RASA3 is a critical inhibitor of RAP1-dependent platelet activation

The small GTPase RAP1 is critical for platelet activation and thrombus formation. RAP1 activity in platelets is controlled by the GEF CalDAG-GEFI and an unknown regulator that operates downstream of the adenosine diphosphate (ADP) receptor, P2Y12, a target of antithrombotic therapy. Here, we provide evidence that the GAP, RASA3, inhibits platelet activation and provides a link between P2Y12 and activation of the RAP1 signaling pathway. In mice, reduced expression of RASA3 led to premature platelet activation and markedly reduced the life span of circulating platelets. The increased platelet turnover and the resulting thrombocytopenia were reversed by concomitant deletion of the gene encoding CalDAG-GEFI. Rasa3 mutant platelets were hyperresponsive to agonist stimulation, both in vitro and in vivo. Moreover, activation of Rasa3 mutant platelets occurred independently of ADP feedback signaling and was insensitive to inhibitors of P2Y12 or PI3 kinase. Together, our results indicate that RASA3 ensures that circulating platelets remain quiescent by restraining CalDAG-GEFI/RAP1 signaling and suggest that P2Y12 signaling is required to inhibit RASA3 and enable sustained RAP1-dependent platelet activation and thrombus formation at sites of vascular injury. These findings provide insight into the antithrombotic effect of P2Y12 inhibitors and may lead to improved diagnosis and treatment of platelet-related disorders

Management of intra-abdominal infections : recommendations by the WSES 2016 consensus conference

This paper reports on the consensus conference on the management of intra-abdominal infections (IAIs) which was held on July 23, 2016, in Dublin, Ireland, as a part of the annual World Society of Emergency Surgery (WSES) meeting. This document covers all aspects of the management of IAIs. The Grading of Recommendations Assessment, Development and Evaluation recommendation is used, and this document represents the executive summary of the consensus conference findings.Peer reviewe

Pulmonary response to inhaled jet-propulsion fuel 8 aerosol in mice

Studies were initiated to characterize the acute and sub-chronic pulmonary responses to inhaled Jet-Propulsion Fuel 8 (JP-8) aerosol. At 24 to 30 hours following JP-8 exposure, physiological, biochemical, cellular, and morphological techniques were used to assay for lung injury. In addition, C57BL/6 and B6.A.D.(Ahyd mice were utilized in the acute study to determine if responsiveness to aryl hydrocarbon hydroxylase (AHH) induction modulates toxicity. JP-8 contains aromatic compounds that are known substrates for AHH. Acute lung injury was evident by increased respiratory permeability that was accompanied by alveolar macrophage infiltration and activation, following exposure to occupational permissible levels of JP-8. Morphological alterations were characterized by terminal bronchiolar lesions of vacuolization and necrosis. AHH responsiveness did not appear to influence the severity of JP-8 induced lung injury. Lung injury following sub-chronic inhalation was found to be progressive in nature. Repeated exposure induced alveolar hemorrhage and alveolar macrophage cytotoxicity. Morphological changes progressed to include epithelial denudation of bronchiolar airways and vacuolization of alveolar type II epithelial cells and adjacent endothelia. The pulmonary clearance of JP-8 following inhalation exposures was determined indirectly by analysis for tetradecane content within lung homogenates from exposed mice. Clearance of JP-8 following acute exposure was determined to have a half-life of 43 minutes and increased by 14 minutes following a toxic sub-chronic exposure. The relatively rapid pulmonary clearance of JP-8 following either acute or sub-chronic exposure implies that JP-8 induced lung injury was independent of pulmonary retention. Studies were also performed to determine if non-cytotoxic concentrations of JP-8 or tetradecane could decrease bronchial epithelial barrier function. Studies showed that one hour of exposure to JP-8 or tetradecane could significantly enhance paracellular permeability to mannitol in the BEAS-2B human bronchial epithelial cell line, at two hours after exposure. Bronchial epithelial permeability appeared to be more sensitive to tetradecane than JP-8. Subsequent recovery studies determined that JP-8 and tetradecane-induced decreases in barrier function reach a maximum at 12 hours and barrier function returns to control by 48 hours post-exposure. These results indicate that JP-8 induced lung injury may be initiated by changes in airway barrier function

