A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.

Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays.

Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning.

The macrodomain contained in the SARS-CoV-2 non-structural protein 3 (NSP3) is required for viral pathogenesis and lethality. Inhibitors that block the macrodomain could be a new therapeutic strategy for viral suppression. We previously performed a large-scale X-ray crystallography-based fragment screen and discovered a sub-micromolar inhibitor by fragment linking.

Thompson Sampling─An Efficient Method for Searching Ultralarge Synthesis on Demand Databases.

Over the last five years, virtual screening of ultralarge synthesis on-demand libraries has emerged as a powerful tool for hit identification in drug discovery programs. As these libraries have grown to tens of billions of molecules, we have reached a point where it is no longer cost-effective to screen every molecule virtually. To address these challenges, several groups have developed heuristic search methods to rapidly identify the best molecules on a virtual screen.

Defining Levels of Automated Chemical Design.

One application area of computational methods in drug discovery is the automated design of small molecules. Despite the large number of publications describing methods and their application in both retrospective and prospective studies, there is a lack of agreement on terminology and key attributes to distinguish these various systems. We introduce Automated Chemical Design (ACD) Levels to clearly define the level of autonomy along the axes of ideation and decision making.

Superwoman's kryptonite: The superwoman schema and perceived barriers to weight management among U.S. Black women.

The role that the superwoman schema (SWS) plays in U.S. Black women's perceptions of barriers (biological, psychological, and sociological) to healthy weight management is unknown.

Ultrasound Examination Techniques for Elbow Injuries in Overhead Athletes.

Elbow pain is a frequent complaint among overhead athletes. Standard evaluation of the elbow uses history and physical examination, with radiographic imaging and MRI aiding in the confirmation of diagnosis. Musculoskeletal ultrasonography (US) provides dynamic, functional assessment of tendons and ligaments in the elbow, allowing the visualization of structures under stress and motion.

Outcomes after Surgical Repair of Medial Meniscal Root Tears: A Review.

At the present time, there is a paucity of literature regarding medial meniscal posterior root repair and outcomes. This review seeks to examine the currently available data to further elucidate the clinical risks and benefits and any associated risks of medial meniscal posterior root repair. A systematic literature search was performed up to July 2018 in the databases of Medline via PubMed, EBSCOhost, and EMBASE.

Smallest Maximum Intramolecular Distance: A Novel Method to Mitigate Pregnane Xenobiotic Receptor Activation.

Induction of cytochrome P450 isoform 3A4 via activation of the pregnane xenobiotic receptor (PXR) is a concern for pharmaceutical discovery and development, as it can lead to drug-drug interactions. We present a novel molecular descriptor, the smallest maximum intramolecular distance (SMID), which is correlated with PXR activation, and a method for using the SMID descriptor to guide discovery chemists in modifying lead compounds to decrease PXR activation.

Early clinical cxperience with the SIGN hip construct: a retrospective case series.

Background: As the population ages, the developing world industrializes, and more urban centers emerge, the burden of orthopedic trauma will steadily increase. SIGN Fracture Care International has developed a unique intramedullary device for fixation of hip fractures in low-resource settings lacking fluoroscopy. The purpose of this study is to report the safety profile and complication rate for a consecutive series of hip fracture patients managed using this implant.

Understanding covariate shift in model performance.

Three (3) different methods (logistic regression, covariate shift and k-NN) were applied to five (5) internal datasets and one (1) external, publically available dataset where covariate shift existed. In all cases, k-NN's performance was inferior to either logistic regression or covariate shift. Surprisingly, there was no obvious advantage for using covariate shift to reweight the training data in the examined datasets.

Perceived Physician-informed Weight Status Predicts Accurate Weight Self-Perception and Weight Self-Regulation in Low-income, African American Women.

