A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43.

Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43 (TAR DNA-binding protein-43), using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered.

Structure and Dynamics of the CCCH-Type Tandem Zinc Finger Domain of POS-1 and Implications for RNA Binding Specificity.

CCCH-type tandem zinc finger (TZF) motifs are found in many RNA-binding proteins involved in regulating mRNA stability, translation, and splicing. In , several RNA-binding proteins that regulate embryonic development and cell fate determination contain CCCH TZF domains, including POS-1. Previous biochemical studies have shown that despite high levels of sequence conservation, POS-1 recognizes a broader set of RNA sequences compared to the human homologue tristetraprolin.

A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43.

Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered.

Probing Bioactive Chemical Space to Discover RNA-Targeted Small Molecules.

Small molecules have become increasingly recognized as invaluable tools to study RNA structure and function and to develop RNA-targeted therapeutics. To rationally design RNA-targeting ligands, a comprehensive understanding and explicit testing of small molecule properties that govern molecular recognition is crucial. To date, most studies have primarily evaluated properties of small molecules that bind RNA , with little to no assessment of properties that are distinct to selective and bioactive RNA-targeted ligands.

Interrupted time-series analysis to evaluate the impact of a behavioral change outpatient antibiotic stewardship intervention.

Objective: We evaluated the effect of a behaviorally enhanced quality improvement intervention in reducing the number of antibiotic prescriptions written for antibiotic nonresponsive acute respiratory infections (ARIs). A secondary objective was identifying whether a reduction in inappropriate antibiotic prescriptions, if present, persisted after the immediate implementation of the intervention.

Design: Nonrandomized, quasi-experimental study conducted from January 2017 through February 2020.

Effects of an Adapted Telehealth Training Curriculum for Registered Behavior Technicians®.

Objectives: We evaluated a telehealth training curriculum to prepare Registered Behavior Technicians® (RBTs®) to conduct caregiver coaching on behavior analytic skills via telehealth.

Methods: A non-concurrent multiple baseline across therapists design was used to evaluate the training procedures delivered by Board Certified Behavior Analysts® (BCBAs®). All therapists (RBTs) worked with one family during the baseline and training phases and an additional session was conducted with a different family during the novelty probe condition to see if therapists were able to perform the newly acquired skills without BCBA support.

A Qualitative Review of Barriers and Facilitators Identified While Implementing the Native Students Together Against Negative Decisions Curriculum in a Multisite Dissemination and Implementation Study.

Unlabelled: Culturally-adapted evidence-based programs (EBPs) are needed to promote healthy behaviors among Native teens and young adults. Little is known about the facilitators and barriers of implementing and sustaining EBPs in Native communities. This paper aims to identify those factors described by educators who implemented the Native Students Together Against Negative Decisions (STAND) curriculum.

Adding a One Health approach to a research framework for minority health and health disparities.

The National Institute on Minority Health and Health Disparities (NIMHD) has developed a framework to guide and orient research into health disparities and minority health. The framework depicts different domains of influence (such as biological and behavioral) and different levels of influence (such as individual and interpersonal). Here, influenced by the "One Health" approach, we propose adding two new levels of influence - interspecies and planetary to this framework to reflect the interconnected nature of human, animal, and environmental health.

Universal HIV screening in the emergency department: an interrupted time series analysis.

We performed a calendar-matched, 12-month, before (November 27, 2017 to November 26, 2018) and after (November 27, 2018 to November 26, 2019) study, to assess the utility of an emergency department-based HIV screening program. There were 710 and 14 335 patients screened for HIV during the pre and post-best practice alert (BPA) periods, respectively, representing more than a 20-fold increase in HIV screening following BPA implementation. Total HIV positive tests increased 5-fold following BPA implementation.

Psychometric evaluation of protective measures in Native STAND: A multi-site cross-sectional study of American Indian Alaska Native high school students.

American Indian and Alaska Native (AI/AN) youth are strong in culture and rich in heritage and experience unique strengths and challenges throughout adolescence. Documenting conditions that protect against risk factors associated with poor health outcomes are needed. We explored scales that measure self-esteem, culture, social support, and community from a sample of 1,456 youth involved in Native STAND, a culturally-relevant evidence-based sexual health intervention.

Identifying Associations in Minimum Inhibitory Concentration Values of Samples Obtained From Weaned Dairy Heifers in California Using Bayesian Network Analysis.

Objective: Many antimicrobial resistance (AMR) studies in both human and veterinary medicine use traditional statistical methods that consider one bacteria and one antibiotic match at a time. A more robust analysis of AMR patterns in groups of animals is needed to improve on traditional methods examining antibiotic resistance profiles, the associations between the patterns of resistance or reduced susceptibility for all isolates in an investigation. The use of Bayesian network analysis can identify associations between distributions; this investigation seeks to add to the growing body of AMR pattern research by using Bayesian networks to identify relationships between susceptibility patterns in () isolates obtained from weaned dairy heifers in California.

The Role of Substrate Mediated Allostery in the Catalytic Competency of the Bacterial Oligosaccharyltransferase PglB.

