Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K

SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GiCT/TTA mice, in which Gi signaling is impaired, suggesting that the effect of SMO is mediated by Gi proteins. Investigation of the mechanism underlying the change in action potential kinetics revealed that activation of SMO selectively reduces outward voltage-gated K+ repolarizing (Kv) currents in isolated cardiomyocytes and that it induces a down-regulation of membrane levels of Kv4.3 in cardiomyocytes and intact hearts from WT but not from GiCT/TTA mice. Moreover, perfusion of intact hearts with Shh or purmorphamine increased the ventricular repolarization time (QT interval) and induced ventricular arrhythmias. Our data constitute the first report that acute, noncanonical Hh signaling mediated by Gi proteins regulates K+ currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias. © 2018 Cheng et al

A preclinical and phase Ib study of palbociclib plus nab-paclitaxel in patients with metastatic adenocarcinoma of the pancreas

PURPOSE: To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m RESULTS: Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis ( CONCLUSIONS: This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met. TRIAL REGISTRATION: Pfizer Inc (NCT02501902). SIGNIFICANCE: In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population

Perturbating intramolecular hydrogen bonds through substituent effects or non-covalent interactions

An analysis of the effects induced by F, Cl, and Br-substituents at the α-position of both, the hydroxyl or the amino group for a series of amino-alcohols, HOCH2(CH2)nCH2NH2 (n = 0–5) on the strength and characteristics of their OH···N or NH···O intramolecular hydrogen bonds (IMHBs) was carried out through the use of high-level G4 ab initio calculations. For the parent unsubstituted amino-alcohols, it is found that the strength of the OH···N IMHB goes through a maximum for n = 2, as revealed by the use of appropriate isodesmic reactions, natural bond orbital (NBO) analysis and atoms in molecules (AIM), and non-covalent interaction (NCI) procedures. The corresponding infrared (IR) spectra also reflect the same trends. When the α-position to the hydroxyl group is substituted by halogen atoms, the OH···N IMHB significantly reinforces following the trend H 2(CH2)nCH2NH2 (n = 0–3) interact with BeF2. Although the presence of the beryllium derivative dramatically increases the strength of the IMHBs, the possibility for the beryllium atom to interact simultaneously with the O and the N atoms of the amino-alcohol leads to the global minimum of the potential energy surface, with the result that the IMHBs are replaced by two beryllium bonds

Network intrusion detection using genetic algorithm to find best DNA signature

Bioinformatics is part of computer science that joins between computer programming and molecular biology. DNA consists of long sequence of nucleotides which formulates the genome. Our method is to generate normal signature sequence and alignment threshold value from processing the system training data and encode observed network connection into corresponding DNA nucleotides sequence, then to align the signature sequence with observed sequence to find similarity degree value and decide whether the connection is attack or normal. Number of DNA sequences makes up each population, and then new generations are produced to select the Signature with best alignment value with normal network connection sequences. This paper ends up with accuracy value and threshold score for detecting the network anomalies that no known conditions exist for them to be discovered in addition for percentage of generating false positive and true negative alarms

Some New Fuzzy Fixed Point Results with Applications

The aim of this article is to establish some fixed point results for fuzzy mappings and derive some corresponding multivalued mappings results of literature. For this purpose, we define some new and generalized contractions in the setting of b-metric spaces. As applications, we find solutions of integral inclusions by our obtained results.Deanship of Scientific Research (DSR), University of Jeddah, Jeddah. Grant No. UJ-02-007-ICGR

The magnetic drivers of campfires seen by the Polarimetric and Helioseismic Imager (PHI) on Solar Orbiter

The Extreme Ultraviolet Imager (EUI) on board the Solar Orbiter (SO) spacecraft observed small extreme ultraviolet (EUV) bursts, termed campfires, that have been proposed to be brightenings near the apexes of low-lying loops in the quiet-Sun atmosphere. The underlying magnetic processes driving these campfires are not understood. During the cruise phase of SO and at a distance of 0.523\,AU from the Sun, the Polarimetric and Helioseismic Imager on Solar Orbiter (SO/PHI) observed a quiet-Sun region jointly with SO/EUI, offering the possibility to investigate the surface magnetic field dynamics underlying campfires at a spatial resolution of about 380~km. In 71\% of the 38 isolated events, campfires are confined between bipolar magnetic features, which seem to exhibit signatures of magnetic flux cancellation. The flux cancellation occurs either between the two main footpoints, or between one of the footpoints of the loop housing the campfire and a nearby opposite polarity patch. In one particularly clear-cut case, we detected the emergence of a small-scale magnetic loop in the internetwork followed soon afterwards by a campfire brightening adjacent to the location of the linear polarisation signal in the photosphere, that is to say near where the apex of the emerging loop lays. The rest of the events were observed over small scattered magnetic features, which could not be identified as magnetic footpoints of the campfire hosting loops. The majority of campfires could be driven by magnetic reconnection triggered at the footpoints, similar to the physical processes occurring in the burst-like EUV events discussed in the literature. About a quarter of all analysed campfires, however, are not associated to such magnetic activity in the photosphere, which implies that other heating mechanisms are energising these small-scale EUV brightenings

Estudio comparativo del conformado en caliente de un acero microaleado usando criterios termodinámicos continuos y criterios fenomenológicos

En las últimas décadas, los mapas de procesado han sido ampliamente utilizados para diseñar, controlar y optimizar los procesos de conformado en caliente. En el presente trabajo, se presenta un estudio comparativo entre mapas de procesado elaborados usando criterios termodinámicos continuos y criterios fenomenológicos. Por ello, se llevaron a cabo ensayos de compresión en caliente en el rango de temperaturas 900 - 1150 °C y de velocidades de deformación =10-4 - 10 s-1. El comportamiento en caliente del acero estudiado ha sido estudiado analizando las curvas de fluencia y la interacción entre el comportamiento microestructural y los parámetros de control del proceso de deformación. El estudio comparativo de los mapas de procesado muestra la diferencia entre las posiciones de los distintos dominios de deformación plástica, según el criterio de inestabilidad usado. Además, el análisis de dichos mapas indica que el acero estudiado no sufre ningún tipo de inestabilidad plástica. Sin embargo, los mapas correspondientes a la deformación¿¿ = 0,6 revelan la existencia de un dominio de recristalización dinámica, considerado como el dominio más eficiente dentro de la región segura de procesado. Este dominio está centrado a 1150 ºC y 10 s-1.Postprint (published version

Uncertainty-sensitive reasoning for inferring sameAs facts in linked data

albakri2016aInternational audienceDiscovering whether or not two URIs described in Linked Data -- in the same or different RDF datasets -- refer to the same real-world entity is crucial for building applications that exploit the cross-referencing of open data. A major challenge in data interlinking is to design tools that effectively deal with incomplete and noisy data, and exploit uncertain knowledge. In this paper, we model data interlinking as a reasoning problem with uncertainty. We introduce a probabilistic framework for modelling and reasoning over uncertain RDF facts and rules that is based on the semantics of probabilistic Datalog. We have designed an algorithm, ProbFR, based on this framework. Experiments on real-world datasets have shown the usefulness and effectiveness of our approach for data linkage and disambiguation