Martini 3 Force Field Parameters for Protein Lipidation Post-Translational Modifications.

Protein lipidations are vital co/post-translational modifications that tether lipid tails to specific protein amino acids, allowing them to anchor to biological membranes, switch their subcellular localization, and modulate association with other proteins. Such lipidations are thus crucial for multiple biological processes including signal transduction, protein trafficking, and membrane localization and are implicated in various diseases as well. Examples of lipid-anchored proteins include the Ras family of proteins that undergo farnesylation; actin and gelsolin that are myristoylated; phospholipase D that is palmitoylated; glycosylphosphatidylinositol-anchored proteins; and others.

Membrane Composition and Raf[CRD]-Membrane Attachment Are Driving Forces for K-Ras4B Dimer Stability.

Ras proteins are membrane-anchored GTPases that regulate key cellular signaling networks. It has been recently shown that different anionic lipid types can affect the properties of Ras in terms of dimerization/clustering on the cell membrane. To understand the effects of anionic lipids on key spatiotemporal properties of dimeric K-Ras4B, we perform all-atom molecular dynamics simulations of the dimer K-Ras4B in the presence and absence of Raf[RBD/CRD] effectors on two model anionic lipid membranes: one containing 78% mol DOPC, 20% mol DOPS, and 2% mol PIP2 and another one with enhanced concentration of anionic lipids containing 50% mol DOPC, 40% mol DOPS, and 10% mol PIP2.

Evaluating the Efficiency of the Martini Force Field to Study Protein Dimerization in Aqueous and Membrane Environments.

Protein-protein complex assembly is one of the major drivers of biological response. Understanding the mechanisms of protein oligomerization/dimerization would allow one to elucidate how these complexes participate in biological activities and could ultimately lead to new approaches in designing novel therapeutic agents. However, determining the exact association pathways and structures of such complexes remains a challenge.

Use of Intramolecular 1,5-Sulfur-Oxygen and 1,5-Sulfur-Halogen Interactions in the Design of -Methyl-5-aryl--(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine SMN2 Splicing Modulators.

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 () gene. Branaplam () elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of enforces a planar conformation of the biaryl system and is critical for the compound activity.

Evolution of Novartis' Small Molecule Screening Deck Design.

This article summarizes the evolution of the screening deck at the Novartis Institutes for BioMedical Research (NIBR). Historically, the screening deck was an assembly of all available compounds. In 2015, we designed a first deck to facilitate access to diverse subsets with optimized properties.

Closing the Gap: A Regional Partnership Model for Perioperative Nursing.

New Jersey is projected to be one of the top three states to experience a nursing shortage. The current practice of health care organizations providing their own education and training in the perioperative setting leads to variability in the degree of staff readiness and competence to address the complexities encountered in this setting. This may result in increased perioperative nursing orientation costs.

Light-controlled thrombin catalysis and clot formation using a photoswitchable G-quadruplex DNA aptamer.

The reversible photocontrol of an enzyme governing blood coagulation is demonstrated. The thrombin binding aptamer (TBA), was rendered photochromic by modification with two anthracene groups. Light-triggered anthracene photodimerisation distorts its structure, inhibiting binding of the enzyme thrombin, which in turn triggers catalysis and the resulting clotting process.

Fracture resistance of cingulum rest seats in CAD-CAM tooth-colored crowns for removable partial denture abutments.

Statement Of Problem: The prevalent use of computer-aided design and computer-aided manufacturing (CAD-CAM) for tooth-colored ceramic materials has led to several case reports and retrospective clinical studies of surveyed crowns used to support removable partial dentures. How the specific contour of a cingulum rest seat affects the fracture resistance of these CAD-CAM tooth-colored materials is unknown.

Purpose: The purpose of this in vitro study was to compare the fracture resistance of monolithic CAD-CAM tooth-colored mandibular canine-surveyed ceramic crowns with cingulum rest seats of different designs.

PathwayMap: Molecular Pathway Association with Self-Normalizing Neural Networks.

Drug discovery suffers from high attrition because compounds initially deemed as promising can later show ineffectiveness or toxicity resulting from a poor understanding of their activity profile. In this work, we describe a deep self-normalizing neural network model for the prediction of molecular pathway association and evaluate its performance, showing an AUC ranging from 0.69 to 0.

Discovery of dual GyrB/ParE inhibitors active against Gram-negative bacteria.

Even though many GyrB and ParE inhibitors have been reported in the literature, few possess activity against Gram-negative bacteria. This is primarily due to limited permeability across Gram-negative bacterial membrane as well as bacterial efflux mechanisms. Permeability of compounds across Gram-negative bacterial membranes depends on many factors including physicochemical properties of the inhibitors.

Structure-Based Design of Selective Noncovalent CDK12 Inhibitors.

Cyclin-dependent kinase (CDK) 12 knockdown via siRNA decreases the transcription of DNA-damage-response genes and sensitizes BRCA wild-type cells to poly(ADP-ribose) polymerase (PARP) inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol].

Effects of Mechanical Complications on Radiation Exposure During Fluoroscopically Guided Gastrojejunostomy Exchange in the Pediatric Population.

