Missense3D-TM: Predicting the Effect of Missense Variants in Helical Transmembrane Protein Regions Using 3D Protein Structures.

Variant effect predictors assess if a substitution is pathogenic or benign. Most predictors, including those that are structure-based, are designed for globular proteins in aqueous environments and do not consider that the variant residue is located within the membrane. We report Missense3D-TM that provides a structure-based assessment of the impact of a missense variant located within a membrane.

Triple Threat: Triple-Valve Endocarditis Case Report and Literature Review.

Triple valve endocarditis (TVE) is a rare presentation of endocarditis often requiring multivalvular surgery. Here we report a case of S. triple valve endocarditis in a patient with a history of intravenous drug use and provide a literature review of TVE identification, treatment, and prognosis.

Missense3D-PPI: A Web Resource to Predict the Impact of Missense Variants at Protein Interfaces Using 3D Structural Data.

In 2019, we released Missense3D which identifies stereochemical features that are disrupted by a missense variant, such as introducing a buried charge. Missense3D analyses the effect of a missense variant on a single structure and thus may fail to identify as damaging surface variants disrupting a protein interface i.e.

Protein structure-based evaluation of missense variants: Resources, challenges and future directions.

We provide an overview of the methods that can be used for protein structure-based evaluation of missense variants. The algorithms can be broadly divided into those that calculate the difference in free energy (ΔΔG) between the wild type and variant structures and those that use structural features to predict the damaging effect of a variant without providing a ΔΔG. A wide range of machine learning approaches have been employed to develop those algorithms.

Thermodilution Assessment of Cardiac Index in Patients With Tricuspid Regurgitation.

Background: Disparities between thermodilution (TD) and Fick measurements of cardiac index (CI) are common in real-world clinical practice. Published studies about the effect of tricuspid regurgitation (TR) on TD are small and describe conflicting results. We tested the correlation between TD and Fick across a wide range of TR severity, in a larger group of patients undergoing right heart catheterization (RHC).

GWYRE: A Resource for Mapping Variants onto Experimental and Modeled Structures of Human Protein Complexes.

Rapid progress in structural modeling of proteins and their interactions is powered by advances in knowledge-based methodologies along with better understanding of physical principles of protein structure and function. The pool of structural data for modeling of proteins and protein-protein complexes is constantly increasing due to the rapid growth of protein interaction databases and Protein Data Bank. The GWYRE (Genome Wide PhYRE) project capitalizes on these developments by advancing and applying new powerful modeling methodologies to structural modeling of protein-protein interactions and genetic variation.

Utility of plasma volume status in ambulatory patients with pulmonary hypertension.

Plasma volume status (PVS) is a noninvasive estimate of intravascular volume status. We studied the utility of PVS to predict short-term outcomes in patients with pulmonary hypertension. Patients with lower PVS had decreased risk of hospitalization and death within 90 days of clinic visit, compared to those with higher PVS.

Multi-reward Reinforcement Learning Based Bond-Order Potential to Study Strain-Assisted Phase Transitions in Phosphorene.

We introduce a multi-reward reinforcement learning (RL) approach to train a flexible bond-order potential (BOP) for 2D phosphorene based on ab initio training data sets. Our approach is based on a continuous action space Monte Carlo tree search algorithm that is general and scalable and presents an efficient multiobjective optimization scheme for high-dimensional materials design problems. As a proof-of-concept, we deploy this scheme to parametrize multiple structural and dynamical properties of 2D phosphorene polymorphs.

A common TMPRSS2 variant has a protective effect against severe COVID-19.

Background: The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus' spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection.

Methods: We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.

Accurate determination of solvation free energies of neutral organic compounds from first principles.

The main goal of molecular simulation is to accurately predict experimental observables of molecular systems. Another long-standing goal is to devise models for arbitrary neutral organic molecules with little or no reliance on experimental data. While separately these goals have been met to various degrees, for an arbitrary system of molecules they have not been achieved simultaneously.

Learning in continuous action space for developing high dimensional potential energy models.

