Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies.

The COVID-19 pandemic has created a global health crisis, with challenges arising from the ongoing evolution of the SARS-CoV-2 virus, the emergence of new strains, and the long-term effects of COVID-19. Aiming to overcome the development of viral resistance, our study here focused on developing broad-spectrum pan-coronavirus antiviral therapies by targeting host protein quality control mechanisms essential for viral replication. Screening an in-house compound library led to the discovery of three candidate compounds targeting cellular proteostasis.

Effects of positive mGlu5 modulation on D signaling and nicotine-conditioned place preference: Mechanisms of epigenetic inheritance in a transgenerational model of drug abuse vulnerability in psychosis.

Background: The metabotropic glutamate type 5 (mGlu5) receptor has emerged as a potential target for the treatment of psychosis that is suggested to have greater efficacy than antipsychotic medications that are currently utilized.

Aims: This study sought to elucidate mechanisms of therapeutic action associated with the modulation of the mGlu5 receptor in a disordered system marked by dopamine dysfunction. We further explored epigenetic mechanisms contributing to heritable transmission of a psychosis-like phenotype in a novel heritable model of drug abuse vulnerability in psychosis.

The NUDGE Framework: Application to Address Behavioral Barriers to Antiretroviral Therapy in Adolescents Living With HIV in Eswatini.

Behavioral economics offers a unique opportunity to understand the social, cognitive, and psychological nuances that may influence health behavior. The purpose of this article is to demonstrate the application of NUDGE, a novel behavioral economics and design thinking framework, to address barriers to antiretroviral therapy adherence among adolescents living with HIV in eSwatini. NUDGE comprises five steps: (1) Narrow the focus to a specific target behavior, (2) Understand the context of the behavior through inquiry, (3) Discover behavioral insights related to the target behavior, (4) Generate intervention design features to address behavioral barriers to the target behavior, and (5) Evaluate the design features through iterative pilot testing.

Corneal application of SOCS1/3 peptides for the treatment of eye diseases mediated by inflammation and oxidative stress.

Several blinding diseases affecting the retina and optic nerve are exacerbated by or caused by dysregulated inflammation and oxidative stress. These diseases include uveitis, age related macular degeneration, diabetic retinopathy and glaucoma. Consequently, despite their divergent symptoms, treatments that reduce oxidative stress and suppress inflammation may be therapeutic.

sendigR: an R package to leverage the value of CDISC SEND datasets for cross-study analysis.

The CDISC Standard for Exchange of Nonclinical Data (SEND) data standard has created new opportunities for collaborative development of open-source software solutions to facilitate cross-study analyses of toxicology study data. A public-private partnership between BioCelerate and the FDA/Center for Drug Evaluation and Research (CDER) was established in part to develop and publicize novel methods to facilitate cross-study analysis of SEND datasets. As part of this work in collaboration with the Pharmaceutical Users Software Exchange (PHUSE), an R package sendigR has been developed to enable users to construct a relational database from a collection of SEND datasets and then query that database to perform cross-study analyses.

Comparative Study on Clinical and Echocardiographic Findings in Ischemic Heart Disease Patients with or without Mitral Annular Calcification in a Tertiary Hospital.

The presence of bright resonance of more than 1 mm or more cusps of the aortic valve, mitral valve or mitral annulus is termed as cardiac valve calcification. If an intense echo producing structure located at the junction of the atrioventricular groove and posterior mitral valve leaflet on Echocardiography that is Mitral annular calcification (MAC). This study was conducted to observe the association of MAC with clinical and echocardiographic findings of ischemic heart disease (IHD) and the role of trans-thoracic echocardiography to detect MAC which is a marker IHD.

Cross study analyses of SEND data: toxicity profile classification.

A SEND toxicology data transformation, harmonization, and analysis platform were created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories.

Peripheral HMGB1 is linked to O pathology of disease-associated astrocytes and amyloid.

