The risk of death according to left ventricular ejection fraction and right ventricular dilatation in 17 321 adults with heart failure from 40 high-, middle- and low-income countries - A Global Congestive Heart Failure (G-CHF) study.

Aims: The aim of this study was to describe the prognostic importance of left ventricular ejection fraction (LVEF) versus right ventricular (RV) dilatation and dysfunction in patients with heart failure (HF) from countries of different income levels.

Methods And Results: We enrolled 17 321 participants with HF from 40 countries. Participants were followed for a median (25th-75th percentile) of 2.

Effects of Implantable Cardioverter-Defibrillator Leads on the Tricuspid Valve and Right Ventricle: A Randomized Trial.

Background: There are no randomized data to inform the extent to which transvenous cardiac leads cause tricuspid regurgitation (TR).

Objectives: This study sought to determine the effect of a transvenous implantable cardioverter-defibrillator (TV-ICD) on TR severity, and secondarily, on right ventricular (RV) size and function.

Methods: We evaluated TR severity before and 6 months after implantable cardioverter-defibrillator insertion in a post hoc analysis of adults randomized to receive a transvenous (n = 252) or subcutaneous implantable cardioverter-defibrillator (S-ICD) (n = 251) device.

Caging Bioactive Triarylimidazoles: An Approach to Create Visible Light-Activatable Drugs.

Imidazoles are crucial structural components in a variety of small-molecule inhibitors designed to target different kinases in anticancer treatment. However, the effectiveness of such inhibitors is often hampered by nonspecific effects and the development of resistance. Photopharmacology provides a compelling solution by enabling external control over drug activity with spatiotemporal precision.

Pseudo-Luciferase Activity of the SARS-CoV-2 Spike Protein for Luciferin.

Enzymatic reactions that involve a luminescent substrate (luciferin) and enzyme (luciferase) from luminous organisms enable a luminescence detection of target proteins and cells with high specificity, albeit that conventional assay design requires a prelabeling of target molecules with luciferase. Here, we report a luciferase-independent luminescence assay in which the target protein directly catalyzes the oxidative luminescence reaction of luciferin. The SARS-CoV-2 antigen (spike) protein catalyzes the light emission of luciferin, whereas no such catalytic function was observed for salivary proteins.

Chaperonin GroEL hydrolyses -nitrophenyl β-galactoside.

We serendipitously found that chaperonin GroEL can hydrolyze -nitrophenyl β-galactoside (ONPG), a well-known substrate of the enzyme β-galactosidase. The ONPG hydrolysis by GroEL follows typical enzyme kinetics. Our experiments and molecular docking studies suggest ONPG binding at the ATP binding site of GroEL.

Structural effects of spike protein D614G mutation in SARS-CoV-2.

A single mutation from aspartate to glycine at position 614 has dominated all circulating variants of the severe acute respiratory syndrome coronavirus 2. D614G mutation induces structural changes in the spike (S) protein that strengthen the virus infectivity. Here, we use molecular dynamics simulations to dissect the effects of mutation and 630-loop rigidification on S-protein structure.

Modified Protein-Water Interactions in CHARMM36m for Thermodynamics and Kinetics of Proteins in Dilute and Crowded Solutions.

Proper balance between protein-protein and protein-water interactions is vital for atomistic molecular dynamics (MD) simulations of globular proteins as well as intrinsically disordered proteins (IDPs). The overestimation of protein-protein interactions tends to make IDPs more compact than those in experiments. Likewise, multiple proteins in crowded solutions are aggregated with each other too strongly.

The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein.

Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions.

Clinical Profiles and Outcomes of Heart Failure in Five African Countries: Results from INTER-CHF Study.

Background: A wide knowledge gap exists on the clinical profiles and outcomes of heart failure (HF) in sub-Saharan Africa.

Objectives: To determine the clinical profiles and outcomes of HF patients from five African countries.

Methods: The INTERnational Congestive Heart Failure Study (INTER-CHF) is a prospective, multicenter cohort study.

Health-Related Quality of Life and Mortality in Heart Failure: The Global Congestive Heart Failure Study of 23 000 Patients From 40 Countries.

Background: Poor health-related quality of life (HRQL) is common in heart failure (HF), but there are few data on HRQL in HF and the association between HRQL and mortality outside Western countries.

Methods: We used the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) to record HRQL in 23 291 patients with HF from 40 countries in 8 different world regions in the G-CHF study (Global Congestive Heart Failure). We compared standardized KCCQ-12 summary scores (adjusted for age, sex, and markers of HF severity) among regions (scores range from 0 to 100, with higher score indicating better HRQL).

Unraveling the Coupling between Conformational Changes and Ligand Binding in Ribose Binding Protein Using Multiscale Molecular Dynamics and Free-Energy Calculations.

