Development of PRC1 Inhibitors Employing Fragment-Based Approach and NMR-Guided Optimization.

Polycomb Repressive Complex 1 (PRC1) is associated with transcriptional silencing, and its dysregulation plays an important role in various cancers. Well-characterized PRC1 inhibitors can facilitate the exploration of PRC1 inhibition as therapeutic agents. By employing an NMR-based fragment screening approach, we have previously identified a very weak millimolar ligand , which directly binds to RING1B-BMI1.

Melanin concentrating hormone projections to the nucleus accumbens enhance the reward value of food consumption and do not induce feeding or REM sleep.

Regulation of food intake and energy balance is critical to survival. Hunger develops as a response to energy deficit and drives food-seeking and consumption. However, motivations to eat are varied in nature, and promoted by factors other than energy deficit.

Acquired torticollis due to an ocular surface foreign body.

Ocular torticollis is traditionally attributed to eye misalignment, nystagmus, ptosis, or refractive error. We present 3 pediatric cases of acquired torticollis caused by a foreign body beneath the upper eyelid. The head posturing presumably developed to minimize contact of the foreign body with the corneal surface and mitigate ocular discomfort.

Improvement of cellular pattern organization and clarity through centrifugal force.

Rapid and strategic cell placement is necessary for high throughput tissue fabrication. Current adhesive cell patterning systems rely on fluidic shear flow to remove cells outside of the patterned regions, but limitations in washing complexity and uniformity prevent adhesive patterns from being widely applied. Centrifugation is commonly used to study the adhesive strength of cells to various substrates; however, the approach has not been applied to selective cell adhesion systems to create highly organized cell patterns.

A scoping review and consensus recommendations for emergency medical services buprenorphine (EMS-Bupe) programs.

Objectives: Emergency Medical Services (EMS) agencies are beginning to provide low-barrier access to treatment for opioid use disorder (OUD) through the development of EMS buprenorphine (EMS-Bupe) programs. However, evidence-based practices for these programs are lacking. Our aim was to review the current literature on EMS and emergency department (ED) based buprenorphine treatment programs to provide consensus recommendations on the EMS-Bupe program development.

Finite mixtures of functional graphical models: Uncovering heterogeneous dependencies in high-dimensional data.

Graphical models have been widely used to explicitly capture the statistical relationships among the variables of interest in the form of a graph. The central question in these models is to infer significant conditional dependencies or independencies from high-dimensional data. In the current literature, it is common to assume that the high-dimensional data come from a homogeneous source and follow a parametric graphical model.

Hazardous exposures and engineering controls in the landscaping services industry.

Landscapers are exposed to noise, carbon monoxide (CO), respirable dust, and respirable crystalline silica (RCS) generated from the tools they use. Although engineering controls are available to reduce these exposures, no previous study has evaluated chronic exposures to landscapers in different work settings and compared exposures from landscaping tools with and without engineering controls. This field study of workers in the landscaping services industry documented the occupational exposures of 80 participants at 11 varied worksites to noise, CO, respirable dust, and RCS using personal breathing zone sampling.

How community connection, homophobia, and racism shape gene expression in sexual minority men with and without HIV.

Objective: Although sexual minority men experience substantial discrimination, in addition to increased risk for several serious mental and somatic health problems, the biological mechanisms underlying these effects are unclear. To address this issue, we examined how experiences of social safety (i.e.

Lineage Analysis at Single-Cell Resolution by Twin-Spot MARCM with Lineage-Restricted Drivers.

Cell lineage analysis is primarily undertaken to understand cell fate specification and diversification along a cell lineage tree. Built with dual repressible markers, twin-spot mosaic analysis with repressible cell markers (MARCM) labels the two daughter cells made by a common precursor in distinct colors. The power of twin-spot MARCM to systematically subdivide complex lineages is exemplified in studies of Drosophila neural stem-cell lineages.

Role of mouse adenovirus type 1 E4orf6-induced degradation of protein kinase R in pathogenesis.

Protein kinase R (PKR) is an interferon-induced antiviral protein activated by autophosphorylation in response to double strand DNA (dsRNA) and other stimuli. Activated PKR causes translation inhibition and apoptosis, and it contributes to proinflammatory responses, cell growth, and differentiation. Mouse adenovirus type 1 (MAV-1) counteracts PKR by causing its degradation via a viral protein, early region 4 open reading frame 6 (E4orf6).

Dengue and Zika virus NS4B proteins differ in topology and in determinants of ER membrane protein complex dependency.

Flaviviruses utilize the cellular endoplasmic reticulum (ER) for all aspects of their lifecycle. Genome replication and other viral activities take place in structures called replication organelles (ROs), which are invaginations induced in the ER membrane. Among the required elements for RO formation is the biogenesis of viral nonstructural proteins NS4A and NS4B.

Systolic Blood Pressure and Pulse Pressure in Heart Failure: Pooled Participant-Level Analysis of 4 Trials.

Background: Hypertension is common in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), and current guidelines recommend treating systolic blood pressure (SBP) to a target <130 mm Hg. However, data supporting treatment to this target are limited. Additionally, pulse pressure (PP), a marker of aortic stiffness, has been associated with increased risk of cardiovascular events, but its prognostic impact in HFpEF has not been extensively studied.

Flaring of Protruding Coronary Stents Before Transcatheter Aortic Valve Replacement to Minimize Interaction-A Feasibility Study.

Background: Protruding coronary artery stents can adversely affect transcatheter aortic valve replacement (TAVR) procedure. Current evidence on the topic is limited.

Aims: We aim to study the clinical feasibility and safety of flaring of protruding coronary artery stents before TAVR to reduce interaction with transcatheter heart valves.

Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers.

SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective SMARCA2 PROTAC degraders, as exemplified by SMD-3236, which was designed using a new, high-affinity SMARCA ligand and a potent VHL-1 ligand. SMD-3236 achieves DC < 1 nM and > 95% against SMARCA2 and >2000-fold degradation selectivity over SMARCA4.

Examining the Impact of Local Constraint Violations on Energy Computations in DFT.

This work examines the impact of locally imposed constraints in Density Functional Theory (DFT). Using a metric referred to as the extent of violation index (EVI), we quantify how well exchange-correlation functionals adhere to local constraints. Applying EVIs to a diverse set of molecules for GGA functionals reveals constraint violations, particularly for semi-empirical functionals.

Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders.

In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands.

Clonal hematopoiesis JAKs up plaque formation.

Clonal hematopoiesis (CH) is a condition in which hematopoietic stem cells (HSCs) acquire mutations seen in leukemia. While individuals with CH generally do not show signs of hematologic disease, the condition becomes more common with age and correlates with age-related diseases, especially cardiovascular disease (CVD). JAK2 mutations in HSCs can lead to CH and correlate with atherosclerosis, but the condition has been difficult to study because of challenges modeling the mutant cells at very low frequency.