertension: A Sub Analysis of the Biomarker Study in the COHARD-PH Registry.

The adrenomedullin level increases in pulmonary arterial hypertension (PAH, and correlates with a high mortality rate. Its active form, bioactive adrenomedullin (bio-ADM), has been recently developed and has significant prognostic applications in acute clinical settings. Aside from idiopathic/hereditary PAH (I/H-PAH), atrial septal defects-associated pulmonary artery hypertension (ASD-PAH) is still prevalent in developing countries and associated with increased mortality.

Effects of enrichment strategies on outcome of adrecizumab treatment in septic shock: analyses of the phase II adrenomedullin and outcome in septic shock 2 trial.

Purpose: Adrecizumab, a non-neutralizing antibody of adrenomedullin (ADM) was recently investigated regarding its potential to restore endothelial barrier function in septic shock patients with high plasma ADM levels. Circulating dipeptidyl peptidase 3 (cDPP3), a protease involved in the degradation of several cardiovascular mediators, represents another biological pathway strongly associated with outcome in septic shock, although unrelated to ADM. Therefore, the prognosis of patients with elevated cDPP3 may not be influenced by Adrecizumab.

Actin remodeling mediates ROS production and JNK activation to drive apoptosis-induced proliferation.

Stress-induced cell death, mainly apoptosis, and its subsequent tissue repair is interlinked although our knowledge of this connection is still very limited. An intriguing finding is apoptosis-induced proliferation (AiP), an evolutionary conserved mechanism employed by apoptotic cells to trigger compensatory proliferation of their neighboring cells. Studies using Drosophila as a model organism have revealed that apoptotic caspases and c-Jun N-terminal kinase (JNK) signaling play critical roles to activate AiP.

The effect of a randomised controlled lifestyle intervention on weight loss and plasma proneurotensin.

Aims: Proneurotensin (Pro-NT) is a strong predictor of cardiometabolic disease including type 2 diabetes and obesity, however, the effect of lifestyle change on Pro-NT has not been investigated in this context. Middle Eastern (ME) immigrants represent the largest and fastest growing minority population in Europe and are a high-risk population for obesity and type 2 diabetes. In this randomised controlled lifestyle intervention (RCT) addressing ME immigrants to Sweden where weight-loss was previously studied as the main outcome, as a secondary analysis we aimed to study change in Pro-NT during follow-up and if baseline Pro-NT predicted weight loss.

In Vitro Cleavage Assays using Purified Recombinant Drosophila Caspases for Substrate Screening.

Caspases are very specific cell death proteases that are involved in apoptotic and non-apoptotic processes. While the role of caspases during apoptosis has been very well defined and many apoptotic proteolytic substrates of caspases have been identified and characterized, the role of caspases for non-apoptotic processes is not well understood. In particular, few non-apoptotic substrates of caspases have been identified thus far.

Growth hormone concentration and risk of all-cause and cardiovascular mortality: The REasons for Geographic And Racial Disparities in Stroke (REGARDS) study.

Background And Aims: Identifying individuals at elevated risk for mortality, especially from cardiovascular disease, may help guide testing and treatment. Risk factors for mortality differ by sex and race. We investigated the association of growth hormone (GH) with all-cause and cardiovascular mortality in a racially diverse cohort in the United States.

Toll-9 interacts with Toll-1 to mediate a feedback loop during apoptosis-induced proliferation in Drosophila.

Drosophila Toll-1 and all mammalian Toll-like receptors regulate innate immunity. However, the functions of the remaining eight Toll-related proteins in Drosophila are not fully understood. Here, we show that Drosophila Toll-9 is necessary and sufficient for a special form of compensatory proliferation after apoptotic cell loss (undead apoptosis-induced proliferation [AiP]).

Identification of Two Non-Peptidergic Small Molecule Inhibitors of CBX2 Binding to K27 Trimethylated Oligonucleosomes.

The dysregulation of the PRC1/2 complex plays a key role in lineage plasticity in prostate cancer and may be required to maintain neuroendocrine phenotype. [1] CBX2, a key component of the canonical PRC1 complex, is an epigenetic reader, recognizing trimethylated lysine on histone 3 (H3K27me3) [2] and is overexpressed in metastatic neuroendocrine prostate cancer. [3,4] We implemented a screening strategy using nucleosome substrates to identify inhibitors of CBX2 binding to chromatin.

Erebosis is a new type of cell death for tissue homeostasis in the Drosophila intestine.

Although there are over a dozen types of cell death known, there is clearly more to discover in this field. In this issue of PLOS Biology, erebosis is identified as a new type of cell death involved in tissue homeostasis of the adult Drosophila intestine.

Metabolic Response in Endothelial Cells to Catecholamine Stimulation Associated with Increased Vascular Permeability.

Disruption to endothelial cell homeostasis results in an extensive variety of human pathologies that are particularly relevant to major trauma. Circulating catecholamines, such as adrenaline and noradrenaline, activate endothelial adrenergic receptors triggering a potent response in endothelial function. The regulation of the endothelial cell metabolism is distinct and profoundly important to endothelium homeostasis.