Conformational changes of proteins upon ligand binding are usually explained in terms of several mechanisms including the induced fit, conformational selection, or their mixtures. Due to the slow time scales, conventional molecular dynamics (cMD) simulations based on the atomistic models cannot easily simulate the open-to-closed conformational transition in proteins. In our previous study, we have developed an enhanced sampling scheme (generalized replica exchange with solute tempering selected surface charged residues: gREST_SSCR) for multidomain proteins and applied it to ligand-mediated conformational changes in the G134R mutant of ribose-binding protein (RBP) in solution.

Elucidation of interactions regulating conformational stability and dynamics of SARS-CoV-2 S-protein.

The ongoing COVID-19 pandemic caused by the new coronavirus, SARS-CoV-2, calls for urgent developments of vaccines and antiviral drugs. The spike protein of SARS-CoV-2 (S-protein), which consists of trimeric polypeptide chains with glycosylated residues on the surface, triggers the virus entry into a host cell. Extensive structural and functional studies on this protein have rapidly advanced our understanding of the S-protein structure at atomic resolutions, although most of these structural studies overlook the effect of glycans attached to the S-protein on the conformational stability and functional motions between the inactive down and active up forms.

Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling.

Conformational transitions in multidomain proteins are essential for biological functions. The Apo conformations are typically open and flexible, while the Holo states form more compact conformations stabilized by protein-ligand interactions. Unfortunately, the atomically detailed mechanisms for such open-closed conformational changes are difficult to be accessed experimentally as well as computationally.

A multinational registry to study the characteristics and outcomes of heart failure patients: The global congestive heart failure (G-CHF) registry.

The goal of the global congestive heart failure (G-CHF) registry is to collect comparative international data on heart failure characteristics, management, and outcomes and to better understand the determinants that impact the clinical course of heart failure. METHODS: G-CHF is a multicenter, prospective cohort study of adult patients with a new or prior clinical diagnosis of heart failure. We have enrolled 23,047 participants from 257 centers in 40 countries from 8 major geographic regions of the world, with recruitment ongoing.

A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

Lessons Learned: Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug-drug interaction.

A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

Purpose: ERK1/2 signaling can be dysregulated in cancer. GDC-0994 is an oral inhibitor of ERK1/2. A first-in-human, phase I dose escalation study of GDC-0994 was conducted in patients with locally advanced or metastatic solid tumors.

MEDiastinal Irradiation and CArdio-Toxic Effects (MEDICATE): Exploring the Relationship between Cardiac Irradiation and High Sensitivity Troponins.

Aims: Radiation-induced heart disease is a late effect of cardiac irradiation and has been shown in patients with lymphoma and thoracic cancers. There is no established measurement tool to detect acute cardiac damage. However, high sensitivity troponin I and T (HsTnI and HsTnT) and echocardiograms have shown promise in some studies.

Randomized controlled trial of influenza vaccine in patients with heart failure to reduce adverse vascular events (IVVE): Rationale and design.

Background: Influenza is associated with an increase in the risk of cardiac and other vascular events. Observational data and small randomized trials suggest that influenza vaccination may reduce such adverse vascular events.

Research Design And Methods: In a randomized controlled trial patients with heart failure are randomized to receive either inactivated influenza vaccine or placebo annually for 3 years.

Prospective Study of Tricuspid Regurgitation Associated With Permanent Leads After Cardiac Rhythm Device Implantation.

Background: Tricuspid regurgitation (TR) has been associated with cardiac rhythm device (CRD) implantation with intracardiac lead insertion. However, data on the incidence of postdevice TR are limited and largely from retrospective studies. We hypothesized that permanent lead implantation would be associated with an increase in TR.

Similarities and Differences between Thymine(6-4)Thymine/Cytosine DNA Lesion Repairs by Photolyases.

Photolyases are ancient enzymes that harvest sunlight to repair DNA pyrimidine lesions such as pyrimidine(6-4)pyrimidone and cyclobutane dimers. Particularly, (6-4) photolyase ((6-4)PHR) plays an important role in maintaining genetic integrity by repairing thymine(6-4)thymine (T(6-4)T) and thymine(6-4)cytosine (T(6-4)C) photolesions. The majority of (6-4)PHR studies have been performed on the basis of the former's activity and assuming the equivalence of the two repair mechanisms, although the latter's activity remains poorly studied.

Vibrational Energy Transfer from Heme through Atomic Contacts in Proteins.

A pathway of vibrational energy flow in myoglobin was studied by time-resolved anti-Stokes ultraviolet resonance Raman spectroscopy combined with site-directed mutagenesis. Our previous study suggested that atomic contacts in proteins provide the dominant pathway for energy transfer while covalent bonds do not. In the present study, we directly examined the contributions of covalent bonds and atomic contacts to the pathway of vibrational energy flow by comparing the anti-Stokes resonance Raman spectra of two myoglobin mutants: one lacked a covalent bond between heme and the polypeptide chain, and the other retained the intact bond.