Benderwilkinson1256

[This corrects the article DOI 10.3389/fphys.2019.01432.].Introduction Chronic exposure to the weightlessness-induced cephalad fluid shift is hypothesized to be a primary contributor to the development of spaceflight-associated neuro-ocular syndrome (SANS) and may be associated with an increased risk of venous thrombosis in the jugular vein. This study characterized the relationship between gravitational level (Gz-level) and acute vascular changes. Methods Internal jugular vein (IJV) cross-sectional area, inferior vena cava (IVC) diameter, and common carotid artery (CCA) flow were measured using ultrasound in nine subjects (5F, 4M) while seated when exposed to 1.00-Gz, 0.75-Gz, 0.50-Gz, and 0.25-Gz during parabolic flight and while supine before flight (0-G analog). Additionally, IJV flow patterns were characterized. Results IJV cross-sectional area progressively increased from 12 (95% CI 9-16) mm2 during 1.00-Gz seated to 24 (13-35), 34 (21-46), 68 (40-97), and 103 (75-131) mm2 during 0.75-Gz, 0.50-Gz, and 0.25-Gz seated and 1.00-Gz supine, respectively. Also, IJV flow pattern shifted from the continuous forward flow observed during 1.00-Gz and 0.75-Gz seated to pulsatile flow during 0.50-Gz seated, 0.25-Gz seated, and 1.00-Gz supine. In contrast, we were unable to detect differences in IVC diameter measured during 1.00-G seated and any level of partial gravity or during 1.00-Gz supine. CCA blood flow during 1.00-G seated was significantly less than 0.75-Gz and 1.00-Gz supine but differences were not detected at partial gravity levels 0.50-Gz and 0.25-Gz. Conclusions Acute exposure to decreasing Gz-levels is associated with an expansion of the IJV and flow patterns that become similar to those observed in supine subjects and in astronauts during spaceflight. These data suggest that Gz-levels greater than 0.50-Gz may be required to reduce the weightlessness-induced headward fluid shift that may contribute to the risks of SANS and venous thrombosis during spaceflight.Discrete dynamical modeling shows promise in prioritizing drug combinations for screening efforts by reducing the experimental workload inherent to the vast numbers of possible drug combinations. We have investigated approaches to predict combination responses across different cancer cell lines using logic models generated from one generic prior-knowledge network representing 144 nodes covering major cancer signaling pathways. Cell-line specific models were configured to agree with baseline activity data from each unperturbed cell line. Testing against experimental data demonstrated a high number of true positive and true negative predictions, including also cell-specific responses. We demonstrate the possible enhancement of predictive capability of models by curation of literature knowledge further detailing subtle biologically founded signaling mechanisms in the model topology. In silico model analysis pinpointed a subset of network nodes highly influencing model predictions. Our results indicate that the performance of logic models can be improved by focusing on high-influence node protein activity data for model configuration and that these nodes accommodate high information flow in the regulatory network.Blood flow produces mechanical frictional forces, parallel to the blood flow exerted on the endothelial wall of the vessel, the so-called wall shear stress (WSS). WSS sensing is associated with several vascular pathologies, but it is first a physiological phenomenon. Endothelial cell sensitivity to WSS is involved in several developmental and physiological vascular processes such as angiogenesis and vascular morphogenesis, vascular remodeling, and vascular tone. Local conditions of blood flow determine the characteristics of WSS, i.e., intensity, direction, pulsatility, sensed by the endothelial cells that, through their effect of the vascular network, impact WSS. All these processes generate a local-global retroactive loop that determines the ability of the vascular system to ensure the perfusion of the tissues. In order to account for the physiological role of WSS, the so-called shear stress set point theory has been proposed, according to which WSS sensing acts locally on vessel remodeling so that WSS is maintained close to a set point value, with local and distant effects of vascular blood flow. The aim of this article is (1) to review the existing literature on WSS sensing involvement on the behavior of endothelial cells and its short-term (vasoreactivity) and long-term (vascular morphogenesis and remodeling) effects on vascular functioning in physiological condition; (2) to present the various hypotheses about WSS sensors and analyze the conceptual background of these representations, in particular the concept of tensional prestress or biotensegrity; and (3) to analyze the relevance, explanatory value, and limitations of the WSS set point theory, that should be viewed as dynamical, and not algorithmic, processes, acting in a self-organized way. We conclude that this dynamic set point theory and the biotensegrity concept provide a relevant explanatory framework to analyze the physiological mechanisms of WSS sensing and their possible shift toward pathological situations.Impaired or insufficient protein kinase G (PKG) signaling and protein quality control (PQC) are hallmarks of most forms of cardiac disease, including heart failure. Their dysregulation has been shown to contribute to and exacerbate cardiac hypertrophy and remodeling, reduced cell survival and disease pathogenesis. Enhancement of PKG signaling and PQC are associated with improved cardiac function and survival in many pre-clinical models of heart disease. While many clinically used pharmacological approaches exist to stimulate PKG, there are no FDA-approved therapies to safely enhance cardiomyocyte PQC. The latter is predominantly due to our lack of knowledge and identification of proteins regulating cardiomyocyte PQC. Recently, multiple studies have demonstrated that PKG regulates PQC in the heart, both during physiological and pathological states. These studies tested already FDA-approved pharmacological therapies to activate PKG, which enhanced cardiomyocyte PQC and alleviated cardiac disease. PBIT Histone Demethylase inhibitor This review examines the roles of PKG and PQC during disease pathogenesis and summarizes the experimental and clinical data supporting the utility of stimulating PKG to target cardiac proteotoxicity.