Representation of Social Determinants of Health terminology in medical subject headings: impact of added terms.

Objectives: To enhance and evaluate the quality of PubMed search results for Social Determinants of Health (SDoH) through the addition of new SDoH terms to Medical Subject Headings (MeSH).

Materials And Methods: High priority SDoH terms and definitions were collated from authoritative sources, curated based on publication frequencies, and refined by subject matter experts. Descriptive analyses were used to investigate how PubMed search details and best match results were affected by the addition of SDoH concepts to MeSH.

Analysis of the health economics portfolio funded by the National Institutes of Health in response to published guidance.

Health services, economics, and outcomes research (referred to as health economics research hereinafter) is one of the interdisciplinary sciences that the National Institutes of Health (NIH) supports in order to pursue its overall mission to improve health. In 2015, NIH guidance was published to clarify the type of health economics research that NIH would continue to fund. This analysis aimed to determine if there were changes in the number of health economics applications received and funded by NIH after the release of the guidance.

Determination of Standard Values for Knee Version in a Healthy Population.

Background: Different measures are used to describe relevant anatomic variations that can result in patellofemoral instability and disorders. Knee version, the relative rotational alignment between the femur and tibia in the axial plane at the level of the knee, may have a decisive effect on the kinematics of the patellofemoral joint. However, data regarding the values of knee version are currently lacking.

Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury.

Background & Aims: Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF.

Aryl Hydrocarbon Receptor Activity in Hepatocytes Sensitizes to Hyperacute Acetaminophen-Induced Hepatotoxicity in Mice.

Background & Aims: Acetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and metabolic signals into complex cellular transcriptional programs, might act as a rheostat for APAP-toxicity.

Ozonation of rivaroxaban production waste water and comparison of generated transformation products with known in vivo and in vitro metabolites.

During production of rivaroxaban, an orally administrated anticoagulant, process waste water is generated at several stages of manufacturing. Due to low biodegradability in conventional waste water treatment plants, it is currently incinerated. Thus, new pre-treatment methods for rivaroxaban-containing waste water could facilitate its subsequent biological processing.

Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1.

Complex conformational dynamics are essential for function of the dimeric molecular chaperone heat shock protein 90 (Hsp90), including transient, ATP-biased N-domain dimerization that is necessary to attain ATPase competence. The intrinsic, but weak, ATP hydrolyzing activity of human Hsp90 is markedly enhanced by the co-chaperone Aha1. However, the cellular concentration of Aha1 is substoichiometric relative to Hsp90.

Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40.

Heat shock protein 90: its inhibition and function.

The molecular chaperone heat shock protein 90 (Hsp90) facilitates metastable protein maturation, stabilization of aggregation-prone proteins, quality control of misfolded proteins and assists in keeping proteins in activation-competent conformations. Proteins that rely on Hsp90 for function are delivered to Hsp90 utilizing a co-chaperone-assisted cycle. Co-chaperones play a role in client transfer to Hsp90, Hsp90 ATPase regulation and stabilization of various Hsp90 conformational states.

A Target-Triggered DNAzyme Motor Enabling Homogeneous, Amplified Detection of Proteins.

We report here the concept of a self-powered, target-triggered DNA motor constructed by engineering a DNAzyme to adapt into binding-induced DNA assembly. An affinity ligand was attached to the DNAzyme motor via a DNA spacer, and a second affinity ligand was conjugated to the gold nanoparticle (AuNP) that was also decorated with hundreds of substrate strands serving as a high-density, three-dimensional track for the DNAzyme motor. Binding of a target molecule to the two ligands induced hybridization between the DNAzyme and its substrate on the AuNP, which are otherwise unable to spontaneously hybridize.

Impact of local heating and cooling on skeletal muscle transcriptional response related to myogenesis and proteolysis.

Purpose: To determine the impact of local muscle heating and cooling on myogenic and proteolytic gene responses following resistance exercise.

Methods: Recreationally trained males (n = 12), age 25.3 ± 1.

Out with the old: Hsp90 finds amino acid residue more useful than co-chaperone protein.

Redundant functions maintained from single to multi-cellular organisms have made an important model for the analysis of conserved com-plex cellular processes. Yeast has been especially useful in understanding the regulation and function of the essential molecular chaperone, Heat Shock Protein 90 (Hsp90). Research focused on Hsp90 has determined that it is highly regulated by both co-chaperones and posttranslational modifications.

Ozone pretreatment of process waste water generated in course of fluoroquinolone production.

