G Protein Coupled Estrogen Receptor Signaling Maintains β Cell Identity in Female Mice.

Type 2 diabetes (T2D) arises in the context of obesity and overnutrition; however, additional demographic features including age and biological sex contribute to T2D risk. Estradiol (E2) is thought to play a protective metabolic role that may govern sex differences in the development of T2D. The mechanisms by which E2 exerts these effects and the impact of reduced E2 signaling in β cells during menopause remain incompletely understood.

Understanding social and environmental risks of firearm injury using geospatial patterns.

Background: For firearm-related injuries (FRI), understanding spatial injury patterns may inform intervention strategies. This study evaluates geographic FRI patterns, emphasizing (1) proximity of home address to injury location and (2) locational social determinants of health (SDOH).

Methods: We performed a retrospective analysis of FRI patients at a Level 1 trauma center between 01/2016-10/2022.

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice.

Background: Tyrosine protein-kinase 2 (TYK2) mediates inflammatory signalling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. TYK2 missense mutations protect against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in other autoimmune conditions.

Methods: We evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D, including human β cells, cadaveric islets, iPSC-derived islets, and mouse models.

miR-146a-5p mediates inflammation-induced β cell mitochondrial dysfunction and apoptosis.

We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with proinflammatory cytokines. Others have reported that miR-146a-5p overexpression is associated with β cell apoptosis and impaired insulin secretion. However, the molecular mechanisms mediating these effects remain elusive.

Sex-specific blood-derived RNA biomarkers for childhood tuberculosis.

Confirmatory diagnosis of childhood tuberculosis (TB) remains a challenge mainly due to its dependence on sputum samples and the paucibacillary nature of the disease. Thus, only ~ 30% of suspected cases in children are diagnosed and the need for minimally invasive, non-sputum-based biomarkers remains unmet. Understanding host molecular changes by measuring blood-based transcriptomic markers has shown promise as a diagnostic tool for TB.

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice.

Tyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D.

miR-146a-5p mediates inflammation-induced β cell mitochondrial dysfunction and apoptosis.

We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with pro-inflammatory cytokines. Others have reported that miR-146a-5p overexpression is associated with β cell apoptosis and impaired insulin secretion. However, the molecular mechanisms mediating these effects remain elusive.

Diversity of CFTR variants across ancestries characterized using 454,727 UK biobank whole exome sequences.

Background: Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF.

Distinct functions and transcriptional signatures in orally induced regulatory T cell populations.

Oral administration of antigen induces regulatory T cells (Treg) that can not only control local immune responses in the small intestine, but also traffic to the central immune system to deliver systemic suppression. Employing murine models of the inherited bleeding disorder hemophilia, we find that oral antigen administration induces three CD4+ Treg subsets, namely FoxP3+LAP-, FoxP3+LAP+, and FoxP3-LAP+. These T cells act in concert to suppress systemic antibody production induced by therapeutic protein administration.

HIRA: Heart Rate Interval based Rapid Alert score to characterize autonomic dysfunction among patients with sepsis-related acute respiratory failure (ARF).

. To examine whether heart rate interval based rapid alert (HIRA) score derived from a combination model of heart rate variability (HRV) and modified early warning score (MEWS) is a surrogate for the detection of acute respiratory failure (ARF) in critically ill sepsis patients..

SERCA2 regulates proinsulin processing and processing enzyme maturation in pancreatic beta cells.

Aims/hypothesis: Increased circulating levels of incompletely processed insulin (i.e. proinsulin) are observed clinically in type 1 and type 2 diabetes.

Stromal Interaction Molecule 1 Maintains β-Cell Identity and Function in Female Mice Through Preservation of G-Protein-Coupled Estrogen Receptor 1 Signaling.

Unlabelled: Altered endoplasmic reticulum (ER) Ca2+ signaling has been linked with β-cell dysfunction and diabetes development. Store-operated Ca2+ entry replenishes ER Ca2+ through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). For characterization of the in vivo impact of STIM1 loss, mice with β-cell-specific STIM1 deletion (STIM1Δβ mice) were generated and challenged with high-fat diet.

β Cell microRNAs Function as Molecular Hubs of Type 1 Diabetes Pathogenesis and as Biomarkers of Diabetes Risk.

MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in modulating gene expression and are enriched in cell-derived extracellular vesicles (EVs). We investigated whether miRNAs from human islets and islet-derived EVs could provide insight into β cell stress pathways activated during type 1 diabetes (T1D) evolution, therefore serving as potential disease biomarkers. We treated human islets from 10 cadaveric donors with IL-1β and IFN-γ to model T1D .

Profiling volatile organic compounds from human plasma using GC × GC-ToFMS.

Volatile organic compounds (VOCs) originating from human metabolic activities can be detected in, for example, breath, urine, feces, and blood. Thus, attention has been given to identifying VOCs from the above matrices. Studies identifying and measuring human blood VOCs are limited to those focusing on monitoring specific pollutants, or blood storage and/or decomposition.