Background: Obese African American women under-appraise their body mass index (BMI) classification and report fewer weight loss attempts than women who accurately appraise their weight status. This cross-sectional study examined whether physician-informed weight status could predict weight self-perception and weight self-regulation strategies in obese women.

Methods: A convenience sample of 118 low-income women completed a survey assessing demographic characteristics, comorbidities, weight self-perception, and weight self-regulation strategies.

Gray Box Optimization for Mk Landscapes (NK Landscapes and MAX-kSAT).

This article investigates Gray Box Optimization for pseudo-Boolean optimization problems composed of M subfunctions, where each subfunction accepts at most k variables. We will refer to these as Mk Landscapes. In Gray Box Optimization, the optimizer is given access to the set of M subfunctions.

Non-medical prescription opioid use, prescription opioid-related harms and public health in Canada: an update 5 years later.

Five years ago, we highlighted Canada's emerging problem of prescription opioid (PO)-related harms and emphasized the need for targeted surveillance, research and interventions. Overall levels of PO use in the Canadian population have grown by 70% since then, while at the same time levels of non-medical PO use (NMPOU) in general and in key risk populations have continued to be high; furthermore, PO-related harms - specifically morbidity (e.g.

From cues to signals: evolution of interspecific communication via aposematism and mimicry in a predator-prey system.

Current theory suggests that many signaling systems evolved from preexisting cues. In aposematic systems, prey warning signals benefit both predator and prey. When the signal is highly beneficial, a third species often evolves to mimic the toxic species, exploiting the signaling system for its own protection.

Iterative refinement of a binding pocket model: active computational steering of lead optimization.

Computational approaches for binding affinity prediction are most frequently demonstrated through cross-validation within a series of molecules or through performance shown on a blinded test set. Here, we show how such a system performs in an iterative, temporal lead optimization exercise. A series of gyrase inhibitors with known synthetic order formed the set of molecules that could be selected for "synthesis.

Within-person relationships among daily self-esteem, need satisfaction, and authenticity.

This study examined the within-person relationships among daily self-esteem, felt authenticity (i.e., the operation of one's "true self"), and satisfaction of psychological needs for autonomy, competence, and relatedness.

Non-medical use of prescription opioids and public health in Canada: an urgent call for research and interventions development.

While the public health problem of psychoactive drug use is well recognized, the emerging phenomenon of non-medical use of prescription opioids has been largely ignored in Canada. Most evidence on this issue and related harms in North America to date come from the United States (US), where the prevalence of non-medical opioid use in key populations, as well as related morbidity and mortality, recently have risen substantially. Also, given the increases in the overall consumption of prescription opioids similar to those in the US, a substantial expansion of problems related to non-medical opioid use appears to be occurring in Canada.

Fentanyl use among street drug users in Toronto, Canada: behavioural dynamics and public health implications.

Prescription opioids (POs) are playing an increasingly central role in street drug use and related harms in North America. One distinct PO substance of interest is Fentanyl (Duragesic), a potent opioid analgesic designed for transdermal time-release application. Studies from Europe and North America have documented the sizeable overdose and mortality burden associated with the non-medical use of this drug.

Mindfulness as a means of reducing aggressive behavior: dispositional and situational evidence.

Recent research and theory suggest that mindfulness, or enhanced attention and awareness in the present moment [Brown and Ryan, 2003], may be linked to lower levels of ego-involvement and, as a result, may have implications for lowering hostility and aggressive behavior. Accordingly, we conducted two studies to examine the potential aggression-mitigating role of mindfulness. In Study 1, we found that dispositional mindfulness correlated negatively with self-reported aggressiveness and hostile attribution bias.

A model for identifying HERG K+ channel blockers.

Acquired long QT syndrome (LQTS) occurs frequently as a side effect of blockade of cardiac HERG K(+) channels by commonly used medications. A large number of structurally diverse compounds have been shown to inhibit K(+) current through HERG. There is considerable interest in developing in silico tools to filter out potential HERG blockers early in the drug discovery process.