During production of active pharmaceutical ingredients, process waste water is generated at several stages of manufacturing. Whenever possible, the resulting waste water will be processed by conventional waste water treatment plants. Currently, incineration of the process waste water is the method to eliminate compounds with high biological activity.

Long-acting water-stable organosilane agent and its sustained effect on reducing microbial load in an intensive care unit.

Background: Contaminated hospital surfaces contribute significantly to the transmission of health care-associated infections. Although disinfectants reduce bioburden by up to 99%, bacterial growth can rebound within hours to precleaning levels. We tested the effectiveness of an innovative, long-acting water-stable organosilane (WSO) to achieve sustained decreases in bioburden on hard surfaces.

An Hsp90 co-chaperone protein in yeast is functionally replaced by site-specific posttranslational modification in humans.

Heat shock protein 90 (Hsp90) is an essential eukaryotic molecular chaperone. To properly chaperone its clientele, Hsp90 proceeds through an ATP-dependent conformational cycle influenced by posttranslational modifications (PTMs) and assisted by a number of co-chaperone proteins. Although Hsp90 conformational changes in solution have been well-studied, regulation of these complex dynamics in cells remains unclear.

Transformation to a recovery-oriented model of care on a veterans administration inpatient unit.

Objectives: Recovery-oriented care is among the highest treatment priorities for the Veteran Health Administration, which has endorsed organizational change of mental health care to reflect recovery values. The purpose of this quality improvement project was to determine whether recovery interventions would yield positive outcomes when delivered on in inpatient psychiatry.

Method: Recovery interventions on the unit included recovery-focused interdisciplinary team meetings, opportunities for stakeholder feedback, recovery staff education, increased group programming, peer support, and changes to treatment planning to include increased Veteran engagement and responsibility.

Clients Place Unique Functional Constraints on Hsp90.

Heat shock protein 90 kDa (Hsp90) is required for the activation and stabilization of numerous client proteins, but the functional requirements of individual clients remain poorly understood. Utilizing yeast growth assays and mutational analysis, Mishra and colleagues explore the constraints placed on Hsp90 by distinct clients and the relationship between these constraints and overall yeast fitness.

Binding-Induced DNA Nanomachines Triggered by Proteins and Nucleic Acids.

We introduce the concept and operation of a binding-induced DNA nanomachine that can be activated by proteins and nucleic acids. This new type of nanomachine harnesses specific target binding to trigger assembly of separate DNA components that are otherwise unable to spontaneously assemble. Three-dimensional DNA tracks of high density are constructed on gold nanoparticles functionalized with hundreds of single-stranded oligonucleotides and tens of an affinity ligand.

Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands.

Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through design of new allosteric ligands aimed at modulating its functional dynamics is proposed.

Regulation and function of the human HSP90AA1 gene.

Heat shock protein 90α (Hsp90α), encoded by the HSP90AA1 gene, is the stress inducible isoform of the molecular chaperone Hsp90. Hsp90α is regulated differently and has different functions when compared to the constitutively expressed Hsp90β isoform, despite high amino acid sequence identity between the two proteins. These differences are likely due to variations in nucleotide sequence within non-coding regions, which allows for specific regulation through interaction with particular transcription factors, and to subtle changes in amino acid sequence that allow for unique post-translational modifications.

Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas.

The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting.

The Hsp90 cochaperones Cpr6, Cpr7, and Cns1 interact with the intact ribosome.

The abundant molecular chaperone Hsp90 is essential for the folding and stabilization of hundreds of distinct client proteins. Hsp90 is assisted by multiple cochaperones that modulate Hsp90's ATPase activity and/or promote client interaction, but the in vivo functions of many of these cochaperones are largely unknown. We found that Cpr6, Cpr7, and Cns1 interact with the intact ribosome and that Saccharomyces cerevisiae lacking CPR7 or containing mutations in CNS1 exhibited sensitivity to the translation inhibitor hygromycin.

Mutation of essential Hsp90 co-chaperones SGT1 or CNS1 renders yeast hypersensitive to overexpression of other co-chaperones.

The essential molecular chaperone Hsp90 functions with over ten co-chaperones in Saccharomyces cerevisiae, but the in vivo roles of many of these co-chaperones are poorly understood. Two of these co-chaperones, Cdc37 and Sgt1, target specific types of clients to Hsp90 for folding. Other co-chaperones have general roles in supporting Hsp90 function, but the degree of overlapping or competing functions is unclear.