Reinforcement learning (RL) approaches that combine a tree search with deep learning have found remarkable success in searching exorbitantly large, albeit discrete action spaces, as in chess, Shogi and Go. Many real-world materials discovery and design applications, however, involve multi-dimensional search problems and learning domains that have continuous action spaces. Exploring high-dimensional potential energy models of materials is an example.

Modeling dark- and light-induced crystal structures and single-crystal optical absorption spectra of ruthenium-based complexes that undergo SO-linkage photoisomerization.

A family of coordination complexes of the type [Ru(SO)(NH)X]Y (m, n = 1 or 2) exhibit optical switching capabilities in their single-crystal states. This striking effect is caused by the light-induced formation of SO-linkage photoisomers, which are metastable if kept at suitably cool temperatures. We modeled the dark- and light-induced states of these large crystalline complexes via plane-wave (PW)- and molecular-orbital (MO)-based density functional theory (DFT) and time-dependent DFT in order to calculate their structural and optical properties; the calculated results are compared with experimental data.

The AlphaFold Database of Protein Structures: A Biologist's Guide.

AlphaFold, the deep learning algorithm developed by DeepMind, recently released the three-dimensional models of the whole human proteome to the scientific community. Here we discuss the advantages, limitations and the still unsolved challenges of the AlphaFold models from the perspective of a biologist, who may not be an expert in structural biology.

Ventriculoseptal Rupture Caused by Takotsubo Syndrome.

Ventriculoseptal rupture (VSR) is a rare complication of takotsubo syndrome that often requires immediate treatment. Patients with VSR experience a range of outcomes and should be managed at centers with cardiac and surgical expertise. We present 2 cases of VSR complicating takotsubo syndrome that highlight potential outcomes.

High-Entropy 2D Carbide MXenes: TiVNbMoC and TiVCrMoC.

Two-dimensional (2D) transition metal carbides and nitrides, known as MXenes, are a fast-growing family of 2D materials. MXenes 2D flakes have + 1 ( = 1-4) atomic layers of transition metals interleaved by carbon/nitrogen layers, but to-date remain limited in composition to one or two transition metals. In this study, by implementing four transition metals, we report the synthesis of multi-principal-element high-entropy MCT MXenes.

Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants.

The interpretation of human genetic variation is one of the greatest challenges of modern genetics. New approaches are urgently needed to prioritize variants, especially those that are rare or lack a definitive clinical interpretation. We examined 10,136,597 human missense genetic variants from GnomAD, ClinVar and UniProt.

The Genome3D Consortium for Structural Annotations of Selected Model Organisms.

Genome3D consortium is a collaborative project involving protein structure prediction and annotation resources developed by six world-leading structural bioinformatics groups, based in the United Kingdom (namely Blundell, Murzin, Gough, Sternberg, Orengo, and Jones). The main objective of Genome3D serves as a common portal to provide both predicted models and annotations of proteins in model organisms, using several resources developed by these labs such as CATH-Gene3D, DOMSERF, pDomTHREADER, PHYRE, SUPERFAMILY, FUGUE/TOCATTA, and VIVACE. These resources primarily use SCOP- and/or CATH-based protein domain assignments.

LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling.

The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown.

Focused Cardiac Ultrasound in Dyspnea of Unclear Etiology in the Emergency Department: Utility of the FLUID Score.

Objectives: We evaluated the utility of focused cardiac ultrasound to predict the length of stay in patients presenting to the emergency department with dyspnea of unclear etiology.

Methods: Patients with focused cardiac ultrasound examinations performed in the emergency department for dyspnea over a 34-month period were retrospectively identified. Patients were excluded if they had a prior diagnosis of heart failure, dialysis requirement, or an etiology of dyspnea unrelated to the volume status.

Sepsis-Induced Cardiomyopathy: a Comprehensive Review.

Purpose Of Review: To briefly review epidemiology and pathophysiology of SICM and provide a more extensive review of the data on diagnostic and management strategies.

Recent Findings: SICM is likely underdiagnosed and that has mortality implications. Current evidence supports speckle tracking echocardiography to identify decreased contractility irrespective of left ventricular ejection fraction for the diagnosis of SICM.