Introduction: Ozone (O) is an air pollutant associated with Alzheimer's disease (AD) risk. The lung-brain axis is implicated in O-associated glial and amyloid pathobiology; however, the role of disease-associated astrocytes (DAAs) in this process remains unknown.

Methods: The O-induced astrocyte phenotype was characterized in 5xFAD mice by spatial transcriptomics and proteomics.

Suppressor of cytokine signaling 3-derived peptide as a therapeutic for inflammatory and oxidative stress-induced damage to the retina.

Purpose: Inflammation and oxidative stress contribute to age-related macular degeneration (AMD) and other retinal diseases. We tested a cell-penetrating peptide from the kinase inhibitory region of an intracellular checkpoint inhibitor suppressor of cytokine signaling 3 (R9-SOCS3-KIR) peptide for its ability to blunt the inflammatory or oxidative pathways leading to AMD.

Methods: We used anaphylatoxin C5a to mimic the effect of activated complement, lipopolysaccharide (LPS), and tumor necrosis factor alpha (TNFα) to stimulate inflammation and paraquat to induce mitochondrial oxidative stress.

Disparate viral pandemics from COVID19 to monkeypox and beyond: a simple, effective and universal therapeutic approach hiding in plain sight.

The field of antiviral therapeutics is fixated on COVID19 and rightly so as the fatalities at the height of the pandemic in the United States were almost 1,000,000 in a twelve month period spanning parts of 2020/2021. A coronavirus called SARS-CoV2 is the causative virus. Development of a vaccine through molecular biology approaches with mRNA as the inducer of virus spike protein has played a major role in driving down mortality and morbidity.

A Systematic Review of Peer Support Interventions for Adolescents Living with HIV in Sub-Saharan Africa.

Despite widespread availability of life-saving antiretroviral therapy (ART) in sub-Saharan Africa, AIDS remains one of the leading causes of death among adolescents living with HIV (ALHIV) in sub-Saharan Africa. The purpose of this article was to review the state of the science regarding interventions to improve ART adherence and/or HIV care retention among ALHIV throughout sub-Saharan Africa. The primary aim of this review was to describe the impact of peer support interventions in improving treatment outcomes (i.

Using Community-Based Participatory Research to Develop Care Recommendations for People Aging With HIV.

Background And Objectives: Over 50% of New Yorkers living with human immunodeficiency virus (HIV) are 50 years old or older, and the emotional and physical consequences of being a long-term survivor are significant. This study aimed to identify the practical needs of long-term survivors and older people with HIV (consumers) in New York State and develop recommendations addressing those needs.

Research Design And Methods: The HIV + Aging/LTS/Perinatally Diagnosed Subcommittee of the Consumer Advisory and Quality Advisory committees in the New York State AIDS Institute used community-based participatory research (CBPR) methods to design a statewide survey about the care needs of consumers in New York State.

Broad spectrum post-entry inhibitors of coronavirus replication: Cardiotonic steroids and monensin.

A small molecule screen identified several cardiotonic steroids (digitoxin and ouabain) and the ionophore monensin as potent inhibitors of HCoV-229E, HCoV-OC43, and SARS-CoV-2 replication with ECs in the low nM range. Subsequent tests confirmed antiviral activity in primary cell models including human nasal epithelial cells and lung organoids. Addition of digitoxin, ouabain, or monensin strongly reduced viral gene expression as measured by both viral protein and RNA accumulation.

On a path toward a broad-spectrum anti-viral: inhibition of HIV-1 and coronavirus replication by SR kinase inhibitor harmine.

This study highlights the crucial role RNA processing plays in regulating viral gene expression and replication. By targeting SR kinases, we identified harmine as a potent inhibitor of HIV-1 as well as coronavirus (HCoV-229E and multiple SARS-CoV-2 variants) replication. Harmine inhibits HIV-1 protein expression and reduces accumulation of HIV-1 RNAs in both cell lines and primary CD4 T cells.