The oligosaccharyltransferase of (PglB) catalyzes the glycosylation of asparagine in the consensus sequence N-X-S/T, where X is any residue except proline. Molecular dynamics simulations of PglB bound to two different substrates were used to characterize the differences in the structure and dynamics of the substrate-enzyme complexes that can explain the higher catalytic efficiency observed for substrates containing threonine at the +2 position rather than serine. We observed that a threonine-containing substrate is more tightly bound than a serine-containing substrate.

ED syphilis and gonorrhea/chlamydia cotesting practices before and after the implementation of an electronic health record-based alert.

Background: The prevalence of syphilis is increasing in many countries, including the USA. The ED is often used by underserved populations, making it an important setting to test and treat patients who are not evaluated in outpatient clinical settings. We aimed to assess the utility of an ED-based syphilis and gonorrhoea/chlamydia cotesting protocol by comparing testing practices before and after its implementation.

ALS-linked PFN1 variants exhibit loss and gain of functions in the context of formin-induced actin polymerization.

Profilin-1 (PFN1) plays important roles in modulating actin dynamics through binding both monomeric actin and proteins enriched with polyproline motifs. Mutations in PFN1 have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, whether ALS-linked mutations affect PFN1 function has remained unclear.

Analysis of Emerging Variants in Structured Regions of the SARS-CoV-2 Genome.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has motivated a widespread effort to understand its epidemiology and pathogenic mechanisms. Modern high-throughput sequencing technology has led to the deposition of vast numbers of SARS-CoV-2 genome sequences in curated repositories, which have been useful in mapping the spread of the virus around the globe. They also provide a unique opportunity to observe virus evolution in real time.

Unexpected specificity within dynamic transcriptional protein-protein complexes.

A key functional event in eukaryotic gene activation is the formation of dynamic protein-protein interaction networks between transcriptional activators and transcriptional coactivators. Seemingly incongruent with the tight regulation of transcription, many biochemical and biophysical studies suggest that activators use nonspecific hydrophobic and/or electrostatic interactions to bind to coactivators, with few if any specific contacts. Here a mechanistic dissection of a set of representative dynamic activator•coactivator complexes, comprised of the ETV/PEA3 family of activators and the coactivator Med25, reveals a different molecular recognition model.

Analysis of Rapidly Emerging Variants in Structured Regions of the SARS-CoV-2 Genome.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has motivated a widespread effort to understand its epidemiology and pathogenic mechanisms. Modern high-throughput sequencing technology has led to the deposition of vast numbers of SARS-CoV-2 genome sequences in curated repositories, which have been useful in mapping the spread of the virus around the globe. They also provide a unique opportunity to observe virus evolution in real time.

R-BIND: An Interactive Database for Exploring and Developing RNA-Targeted Chemical Probes.

While the opportunities available for targeting RNA with small molecules have been widely appreciated, the challenges associated with achieving specific RNA recognition in biological systems have hindered progress and prevented many researchers from entering the field. To facilitate the discovery of RNA-targeted chemical probes and their subsequent applications, we curated the RNA-targeted BIoactive ligaNd Database (R-BIND). This collection contains an array of information on reported chemical probes that target non-rRNA and have biological activity, and analysis has led to the discovery of RNA-privileged properties.

Instrument-assisted soft tissue mobilization and proprioceptive neuromuscular facilitation techniques improve hamstring flexibility better than static stretching alone: a randomized clinical trial.

: Tight hamstrings contribute to inefficiency of movement and increased risk for injury. Static stretching is the most common intervention for this problem, but the use of alternatives like instrument-assisted soft tissue mobilization (IASTM) and proprioceptive neuromuscular facilitation (PNF) is increasing among clinicians. This study examined two prospective studies with the common aim of demonstrating the effectiveness of IASTM or PNF over static stretching for improving hamstring tightness.

Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA-Binding Scaffold.

Structural studies of the 3'-end of the oncogenic long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) confirmed a unique triple-helix structure. This structure enables accumulation of the transcript, and high levels of MALAT1 are found in several cancers. Here, we synthesize a small molecule library based on an RNA-binding scaffold, diphenylfuran (DPF), screen it against a variety of nucleic acid constructs, and demonstrate for the first time that the MALAT1 triple helix can be selectively targeted with small molecules.

Insights into the development of chemical probes for RNA.

Over the past decade, the RNA revolution has revealed thousands of non-coding RNAs that are essential for cellular regulation and are misregulated in disease. While the development of methods and tools to study these RNAs has been challenging, the power and promise of small molecule chemical probes is increasingly recognized. To harness existing knowledge, we compiled a list of 116 ligands with reported activity against RNA targets in biological systems (R-BIND).

Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA-Targeted Bioactive Ligands.

While a myriad non-coding RNAs are known to be essential in cellular processes and misregulated in diseases, the development of RNA-targeted small molecule probes has met with limited success. To elucidate the guiding principles for selective small molecule/RNA recognition, we analyzed cheminformatic and shape-based descriptors for 104 RNA-targeted ligands with demonstrated biological activity (RNA-targeted BIoactive ligaNd Database, R-BIND). We then compared R-BIND to both FDA-approved small molecule drugs and RNA ligands without reported bioactivity.