Sialic acid identity modulates host tropism of sialoglycan-binding viridans group streptococci.

Microbial interactions with multiple species may expand the range of potential hosts, supporting both pathogen reservoirs and zoonotic spillover. Viridans group streptococci interact with host cells by engaging protein-attached glycosylations capped with terminal sialic acids (sialoglycans). One potential origin for host tropism of these streptococci arises because humans exclusively synthesize the N-acetylneuraminic acid (Neu5Ac) form of sialic acid, while non-human mammals synthesize both Neu5Ac and a hydroxylated N-glycolylneuraminic acid (Neu5Gc).

Sialic Acid Identity Modulates Host Tropism of Sialoglycan-binding Viridans Group Streptococci.

Microbial interactions with multiple species may expand the range of potential hosts, supporting both pathogen reservoirs and zoonotic spillover. Viridans group streptococci interact with host cells by engaging protein-attached glycosylations capped with terminal sialic acids (sialoglycans). One potential origin for host tropism of these streptococci arises because humans exclusively synthesize the N-acetylneuraminic acid (Neu5Ac) form of sialic acid, while non-human mammals synthesize both Neu5Ac and a hydroxylated N-glycolylneuraminic acid (Neu5Gc).

Structure-Based Design of Small-Molecule Inhibitors of Human Interleukin-6.

Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. A critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies are in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high throughput structure-based computational screening using ensemble docking for small molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein.

GPRC6A is a Potential Therapeutic Target for Metformin Regulation of Glucose Homeostasis in Mice.

Understanding the mechanism of metformin actions in treating type 2 diabetes is limited by an incomplete knowledge of the specific protein targets mediating its metabolic effects. Metformin has structural similarities to L-Arginine (2-amino-5-guanidinopentanoic acid), which is a ligand for GPRC6A, a Family C G-protein coupled receptor that regulates energy metabolism. Ligand activation of GPRC6A results in lowering of blood glucose and other metabolic changes resembling the therapeutic effect of metformin.

Structure-Based Identification of Novel Histone Deacetylase 4 (HDAC4) Inhibitors.

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. However, engineering specificity is an important goal.

Comparative Assessment of Pose Prediction Accuracy in RNA-Ligand Docking.

Structure-based virtual high-throughput screening is used in early-stage drug discovery. Over the years, docking protocols and scoring functions for protein-ligand complexes have evolved to improve the accuracy in the computation of binding strengths and poses. In the past decade, RNA has also emerged as a target class for new small-molecule drugs.

SARS-CoV2 billion-compound docking.

This dataset contains ligand conformations and docking scores for 1.4 billion molecules docked against 6 structural targets from SARS-CoV2, representing 5 unique proteins: MPro, NSP15, PLPro, RDRP, and the Spike protein. Docking was carried out using the AutoDock-GPU platform on the Summit supercomputer and Google Cloud.

Speed vs Accuracy: Effect on Ligand Pose Accuracy of Varying Box Size and Exhaustiveness in AutoDock Vina.

Structure-based virtual high-throughput screening involves docking chemical libraries to targets of interest. A parameter pertinent to the accuracy of the resulting pose is the root mean square deviation (RMSD) from a known crystallographic structure, i. e.

Origins of glycan selectivity in streptococcal Siglec-like adhesins suggest mechanisms of receptor adaptation.

Bacterial binding to host receptors underlies both commensalism and pathogenesis. Many streptococci adhere to protein-attached carbohydrates expressed on cell surfaces using Siglec-like binding regions (SLBRs). The precise glycan repertoire recognized may dictate whether the organism is a strict commensal versus a pathogen.

Hit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor.

Inhibition of the SARS-CoV-2 main protease (M) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of M. Starting from a recently discovered scaffold (The COVID Moonshot Consortium.

Revised Glycemic Index for Diagnosing and Monitoring of Diabetes Mellitus in South Indian Population.

Aim: To find the optimal threshold of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) for diagnosis of diabetes mellitus (DM) and to evaluate the association with diabetic retinopathy (DR) in the South Indian population.

Settings And Design: A retrospective population-based study.

Methods And Materials: A total of 909 newly detected type 2 DM patients were selected from our two previously conducted studies, which include an urban and a rural population of South India.

A Model for the Signal Initiation Complex Between Arrestin-3 and the Src Family Kinase Fgr.

Arrestins regulate a wide range of signaling events, most notably when bound to active G protein-coupled receptors (GPCRs). Among the known effectors recruited by GPCR-bound arrestins are Src family kinases, which regulate cellular growth and proliferation. Here, we focus on arrestin-3 interactions with Fgr kinase, a member of the Src family.

COVID-19 induced ventricular tachycardia storm unmasking a clinically silent cardiomyopathy: a case report.

Background: Coronavirus disease (COVID-19) is a systemic illness characterized by raging impact of cytokine storm on multiple organs. This may trigger malignant ventricular arrhythmias and unmask a clinically silent cardiomyopathy.