Assessment of atrial septal defects using 3-dimensional transthoracic echocardiography prior to percutaneous device closure: first report from Bangladesh.

Background: Secundum atrial septal defect (ASD) is treated following trans-catheter closure in alternative to surgical treatment. Per-intervention selection of device size with balloon occlusive diameter (BOD) often cause tearing or enlarging, causing arrhythmias and hypotension. We assessed the suitability of percutaneous device closure for ASD using 3-dimensional transthoracic echocardiography (3DTTE).

Youth perspectives of working with near peer youth lay counsellors: The Safe Haven Pilot.

Youth living with HIV (YLWH) have higher rates of common mental disorders (CMDs) when compared with HIV-negative youth. We adapted the Friendship Bench to create a problem solving-based counselling intervention in Botswana delivered by near peer youth lay counsellors for YLWH called Safe Haven. In August 2020, and from June to August 2021, we conducted 22 semistructured interviews with youth aged 13-25 years with mild-to-moderate symptoms of CMDs.

Physical activity level and sedentary time determinants among Moroccan hypertensive patients.

Introduction: Hypertension is closely associated with an inactive lifestyle. Physical activity and/or exercise have been shown to delay the development of hypertension. This study aimed to assess the level of physical activity and sedentary time, and its determinants among Moroccan Hypertensive patients.

Designing implementation strategies to improve identification, cascade testing, and management of families with familial hypercholesterolemia: An intervention mapping approach.

Introduction: Familial hypercholesterolemia (FH) is a common inherited cholesterol disorder that, without early intervention, leads to premature cardiovascular disease. Multilevel strategies that target all components of FH care including identification, cascade testing, and management are needed to address gaps that exist in FH care. We utilized intervention mapping, a systematic implementation science approach, to identify and match strategies to existing barriers and develop programs to improve FH care.

Efficacy of dopamine, epinephrine and blood transfusion for treatment of fluid refractory shock in children with severe acute malnutrition or severe underweight and cholera or other dehydrating diarrhoeas: protocol for a randomised controlled clinical trial.

Introduction: Diarrhoea is one of the leading causes of under-5 childhood mortality and accounts for 8% of 5.4 million global under-5 deaths. In severely malnourished children, diarrhoea progresses to shock, where the risk of mortality is even higher.

Optimizing communication strategies and designing a comprehensive program to facilitate cascade testing for familial hypercholesterolemia.

Background: This project aimed to optimize communication strategies to support family communication about familial hypercholesterolemia (FH) and improve cascade testing uptake among at-risk relatives. Individuals and families with FH provided feedback on multiple strategies including: a family letter, digital tools, and direct contact.

Methods: Feedback from participants was collected via dyadic interviews (n = 11) and surveys (n = 98) on communication strategies and their proposed implementation to improve cascade testing uptake.

Roles and responsibilities of expert clients in adolescent HIV service delivery in Eswatini: a conventional content analysis.

We aimed to elucidate the specific roles and responsibilities of expert clients in service delivery among adolescents living with HIV in Eswatini, and to provide recommendations for enhancing adolescent service provision among expert clients and similar lay health workers throughout low- and middle-income countries. An exploratory qualitative descriptive methodology using conventional content analysis was used to meet our study aims. We recruited 20 expert clients and 12 key informants (programme managers, programme coordinators and nurses) to participate in semi-structured interviews, and we arranged four focus group discussions among adolescents living with HIV with seven to ten participants per focus group.

Altered long non-coding RNAs expression in normal and diseased primary human airway epithelial cells exposed to diesel exhaust particles.

Background: Exposure to diesel exhaust particles (DEP) has been linked to a variety of adverse health effects, including increased morbidity and mortality from cardiovascular diseases, chronic obstructive pulmonary disease (COPD), metabolic syndrome, and lung cancer. The epigenetic changes caused by air pollution have been associated with increased health risks. However, the exact molecular mechanisms underlying the lncRNA-mediated pathogenesis induced by DEP exposure have not been revealed.