Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells

Invariant natural killer T cells (iNKT cells) are innate-like T lymphocytes that act as critical regulators of the immune response. To better characterize this population, we profiled gene expression in iNKT cells during ontogeny and in peripheral subsets as part of the Immunological Genome Project. High-resolution comparative transcriptional analyses defined developmental and subset-specific programs of gene expression by iNKT cells. In addition, we found that iNKT cells shared an extensive transcriptional program with NK cells, similar in magnitude to that shared with major histocompatibility complex (MHC)-restricted T cells. Notably, the program shared by NK cells and iNKT cells also operated constitutively in γδ T cells and in adaptive T cells after activation. Together our findings highlight a core effector program regulated distinctly in innate and adaptive lymphocytes

Nuclear Calcium Signaling Controls Expression of a Large Gene Pool: Identification of a Gene Program for Acquired Neuroprotection Induced by Synaptic Activity

Synaptic activity can boost neuroprotection through a mechanism that requires synapse-to-nucleus communication and calcium signals in the cell nucleus. Here we show that in hippocampal neurons nuclear calcium is one of the most potent signals in neuronal gene expression. The induction or repression of 185 neuronal activity-regulated genes is dependent upon nuclear calcium signaling. The nuclear calcium-regulated gene pool contains a genomic program that mediates synaptic activity-induced, acquired neuroprotection. The core set of neuroprotective genes consists of 9 principal components, termed Activity-regulated Inhibitor of Death (AID) genes, and includes Atf3, Btg2, GADD45β, GADD45γ, Inhibin β-A, Interferon activated gene 202B, Npas4, Nr4a1, and Serpinb2, which strongly promote survival of cultured hippocampal neurons. Several AID genes provide neuroprotection through a common process that renders mitochondria more resistant to cellular stress and toxic insults. Stereotaxic delivery of AID gene-expressing recombinant adeno-associated viruses to the hippocampus confers protection in vivo against seizure-induced brain damage. Thus, treatments that enhance nuclear calcium signaling or supplement AID genes represent novel therapies to combat neurodegenerative conditions and neuronal cell loss caused by synaptic dysfunction, which may be accompanied by a deregulation of calcium signal initiation and/or propagation to the cell nucleus

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Do Low Levels of Blood Lead Reduce Children's Future Test Scores?

We construct a unique individual-level dataset linking preschool blood lead levels with third grade test scores for Rhode Island children born 1997–2005. Using two identification strategies, we show for the first time that reductions of lead from even historically low levels have significant positive effects. A one-unit decrease in average blood lead levels reduces the probability of being substantially below proficient in reading (math) by 0.96 (0.79) percentage points on a baseline of 12 (16) percent. Since disadvantaged children have greater exposure to lead, lead poisoning may be one of the causes of continuing disparities in test scores

Differences in Presentation and Management of Pediatric Facial Lacerations by Type of Health Insurance

Introduction: Limited data are available regarding differences in presentation and management of pediatric emergency department (PED) patients based on insurance status. The objective of the study was to assess the difference in management of pediatric facial lacerations based on medical insurance status.Methods: We conducted a retrospective cohort study with universal sampling of patients with facial lacerations who were treated in an urban PED (45K visits/year) over a one-year period. Demographic features and injury characteristics for patients with commercial (private) insurance and those with Medicaid or Medicare (public) insurance were compared.Results: Of 1235 children included in the study, 667 (54%) had private insurance and 485 (39%) had public insurance. The two groups did not differ in age or gender, arrival by ambulance, location of injury occurrence, mechanism of injury, part of face involved, length or depth of laceration, use of local anesthetic, or method of repair but differed in acuity assigned at triage. Patients with public insurance were found less likely to have subspecialty consultation in bivariable (OR=0.41, 95% CI [0.24–0.68]) and multivariable logistic regression analyses (OR=0.45, 95% CI [0.25-0.78]). Patients with public insurance received procedural sedation significantly less often than those with private insurance (OR=0.48, 95% CI [0.29-0.76]). This difference was not substantiated in multivariable models (OR=0.74, 95% CI [0.40-1.31]).Conclusion: Patients with public insurance received less subspecialty consultation compared to privately insured patients despite a similarity in the presentation and characteristics of their facial lacerations. The reasons for these disparities require further investigation. [West J Emerg Med 2015;16(4)-0.

Differences in Presentation and Management of Pediatric Facial Lacerations by Type of Health Insurance

Introduction: Limited data are available regarding differences in presentation and management of pediatric emergency department (PED) patients based on insurance status. The objective of the study was to assess the difference in management of pediatric facial lacerations based on medical insurance status. Methods: We conducted a retrospective cohort study with universal sampling of patients with facial lacerations who were treated in an urban PED (45K visits/year) over a one-year period. Demographic features and injury characteristics for patients with commercial (private) insurance and those with Medicaid or Medicare (public) insurance were compared. Results: Of 1235 children included in the study, 667 (54%) had private insurance and 485 (39%) had public insurance. The two groups did not differ in age or gender, arrival by ambulance, location of injury occurrence, mechanism of injury, part of face involved, length or depth of laceration, use of local anesthetic, or method of repair but differed in acuity assigned at triage. Patients with public insurance were found less likely to have subspecialty consultation in bivariable (OR=0.41, 95% CI [0.24–0.68]) and multivariable logistic regression analyses (OR=0.45, 95% CI [0.25–0.78]). Patients with public insurance received procedural sedation significantly less often than those with private insurance (OR=0.48, 95% CI [0.29–0.76]). This difference was not substantiated in multivariable models (OR=0.74, 95% CI [0.40–1.31]). Conclusion: Patients with public insurance received less subspecialty consultation compared to privately insured patients despite a similarity in the presentation and characteristics of their facial lacerations. The reasons for these disparities require further investigation