Distinct properties and activation of hexameric and heptameric Pannexin 1 channel concatemers.

Pannexin 1 (PANX1) is a member of a topologically related and stoichiometrically diverse family of large pore membrane ion channels that support the flux of signaling metabolites (e.g., ATP) and fluorescent dyes.

Analogs of FTY720 inhibit TRPM7 but not S1PRs and exert multimodal anti-inflammatory effects.

TRPM7, a TRP channel with ion conductance and kinase activities, has emerged as an attractive drug target for immunomodulation. Reverse genetics and cell biological studies have already established a key role for TRPM7 in the inflammatory activation of macrophages. Advancing TRPM7 as a viable molecular target for immunomodulation requires selective TRPM7 inhibitors with in vivo tolerability and efficacy.

Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging.

Mitochondrial dysfunction is linked to age-associated inflammation or inflammaging, but underlying mechanisms are not understood. Analyses of 700 human blood transcriptomes revealed clear signs of age-associated low-grade inflammation. Among changes in mitochondrial components, we found that the expression of mitochondrial calcium uniporter (MCU) and its regulatory subunit MICU1, genes central to mitochondrial Ca (mCa) signaling, correlated inversely with age.

Classification of Health Information Technology Safety Events in a Pediatric Tertiary Care Hospital.

Objective: State agencies have developed reporting systems of safety events that include events related to health information technology (HIT). These data come from hospital reporting systems where staff submit safety reports and nurses, in the role of safety managers, review, and code events. Safety managers may have varying degrees of experience with identifying events related to HIT.

Macrophage acetyl-CoA carboxylase regulates acute inflammation through control of glucose and lipid metabolism.

Acetyl-CoA carboxylase (ACC) regulates lipid synthesis; however, its role in inflammatory regulation in macrophages remains unclear. We generated mice that are deficient in both ACC isoforms in myeloid cells. ACC deficiency altered the lipidomic, transcriptomic, and bioenergetic profile of bone marrow-derived macrophages, resulting in a blunted response to proinflammatory stimulation.

PheNominal: an EHR-integrated web application for structured deep phenotyping at the point of care.

Background: Clinical phenotype information greatly facilitates genetic diagnostic interpretations pipelines in disease. While post-hoc extraction using natural language processing on unstructured clinical notes continues to improve, there is a need to improve point-of-care collection of patient phenotypes. Therefore, we developed "PheNominal", a point-of-care web application, embedded within Epic electronic health record (EHR) workflows, to permit capture of standardized phenotype data.

Efferocytosis requires periphagosomal Ca-signaling and TRPM7-mediated electrical activity.

Efficient clearance of apoptotic cells by phagocytosis, also known as efferocytosis, is fundamental to developmental biology, organ physiology, and immunology. Macrophages use multiple mechanisms to detect and engulf apoptotic cells, but the signaling pathways that regulate the digestion of the apoptotic cell cargo, such as the dynamic Ca signals, are poorly understood. Using an siRNA screen, we identify TRPM7 as a Ca-conducting ion channel essential for phagosome maturation during efferocytosis.

Pannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation.

Allergic airway inflammation is driven by type-2 CD4 T cell inflammatory responses. We uncover an immunoregulatory role for the nucleotide release channel, Panx1, in T cell crosstalk during airway disease. Inverse correlations between Panx1 and asthmatics and our mouse models revealed the necessity, specificity, and sufficiency of Panx1 in T cells to restrict inflammation.

Neuronal hyperexcitability is a DLK-dependent trigger of herpes simplex virus reactivation that can be induced by IL-1.

Herpes simplex virus-1 (HSV-1) establishes a latent infection in neurons and periodically reactivates to cause disease. The stimuli that trigger HSV-1 reactivation have not been fully elucidated. We demonstrate HSV-1 reactivation from latently infected mouse neurons induced by forskolin requires neuronal excitation.

Targeting the ion channel TRPM7 promotes the thymic development of regulatory T cells by promoting IL-2 signaling.

The thymic development of regulatory T (T) cells, crucial suppressors of the responses of effector T (T) cells, is governed by the transcription factor FOXP3. Despite the clinical importance of T cells, there is a dearth of druggable molecular targets capable of increasing their numbers in vivo. We found that inhibiting the function of the TRPM7 chanzyme (ion channel and enzyme) potentiated the thymic development of T cells in mice and led to a substantially higher frequency of functional T cells in the periphery.

Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels.

Objective: Brown adipose tissue (BAT) is specialized in thermogenesis. The conversion of energy into heat in brown adipocytes proceeds via stimulation of β-adrenergic receptor (βAR)-dependent signaling and activation of mitochondrial uncoupling protein 1 (UCP1). We have previously demonstrated a functional role for pannexin-1 (Panx1) channels in white adipose tissue; however, it is not known whether Panx1 channels play a role in the regulation of brown adipocyte function.

Distinct insulin granule subpopulations implicated in the secretory pathology of diabetes types 1 and 2.

Insulin secretion from β-cells is reduced at the onset of type-1 and during type-2 diabetes. Although inflammation and metabolic dysfunction of β-cells elicit secretory defects associated with type-1 or type-2 diabetes, accompanying changes to insulin granules have not been established. To address this, we performed detailed functional analyses of insulin granules purified from cells subjected to model treatments that mimic type-1 and type-2 diabetic conditions and discovered striking shifts in calcium affinities and fusion characteristics.

Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis.

Kidney function and blood pressure homeostasis are regulated by purinergic signaling mechanisms. These autocrine/paracrine signaling pathways are initiated by the release of cellular ATP, which influences kidney hemodynamics and steady-state renin secretion from juxtaglomerular cells. However, the mechanism responsible for ATP release that supports tonic inputs to juxtaglomerular cells and regulates renin secretion remains unclear.

Pediatric trainees systematically under-report duty hour violations compared to electronic health record defined shifts.

Duty hour monitoring is required in accredited training programs, however trainee self-reporting is onerous and vulnerable to bias. The objectives of this study were to use an automated, validated algorithm to measure duty hour violations of pediatric trainees over a full academic year and compare to self-reported violations. Duty hour violations calculated from electronic health record (EHR) logs varied significantly by trainee role and rotation.

Structured override reasons for drug-drug interaction alerts in electronic health records.

Objective: The study sought to determine availability and use of structured override reasons for drug-drug interaction (DDI) alerts in electronic health records.

Materials And Methods: We collected data on DDI alerts and override reasons from 10 clinical sites across the United States using a variety of electronic health records. We used a multistage iterative card sort method to categorize the override reasons from all sites and identified best practices.

Automatic Detection of Front-Line Clinician Hospital Shifts: A Novel Use of Electronic Health Record Timestamp Data.

Objective: Excess physician work hours contribute to burnout and medical errors. Self-report of work hours is burdensome and often inaccurate. We aimed to validate a method that automatically determines provider shift duration based on electronic health record (EHR) timestamps across multiple inpatient settings within a single institution.

SCOSY: A Biomedical Collaboration Recommendation System.

Finding relevant scientific articles and collaborators is a time-consuming and challenging task in today's information-rich environment. Despite this challenge, the study and development of recommendation systems, based on the authors' collaboration network, productivity and area of research, as topics of interest, have not been practically deployed in healthcare organizations. To address this known practice gap and to promote collaboration, Schosy was developed.