Case Summary: A 57-year-old gentleman, known case of hyperthyroidism and diabetes, was referred to our emergency department with history of two ventricular tachycardia (VT) episodes requiring direct current cardioversion in last 3 h followed by another episode in our emergency department that was cardioverted.

Cross-reactive immunogenicity of group A streptococcal vaccines designed using a recurrent neural network to identify conserved M protein linear epitopes.

The M protein of group A streptococci (Strep A) is a major virulence determinant and protective antigen. The N-terminal sequence of the protein defines the more than 200 M types of Strep A and also contains epitopes that elicit opsonic antibodies, some of which cross-react with heterologous M types. Current efforts to develop broadly protective M protein-based vaccines are directed at identifying potential cross-protective epitopes located in the N-terminal regions of cluster-related M proteins for use as vaccine antigens.

Structure based virtual screening identifies small molecule effectors for the sialoglycan binding protein Hsa.

Infective endocarditis (IE) is a cardiovascular disease often caused by bacteria of the viridans group of streptococci, which includes Streptococcus gordonii and Streptococcus sanguinis. Previous research has found that serine-rich repeat (SRR) proteins on the S. gordonii bacterial surface play a critical role in pathogenesis by facilitating bacterial attachment to sialylated glycans displayed on human platelets.

Molecular dynamics analysis of the binding of human interleukin-6 with interleukin-6 α-receptor.

Human interleukin-6 (hIL-6) is a multifunctional cytokine that regulates immune and inflammatory responses in addition to metabolic and regenerative processes and cancer. hIL-6 binding to the IL-6 receptor (IL-6Rα) induces homodimerization and recruitment of the glycoprotein (gp130) to form a hexameric signaling complex. Anti-IL-6 and IL-6R antibodies are clinically approved inhibitors of IL-6 signaling pathway for treating rheumatoid arthritis and Castleman's disease, respectively.

[Evolving Consensus of International Uveitis Study Group, Intraocular Inflammation Society, and Foster Ocular Inflammation Society with Uveitis in the Time of COVID-19 Infection].

This document summarizes the experience of the International Uveitis Study Group (IUSG), the Intraocular Inflammation Society (IOIS) and the Foster Ocular Inflammation Society (FOIS) and can aid as a guide for the treatment of uveitis patients in the era of COVID-19 pandemic.

GPU-Accelerated Drug Discovery with Docking on the Summit Supercomputer: Porting, Optimization, and Application to COVID-19 Research.

Protein-ligand docking is an in silico tool used to screen potential drug compounds for their ability to bind to a given protein receptor within a drug-discovery campaign. Experimental drug screening is expensive and time consuming, and it is desirable to carry out large scale docking calculations in a high-throughput manner to narrow the experimental search space. Few of the existing computational docking tools were designed with high performance computing in mind.

Mesophilic Pyrophosphatase Function at High Temperature: A Molecular Dynamics Simulation Study.

The mesophilic inorganic pyrophosphatase from Escherichia coli (EcPPase) retains function at 353 K, the physiological temperature of hyperthermophilic Thermococcus thioreducens, whereas the homolog protein (TtPPase) from this hyperthermophilic organism cannot function at room temperature. To explain this asymmetric behavior, we examined structural and dynamical properties of the two proteins using molecular dynamics simulations. The global flexibility of TtPPase is significantly higher than its mesophilic homolog at all tested temperature/pressure conditions.

Evolving consensus on managing vitreo-retina and uvea practice in post-COVID-19 pandemic era.

The COVID-19 pandemic has brought new challenges to the health care community. Many of the super-speciality practices are planning to re-open after the lockdown is lifted. However there is lot of apprehension in everyone's mind about conforming practices that would safeguard the patients, ophthalmologists, healthcare workers as well as taking adequate care of the equipment to minimize the damage.

Capturing Deuteration Effects in a Molecular Mechanics Force Field: Deuterated THF and the THF-Water Miscibility Gap.

Deuteration is a common chemical modification used in conjunction with experiments such as neutron scattering, NMR, and Fourier-transform infrared for the study of molecular systems. Under the Born-Oppenheimer (BO) approximation, while the underlying potential energy surface remains unchanged by isotopic substitutions, isotopic substitution still alters intramolecular vibrations, which in turn may alter intermolecular interactions. Molecular mechanics (MM) force fields used in classical molecular dynamics simulations are assumed to represent local approximations of the BO potential energy surfaces, and hence, MD simulations using simple isotopic mass substitutions should capture BO-compatible isotope effects.

Deletion of GOLGA2P3Y but not GOLGA2P2Y is a risk factor for oligozoospermia.

The AZFc locus on the human Y chromosome harbours several multicopy genes, some of which are required for spermatogenesis. It is believed that deletion of one or more copies of these genes is a cause of infertility in some men. GOLGA2LY is one of the genes in the AZFc locus and it exists in two copies, GOLGA2P2Y and GOLGA2P3Y.