Nota editorial, marzo 1962

Esta sección recoge una diversidad de textos que dan cuenta de la contribución de expertos analistas que desde distintos enfoques se han referido sobre los acontecimientos financieros y económicos más relevantes ocurridos en Colombia y otros países. Se halla, en especial, noticias relativas a la producción y comercio del café dentro del panorama nacional y mundial; análisis sobre la propiedad raíz en diversos lugares de Colombia; cifras de interés; también se rememora el contenido de revistas anteriores. En esta sección se compilan, además, reseñas, reflexiones, cartas y notas sobre la pluralidad de eventos académicos, sociales y culturales que han configurado el escenario económico nacional.En esta edición se tratan los siguientes temas:-       La situación general; el costo de la vida; la situación fiscal; giros por importaciones; la banca y el mercado monetario; el mercado bursátil; el café-       El mercado de café en Nueva York-       El financiamiento externo del desarrollo económico de la América Latina. Algunos problemas básicos, por Raymond F. Mikesell, profesor de economía, Universidad de Oregon, traducido por James A. Ternent   -       Proyecto de presupuesto de los Estados Unidos para el año fiscal de 1963-       Veinticinco años atrás (número 113, marzo 1937)-       Comentarios bibliográficos, por Alberto Lozano Simonell

The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development

Dlx homeobox genes are mammalian homologs of the Drosophila Distal-less (Dll) gene. The Dlx/Dll gene family is of ancient origin and appears to play a role in appendage development in essentially all species in which it has been identified. In Drosophila, Dll is expressed in the distal portion of the developing appendages and is critical for the development of distal structures. In addition, human Dlx5 and Dlx6 homeobox genes have been identified as possible candidate genes for the autosomal dominant form of the split-hand/split-foot malformation (SHFM), a heterogeneous limb disorder characterized by missing central digits and claw-like distal extremities. Targeted inactivation of Dlx5 and Dlx6 genes in mice results in severe craniofacial, axial, and appendicular skeletal abnormalities, leading to perinatal lethality. For the first time, Dlx/Dll gene products are shown to be critical regulators of mammalian limb development, as combined loss-of-function mutations phenocopy SHFM. Furthermore, spatiotemporal-specific transgenic overexpression of Dlx5, in the apical ectodermal ridge of Dlx5/6 null mice can fully rescue Dlx/Dll function in limb outgrowth

Strain-specific hyperkyphosis and megaesophagus in Add1 null mice.

The three adducin proteins (α, β, and γ) share extensive sequence, structural, and functional homology. Heterodimers of α- and β-adducin are vital components of the red cell membrane skeleton, which is required to maintain red cell elasticity and structural integrity. In addition to anemia, targeted deletion of the α-adducin gene (Add1) reveals unexpected, strain-dependentnon-erythroid phenotypes. On an inbred 129 genetic background, Add1 null mice show abnormal inward curvature of the cervicothoracic spine with complete penetrance. More surprisingly, a subset of 129-Add1 null mice develop severe megaesophagus, while examination of peripheral nerves reveals a reduced number of axons in 129-Add1 null mice at four months of age. These unforeseen phenotypes, described here, reveal new functions for adducin and provide new models of mammalian disease. genesis 1-10, 2012. © 2012 Wiley Periodicals, Inc

Reference Trait Analysis Reveals Correlations Between Gene Expression and Quantitative Traits in Disjoint Samples.

Systems genetic analysis of complex traits involves the integrated analysis of genetic, genomic, and disease-related measures. However, these data are often collected separately across multiple study populations, rendering direct correlation of molecular features to complex traits impossible. Recent transcriptome-wide association studies (TWAS) have harnessed gene expression quantitative trait loci (eQTL) to associate unmeasured gene expression with a complex trait in genotyped individuals, but this approach relies primarily on strong eQTL. We propose a simple and powerful alternative strategy for correlating independently obtained sets of complex traits and molecular features. In contrast to TWAS, our approach gains precision by correlating complex traits through a common set of continuous phenotypes instead of genetic predictors, and can identify transcript-trait correlations for which the regulation is not genetic. In our approach, a set of multiple quantitative reference traits is measured across all individuals, while measures of the complex trait of interest and transcriptional profiles are obtained in disjoint subsamples. A conventional multivariate statistical method, canonical correlation analysis, is used to relate the reference traits and traits of interest to identify gene expression correlates. We evaluate power and sample size requirements of this methodology, as well as performance relative to other methods, via extensive simulation and analysis of a behavioral genetics experiment in 258 Diversity Outbred mice involving two independent sets of anxiety-related behaviors and hippocampal gene expression. After splitting the data set and hiding one set of anxiety-related traits in half the samples, we identified transcripts correlated with the hidden traits using the other set of anxiety-related traits and exploiting the highest canonical correlation (R = 0.69) between the trait data sets. We demonstrate that this approach outperforms TWAS in identifying associated transcripts. Together, these results demonstrate the validity, reliability, and power of reference trait analysis for identifying relations between complex traits and their molecular substrates