Development of a curriculum in cultural determinants of health and health disparities.

Introduction: Current sociopolitical events coupled with requirement modifications by the Liaison Committee on Medical Education have reinvigorated a need for training in cultural awareness and health disparities in undergraduate medical education. Many institutions, however, have not established longitudinal courses designed to address this content. Additionally, little is known about the change in learners' awareness of cultural determinants of health and health disparities after enrollment in such curricula.

Disruption of a ∼23-24 nucleotide small RNA pathway elevates DNA damage responses in .

Endogenous RNA interference (RNAi) pathways regulate a wide range of cellular processes in diverse eukaryotes, yet in the ciliated eukaryote, , the cellular purpose of RNAi pathways that generate ∼23-24 nucleotide (nt) small (s)RNAs has remained unknown. Here, we investigated the phenotypic and gene expression impacts on vegetatively growing cells when genes involved in ∼23-24 nt sRNA biogenesis are disrupted. We observed slower proliferation and increased expression of genes involved in DNA metabolism and chromosome organization and maintenance in sRNA biogenesis mutants Δ, Δ, and Δ.

Understanding the characteristics of nonspecific binding of drug-like compounds to canonical stem-loop RNAs and their implications for functional cellular assays.

Identifying small molecules that selectively bind an RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that minimize electrostatic and stacking interactions that lead to nonspecific binding of aminoglycosides and intercalators to many stem-loop RNAs. Many such compounds have been reported to bind RNAs and inhibit their cellular activities.

Publisher Correction: High-performance virtual screening by targeting a high-resolution RNA dynamic ensemble.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Probing RNA Conformational Equilibria within the Functional Cellular Context.

Low-abundance short-lived non-native conformations referred to as excited states (ESs) are increasingly observed in vitro and implicated in the folding and biological activities of regulatory RNAs. We developed an approach for assessing the relative abundance of RNA ESs within the functional cellular context. Nuclear magnetic resonance (NMR) spectroscopy was used to estimate the degree to which substitution mutations bias conformational equilibria toward the inactive ES in vitro.

Demonstration that Small Molecules can Bind and Stabilize Low-abundance Short-lived RNA Excited Conformational States.

Many promising RNA drug targets have functions that require the formation of RNA-protein complexes, but inhibiting RNA-protein interactions can prove difficult using small molecules. Regulatory RNAs have been shown to transiently form excited conformational states (ESs) that remodel local aspects of secondary structure. In some cases, the ES conformation has been shown to be inactive and to be poorly recognized by protein binding partners.

The roles of structural dynamics in the cellular functions of RNAs.

RNAs fold into 3D structures that range from simple helical elements to complex tertiary structures and quaternary ribonucleoprotein assemblies. The functions of many regulatory RNAs depend on how their 3D structure changes in response to a diverse array of cellular conditions. In this Review, we examine how the structural characterization of RNA as dynamic ensembles of conformations, which form with different probabilities and at different timescales, is improving our understanding of RNA function in cells.

High-performance virtual screening by targeting a high-resolution RNA dynamic ensemble.

Dynamic ensembles hold great promise in advancing RNA-targeted drug discovery. Here we subjected the transactivation response element (TAR) RNA from human immunodeficiency virus type-1 to experimental high-throughput screening against ~100,000 drug-like small molecules. Results were augmented with 170 known TAR-binding molecules and used to generate sublibraries optimized for evaluating enrichment when virtually screening a dynamic ensemble of TAR determined by combining NMR spectroscopy data and molecular dynamics simulations.

A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites.

Isoprenoid biosynthesis through the methylerythritol phosphate (MEP) pathway generates commercially important products and is a target for antimicrobial drug development. MEP pathway regulation is poorly understood in microorganisms. Here we employ a forward genetics approach to understand MEP pathway regulation in the malaria parasite, Plasmodium falciparum.

Synthesis, characterization, and biological activity of poly(arginine)-derived cancer-targeting peptides in HepG2 liver cancer cells.

The solid-phase synthesis, structural characterization, and biological evaluation of a small library of cancer-targeting peptides have been determined in HepG2 hepatoblastoma cells. These peptides are based on the highly specific Pep42 motif, which has been shown to target the glucose-regulated protein 78 receptors overexpressed and exclusively localized on the cell surface of tumors. In this study, Pep42 was designed to contain varying lengths (3-12) of poly(arginine) sequences to assess their influence on peptide structure and biology.

TNF receptor 2, not TNF receptor 1, enhances mesenchymal stem cell-mediated cardiac protection following acute ischemia.

Mesenchymal stem cells (MSCs) may improve myocardial function after I/R injury via paracrine effects, including the release of growth factors. Genetic modification of MSCs is an appealing method to enhance MSC paracrine action. Ablation of TNF receptor 1 (TNFR1), but not TNFR2, increases MSC growth factor production.

MEK, p38, and PI-3K mediate cross talk between EGFR and TNFR in enhancing hepatocyte growth factor production from human mesenchymal stem cells.

Human bone marrow mesenchymal stem cells (MSCs) are a potent source of growth factors, which are partly responsible for their beneficial paracrine effects. We reported previously that transforming growth factor-alpha (TGF-alpha), a putative mediator of wound healing and the injury response, increases the release of vascular endothelial growth factor (VEGF), augments tumor necrosis factor-alpha (TNF-alpha)-stimulated VEGF production, and activates mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI-3K) pathway in human MSCs. The experiments described in this report indicate that TGF-alpha increases MSC-derived hepatocyte growth factor (HGF) production.

Stem cells in sepsis.

Objective: To review the characteristics of stem cells that may qualify them to be useful as therapeutic agents in sepsis.

Summary Background Data: Sepsis is a devastating syndrome and is the leading cause of death among critically ill surgical patients in the United States. Despite decades of research and numerous clinical trials, little progress has been made in the development of new treatments and mortality rates are much the same as they have been for the last 20 to 30 years.

Role of tumor necrosis factor receptor 1 in sex differences of stem cell mediated cardioprotection.

Background: Mesenchymal stem cells (MSCs) hold great therapeutic potential for the repair and regeneration of ischemic tissue, possibly through the release of beneficial paracrine factors. Sex differences have been observed in the paracrine function of MSCs. Female stem cells produce lower proinflammatory cytokines and higher levels of growth factors compared with their male counterparts.