A physics-aware neural network for protein-ligand interactions with quantum chemical accuracy.

Quantifying intermolecular interactions with quantum chemistry (QC) is useful for many chemical problems, including understanding the nature of protein-ligand interactions. Unfortunately, QC computations on protein-ligand systems are too computationally expensive for most use cases. The flourishing field of machine-learned (ML) potentials is a promising solution, but it is limited by an inability to easily capture long range, non-local interactions.

A quantum chemical interaction energy dataset for accurately modeling protein-ligand interactions.

Fast and accurate calculation of intermolecular interaction energies is desirable for understanding many chemical and biological processes, including the binding of small molecules to proteins. The Splinter ["Symmetry-adapted perturbation theory (SAPT0) protein-ligand interaction"] dataset has been created to facilitate the development and improvement of methods for performing such calculations. Molecular fragments representing commonly found substructures in proteins and small-molecule ligands were paired into >9000 unique dimers, assembled into numerous configurations using an approach designed to adequately cover the breadth of the dimers' potential energy surfaces while enhancing sampling in favorable regions.

Characterizing Pure Polymers under High Speed Compression for the Micromechanical Prediction of Unidirectional Composites.

The nonlinear behaviour of fibre-reinforced polymer composites (FRPC) in transverse loading is mainly induced by the constituent polymer matrix. The thermoset and thermoplastic matrices are typically rate- and temperature-dependent, complicating the dynamic material characterization process. Under dynamic compression, the microstructure of the FRPC develops local strains and local strain rates whose values can be much higher than those applied at macroscopic level.

Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1-pyrazol-1-yl)methyl)phosphonate (BMS-820132).

Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators.

Electron-Passing Neural Networks for Atomic Charge Prediction in Systems with Arbitrary Molecular Charge.

Atomic charges are critical quantities in molecular mechanics and molecular dynamics, but obtaining these quantities requires heuristic choices based on atom typing or relatively expensive quantum mechanical computations to generate a density to be partitioned. Most machine learning efforts in this domain ignore total molecular charges, relying on overfitting and arbitrary rescaling in order to match the total system charge. Here, we introduce the electron-passing neural network (EPNN), a fast, accurate neural network atomic charge partitioning model that conserves total molecular charge by construction.

Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase.

Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT).

AP-Net: An atomic-pairwise neural network for smooth and transferable interaction potentials.

Intermolecular interactions are critical to many chemical phenomena, but their accurate computation using ab initio methods is often limited by computational cost. The recent emergence of machine learning (ML) potentials may be a promising alternative. Useful ML models should not only estimate accurate interaction energies but also predict smooth and asymptotically correct potential energy surfaces.

Approaches for machine learning intermolecular interaction energies and application to energy components from symmetry adapted perturbation theory.

Accurate prediction of intermolecular interaction energies is a fundamental challenge in electronic structure theory due to their subtle character and small magnitudes relative to total molecular energies. Symmetry adapted perturbation theory (SAPT) provides rigorous quantum mechanical means for computing such quantities directly and accurately, but for a computational cost of at least O(N), where N is the number of atoms. Here, we report machine learned models of SAPT components with a computational cost that scales asymptotically linearly, O(N).

An empirical study of how the Dutch healthcare regulator first formulates the concept of trust and then puts it into practice.

Background: Responsive regulation assumes that the parties being regulated are trustworthy and motivated by social responsibility. This assumes that regulation based upon trust will improve the regulated organization more effectively than other regulation models. The purpose of our qualitative study was to unravel the most important elements of trust in the inspectee which can support the inspector's work and to develop a model and a framework of trust that can be used by the inspectors to legitimize their trust in the inspectee.

Endovascular revascularisation versus conservative management for intermittent claudication.

Background: Intermittent claudication (IC) is the classic symptomatic form of peripheral arterial disease affecting an estimated 4.5% of the general population aged 40 years and older. Patients with IC experience limitations in their ambulatory function resulting in functional disability and impaired quality of life (QoL).

Improving Accuracy, Diversity, and Speed with Prime Macrocycle Conformational Sampling.

A novel method for exploring macrocycle conformational space, Prime macrocycle conformational sampling (Prime-MCS), is introduced and evaluated in the context of other available algorithms (Molecular Dynamics, LowModeMD in MOE, and MacroModel Baseline Search). The algorithms were benchmarked on a data set of 208 macrocycles which was curated for diversity from the Cambridge Structural Database, the Protein Data Bank, and the Biologically Interesting Molecule Reference Dictionary. The algorithms were evaluated in terms of accuracy (ability to reproduce the crystal structure), diversity (coverage of conformational space), and computational speed.

Endovascular Revascularization and Supervised Exercise for Peripheral Artery Disease and Intermittent Claudication: A Randomized Clinical Trial.

Importance: Supervised exercise is recommended as a first-line treatment for intermittent claudication. Combination therapy of endovascular revascularization plus supervised exercise may be more promising but few data comparing the 2 therapies are available.

Objective: To assess the effectiveness of endovascular revascularization plus supervised exercise for intermittent claudication compared with supervised exercise only.

