Review and Meta-Analyses of TAAR1 Expression in the Immune System and Cancers

Since its discovery in 2001, the major focus of TAAR1 research has been on its role in monoaminergic regulation, drug-induced reward and psychiatric conditions. More recently, TAAR1 expression and functionality in immune system regulation and immune cell activation has become a topic of emerging interest. Here, we review the immunologically-relevant TAAR1 literature and incorporate open-source expression and cancer survival data meta-analyses. We provide strong evidence for TAAR1 expression in the immune system and cancers revealed through NCBI GEO datamining and discuss its regulation in a spectrum of immune cell types as well as in numerous cancers. We discuss connections and logical directions for further study of TAAR1 in immunological function, and its potential role as a mediator or modulator of immune dysregulation, immunological effects of psychostimulant drugs of abuse, and cancer progression

Non-invasive intraventricular pressure differences estimated with cardiac MRI in subjects without heart failure and with heart failure with reduced and preserved ejection fraction

Objective Non-invasive assessment of left ventricular (LV) diastolic and systolic function is important to better understand physiological abnormalities in heart failure (HF). The spatiotemporal pattern of LV blood flow velocities during systole and diastole can be used to estimate intraventricular pressure differences (IVPDs). We aimed to demonstrate the feasibility of an MRI-based method to calculate systolic and diastolic IVPDs in subjects without heart failure (No-HF), and with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Methods We studied 159 subjects without HF, 47 subjects with HFrEF and 32 subjects with HFpEF. Diastolic and systolic intraventricular flow was measured using two-dimensional in-plane phase-contrast MRI. The Euler equation was solved to compute IVPDs in diastole (mitral base to apex) and systole (apex to LV outflow tract). Results Subjects with HFpEF demonstrated a higher magnitude of the early diastolic reversal of IVPDs (-1.30 mm Hg) compared with the No-HF group (-0.78 mm Hg) and the HFrEF group (-0.75 mm Hg; analysis of variance p=0.01). These differences persisted after adjustment for clinical variables, Doppler-echocardiographic parameters of diastolic filling and measures of LV structure (No-HF=-0.72; HFrEF=-0.87; HFpEF=-1.52 mm Hg; p=0.006). No significant differences in systolic IVPDs were found in adjusted models. IVPD parameters demonstrated only weak correlations with standard Doppler-echocardiographic parameters. Conclusions Our findings suggest distinct patterns of systolic and diastolic IVPDs in HFpEF and HFrEF, implying differences in the nature of diastolic dysfunction between the HF subtypes

Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function

The glycocalyx component and sialomucin podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumor types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high and low surface levels occur in parallel subpopulations within cancer cells. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which PODXL promotes invasion and metastasis

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

The Earth System Grid Federation : an Open Infrastructure for Access to Distributed Geospatial Data

The Earth System Grid Federation (ESGF) is a multi-agency, international collaboration that aims at developing the software infrastructure needed to facilitate and empower the study of climate change on a global scale. The ESGF's architecture employs a system of geographically distributed peer nodes, which are independently administered yet united by the adoption of common federation protocols and application programming interfaces (APIs). The cornerstones of its interoperability are the peer-to-peer messaging that is continuously exchanged among all nodes in the federation; a shared architecture and API for search and discovery; and a security infrastructure based on industry standards (OpenID, SSL, GSI and SAML). The ESGF software is developed collaboratively across institutional boundaries and made available to the community as open source. It has now been adopted by multiple Earth science projects and allows access to petabytes of geophysical data, including the entire model output used for the next international assessment report on climate change (IPCC-AR5) and a suite of satellite observations (obs4MIPs) and reanalysis data sets (ANA4MIPs)