The purpose of the article is to evaluate the effects of mechanical complications, such as clogging or coiling, of gastrojejunostomy tubes on radiation exposure during exchange in the pediatric population. In this HIPAA-compliant and IRB-approved study, we retrospectively reviewed procedural records for patients undergoing gastrojejunostomy (GJ) tube exchange during a 4-month period in 2014. Success of the procedure, specifications of the tube, age, and sex of the patient as well as radiation exposure during the procedure were included.

The Benefits and Risks of Energy Drinks in Young Adults and Military Service Members.

Introduction: Energy drinks (EDs) have become an integral part of the young adult, athletic, and military culture. Many athletes are convinced that EDs enhance performance, and service members as well as college students frequently use EDs as stimulants to counter sleep deprivation, or to improve academic performance. However, concerns have been raised by some military leaders about potential adverse effects of EDs.

ESKAPEing the labyrinth of antibacterial discovery.

Antimicrobial drug resistance is a growing threat to global public health. Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. - is of particular concern because they are responsible for many serious infections in hospitals.

Toward the rational design of carbapenem uptake in Pseudomonas aeruginosa.

Understanding how compound penetration occurs across the complex cell walls of Gram-negative bacteria is one of the greatest challenges in discovering new drugs to treat the infections they cause. A combination of next-generation transposon sequencing, computational metadynamics simulations (CMDS), and medicinal chemistry was used to define genetic and structural elements involved in facilitated carbapenem entry into Pseudomonas aeruginosa. Here we show for the first time that these compounds are taken up not only by the major outer membrane channel OccD1 (also called OprD or PA0958) but also by a closely related channel OccD3 (OpdP or PA4501).

A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV.

The introduction into clinical practice of an ATPase inhibitor of bacterial DNA gyrase and topoisomerase IV (topo IV) would represent a new-class agent for the treatment of resistant bacterial infections. Novobiocin, the only historical member of this class, established the clinical proof of concept for this novel mechanism during the late 1950s, but its use declined rapidly and it was eventually withdrawn from the market. Despite significant and prolonged effort across the biopharmaceutical industry to develop other agents of this class, novobiocin remains the only ATPase inhibitor of gyrase and topo IV ever to progress beyond Phase I.

Facilitating Lewin's change model with collaborative evaluation in promoting evidence based practices of health professionals.

Evidence based practices (EBPs) in clinical settings interact with and adapt to host organizational characteristics. The contextual factors themselves, surrounding health professions' practices, also adapt as practices become sustained. The authors assert the need for better planning models toward these contextual factors, the influence of which undergird a well-documented science to practice gap in literature on EBPs.

Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099).

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid.

Neurointerventions in children: radiation exposure and its import.

Background And Purpose: Neurointerventions in children have dramatically improved the clinical outlook for patients with previously intractable cerebrovascular conditions, such as vein of Galen malformations and complex arteriovenous fistulas. However, these complex and sometimes lengthy procedures are performed under fluoroscopic guidance and thus unavoidably expose vulnerable pediatric patients to the effects of ionizing radiation. Recent epidemiologic evidence from a national registry of children who underwent CT scans suggests a higher-than-expected incidence of secondary tumors.

Fragment-to-hit-to-lead discovery of a novel pyridylurea scaffold of ATP competitive dual targeting type II topoisomerase inhibiting antibacterial agents.

The discovery and optimization of a new class of bacterial topoisomerase (DNA gyrase and topoisomerase IV) inhibitors binding in the ATP domain are described. A fragment molecule, 1-ethyl-3-(2-pyridyl)urea, provided sufficiently potent enzyme inhibition (32 μM) to prompt further analogue work. Acids and acid isosteres were incorporated at the 5-pyridyl position of this fragment, bridging to a key asparagine residue, improving enzyme inhibition, and leading to measurable antibacterial activity.

Novel topoisomerase inhibitors: microbiological characterisation and in vivo efficacy of pyrimidines.

Pyrimidine compounds were identified as inhibitors of DNA topoisomerase IV through high-throughput screening. This study was designed to exemplify the in vitro activity of the pyrimidines against Gram-positive and Gram-negative microorganisms, to reveal the mode of action of these compounds and to demonstrate their in vivo efficacy. Frequencies of resistance to pyrimidines among Staphylococcus aureus and Streptococcus pneumoniae were <10(-10) at four times their minimum inhibitory concentrations (MICs).

Antimicrobial Activity of Adenine-Based Inhibitors of NAD(+)-Dependent DNA Ligase.

The relationship between enzyme inhibition and antimicrobial potency of adenine-based NAD(+)-dependent DNA ligase (LigA) inhibitors was investigated using a strain of the Gram-negative pathogen Haemophilus influenzae lacking its major AcrAB-TolC efflux pump and the Gram-positive pathogen Streptococcus pneumoniae. To this end, biochemical inhibitors not mediating their antibacterial mode of action (MOA) via LigA were removed from the analysis. In doing so, a significant number of compounds were identified that acted via inhibition of LigA in S.

Gerontological nursing content in general medical/surgical textbooks: where is it?

To provide quality care to the rapidly growing aging population, nursing education will need to be transformed. Although several approaches will be used to meet this challenge, fundamental to most nursing programs is the use of a general medical/surgical nursing textbook. This article examines the quantity and quality of gerontological nursing content found in five general medical/surgical nursing textbooks published between 2009 and 2011.