Assessment of CF lung disease using motion corrected PROPELLER MRI: a comparison with CT.

Objectives: To date, PROPELLER MRI, a breathing-motion-insensitive technique, has not been assessed for cystic fibrosis (CF) lung disease. We compared this technique to CT for assessing CF lung disease in children and adults.

Methods: Thirty-eight stable CF patients (median 21 years, range 6-51 years, 22 female) underwent MRI and CT on the same day.

Modes of exercise training for intermittent claudication.

Background: According to international guidelines and literature, all patients with intermittent claudication should receive an initial treatment of cardiovascular risk modification, lifestyle coaching, and supervised exercise therapy. In most studies, supervised exercise therapy consists of treadmill or track walking. However, alternative modes of exercise therapy have been described and yielded similar results to walking.

4-Benzothiazole-7-hydroxyindolinyl diaryl ureas are potent P2Y1 antagonists with favorable pharmacokinetics: low clearance and small volume of distribution.

Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas.

The role of imaging specialists as authors of systematic reviews on diagnostic and interventional imaging and its impact on scientific quality: report from the EuroAIM Evidence-based Radiology Working Group.

Purpose: To evaluate the inclusion of radiologists or nuclear medicine physicians (imaging specialists) as authors of systematic reviews (SRs) on imaging and imaging-guided diagnostic procedures and to determine the impact of imaging specialists' presence as authors on the overall quality of the reviews.

Materials And Methods: A MEDLINE and EMBASE search was performed for SRs of diagnostic and interventional image-guided procedures that were published from January 2001 to December 2010. SRs about procedures primarily performed by nonimaging specialists were excluded.

Percutaneous transhepatic biliary drainage in patients with postsurgical bile leakage and nondilated intrahepatic bile ducts.

Objective And Background: Bile leakage is a serious postoperative complication and percutaneous transhepatic biliary drainage (PTBD) may be an option when endoscopic treatment is not feasible. In this retrospective study, we established technical and clinical success rates as well as the complication rates of PTBD in a large group of patients with postoperative bile leakage.

Methods: Data on all patients with nondilated intrahepatic bile ducts who underwent a PTBD procedure for the treatment of bile leakage between January 2000 and August 2012 were retrospectively assessed.

Can magnetic resonance imaging at 3.0-Tesla reliably detect patients with endometriosis? Initial results.

Aim: The aim of this study was to determine whether an optimized 3.0-Tesla magnetic resonance imaging (MRI) protocol is sensitive and specific enough to detect patients with endometriosis.

Material And Methods: This was a prospective cohort study with consecutive patients.

Conformationally constrained ortho-anilino diaryl ureas: discovery of 1-(2-(1'-neopentylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist.

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats.

Lifestyle interventions in patients with coronary heart disease: a systematic review.

Context: Coronary heart disease (CHD) is responsible for about 15% of all deaths worldwide and is identified as a top priority for decision makers. Both primary and secondary prevention are considered key strategies in the prevention of CHD. The aim of this study was to assess the efficacy of nonpharmacologic interventions with multiple lifestyle components in patients with established CHD in comparison to usual care.

Long-term clinical effectiveness of supervised exercise therapy versus endovascular revascularization for intermittent claudication from a randomized clinical trial.

Background: Long-term comparisons of supervised exercise therapy (SET) and endovascular revascularization (ER) for patients with intermittent claudication are scarce. The long-term clinical effectiveness of SET and ER was assessed in patients from a randomized trial.

Methods: Consenting patients with intermittent claudication were assigned randomly to either SET or ER.

Clinical examination versus magnetic resonance imaging in the pretreatment staging of cervical carcinoma: systematic review and meta-analysis.

Objectives: To review the literature on the diagnostic performance of clinical examination and magnetic resonance imaging (MRI) in detecting parametrial invasion and advanced stage disease (FIGO stage ≥ IIB) in patients with cervical carcinoma.

Methods: Reports of studies were searched using the MEDLINE, EMBASE and Cochrane databases. Two observers reported on data relevant for analysis and methodological quality using the QUADAS scoring system.

Preoperative breast MRI can reduce the rate of tumor-positive resection margins and reoperations in patients undergoing breast-conserving surgery.

Objective: In breast cancer patients eligible for breast-conserving surgery, we evaluated whether the information provided by preoperative MRI of the breast would result in fewer tumor-positive resection margins and fewer reoperations.

Subjects And Methods: The study group consisted of 123 consecutive patients diagnosed with either breast cancer or ductal carcinoma in situ eligible for breast-conserving surgery between April 2007 and July 2010. For these patients, a first plan for breast-conserving surgery was made on the basis of clinical examination and conventional imaging.

Personalized prediction of lifetime benefits with statin therapy for asymptomatic individuals: a modeling study.

Background: Physicians need to inform asymptomatic individuals about personalized outcomes of statin therapy for primary prevention of cardiovascular disease (CVD). However, current prediction models focus on short-term outcomes and ignore the competing risk of death due to other causes. We aimed to predict the potential lifetime benefits with statin therapy, taking into account competing risks.