Phase 1 study of safety, pharmacokinetics, and antiviral activity of SARS-CoV-2 neutralizing monoclonal antibody ABBV-47D11 in patients with COVID-19.

ABBV-47D11 is a neutralizing monoclonal antibody that targets a mutationally conserved hydrophobic pocket distal to the ACE2 binding site of SARS-CoV-2. This first-in-human safety, pharmacokinetics, and antiviral pharmacodynamic assessment in patients with COVID-19 provide an initial evaluation of this antibody that may allow further development. This multicenter, randomized, double-blind, and placebo-controlled single ascending dose study of ABBV-47D11 (180, 600, or 2400 mg) as an intravenous infusion, was in hospitalized and non-hospitalized (confined) adults with mild to moderate COVID-19.

A discovery-based proteomics approach identifies protein disulphide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes.

Background: Stress responses within the β cell have been linked with both increased β cell death and accelerated immune activation in type 1 diabetes (T1D). At present, information on the timing and scope of these responses as well as disease-related changes in islet β cell protein expression during T1D development is lacking.

Methods: Data independent acquisition-mass spectrometry was performed on islets collected longitudinally from NOD mice and NOD-SCID mice rendered diabetic through T cell adoptive transfer.

Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-to-in vivo predictions of hepatic clearance.

Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation methods are frequently inaccurate and problematic. Multiple strategies are being pursued to disentangle responsible mechanisms. The objective of this work is to evaluate the feasibility of using insights gained from independent virtual experiments on two model systems to begin unraveling responsible mechanisms.

Durability of sustained virological response to glecaprevir/pibrentasvir and resistance development: A long-term follow-up study.

Background And Aims: This study aimed to determine durability of sustained virologic response (SVR) in hepatitis C virus-infected participants treated with glecaprevir- and/or pibrentasvir-containing regimens.

Methods: M13-576, a rollover study, evaluated the durability of SVR in a follow-up period of approximately 3 years after hepatitis C virus genotype 1-6-infected participants received a glecaprevir- and/or pibrentasvir-containing regimen in previous phase 2/3 clinical trials. The primary efficacy endpoint was the percentage of participants maintaining SVR and the percentage of participants experiencing relapse or reinfections.

Biomarkers for the clinical development of antiviral therapies.

With the morbidity and mortality associated with the COVID-19 pandemic that we are witnessing this year, the risks posed by emerging viral diseases to global health are all too obvious. This pandemic highlights the importance of antiviral drug discovery, which targets emerging viral pathogens, as well as existing pathogenic viruses that undergo continuous evolution. Drug discovery and development is a long and resource intensive process; however, the use of biomarkers can accelerate clinical development of antivirals by providing information regarding diagnosis of specific viral infections, status of infection, potential safety parameters, and antiviral responses.

Periodontal approach in the management of alveolar cleft.

The alveolar cleft is a bone-related developmental defect in the alveolar process of the maxillae, which is termed as cleft alveolus. The deformity occurs in 75% of the cleft palate and lip patients. Reconstructive surgery can provide both functional and esthetic benefits to such individuals.

Efficacy and safety of glecaprevir/pibrentasvir in treatment-naïve adults with chronic hepatitis C virus genotypes 1-6 in Brazil.

Introduction And Objectives: Glecaprevir/pibrentasvir is a highly effective and well tolerated treatment for hepatitis C infection. Brazilian patients were not included in the original development studies for glecaprevir/pibrentasvir. This study aimed to assess safety and efficacy of glecaprevir/pibrentasvir in treatment-naïve Brazilian adults without cirrhosis or with compensated cirrhosis.

Evaluation of deoxypyridinoline levels in gingival crevicular fluid and serum as alveolar bone loss biomarker in patients with periodontitis.

Background: Several components of gingival crevicular fluid (GCF) reflect the course and predictability of periodontal disease and provide a pointer toward disease status. Potential biomarkers deoxypyridinoline (DPD), a metallophosphoesterase would correctly determine the presence of osteoclast-mediated bone turnover activity and seems to hold great promise as a predictive marker to determine bone destruction and active phases in the disease progression.

Aim: The aim of the current study is proposed to investigate the biologic plausibility for the levels of DPD as biomarker in chronic periodontitis patients.

A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes.

The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We used an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray data sets generated using human islets from donors with diabetes and islets where type 1 (T1D) and type 2 (T2D) diabetes had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.

Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies- a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2).

Background: Glecaprevir-pibrentasvir results in high rates of sustained virological response in patients with chronic hepatitis C virus (HCV) genotype 1-6 infection. Data for glecaprevir-pibrentasvir in non-Japanese Asian patients have been minimal. The aim of these studies was to assess the efficacy and safety of glecaprevir-pibrentasvir in treatment-naive and treatment-experienced Asian patients with chronic HCV genotype 1-6 infection without cirrhosis (VOYAGE-1) and with compensated cirrhosis (VOYAGE-2).