The CONCERTO methodology for model-based development of avionics SW

20th International Conference on Reliable Software Technologies - Ada-Europe 2015 (Ada-Europe 2015), 22 to 26, Jun, 2015, Madrid, Spain.The development of high-integrity real-time systems, including their certification, is a demanding endeavour in terms of time, skills and effort involved. This is particularly true in application domains such as the avionics, where composable design is to be had to allow subdividing monolithic systems into components of smaller complexity, to be outsourced to developers subcontracted down the supply chain. Moreover, the increasing demand for computational power and the consequent interest in multicore HW architectures complicates system deployment. For these reasons, appropriate methodologies and tools need to be devised to help the industrial stakeholders master the overall system design complexity, while keeping manufacturing costs affordable. In this paper we present some elements of the CONCERTO platform, a toolset to support the end-to-end system development process from system modelling to analysis and validation, prior to code generation and deployment. The approach taken by CONCERTO is demonstrated for an illustrative avionics setup, however it is general enough to be applied to a number of industrial domains including the space, telecom and automotive. We finally reason about the benefits to an industrial user by comparing to similar initiatives in the research landscape

Tyrosine Phosphorylation of Eps15 Is Required for Ligand-Regulated, but Not Constitutive, Endocytosis

Membrane receptors are internalized either constitutively or upon ligand engagement. Whereas there is evidence for differential regulation of the two processes, little is known about the molecular machinery involved. Previous studies have shown that an unidentified kinase substrate is required for endocytosis of the epidermal growth factor receptor (EGFR), the prototypical ligand-inducible receptor, but not of the transferrin receptor (TfR), the prototypical constitutively internalized receptor. Eps15, an endocytic protein that is tyrosine phosphorylated by EGFR, is a candidate for such a function. Here, we show that tyrosine phosphorylation of Eps15 is necessary for internalization of the EGFR, but not of the TfR. We mapped Tyr 850 as the major in vivo tyrosine phosphorylation site of Eps15. A phosphorylation-negative mutant of Eps15 acted as a dominant negative on the internalization of the EGFR, but not of the TfR. A phosphopeptide, corresponding to the phosphorylated sequence of Eps15, inhibited EGFR endocytosis, suggesting that phosphotyrosine in Eps15 serves as a docking site for a phosphotyrosine binding protein. Thus, tyrosine phosphorylation of Eps15 represents the first molecular determinant, other than those contained in the receptors themselves, which is involved in the differential regulation of constitutive vs. regulated endocytosis

Languages for safety-certification related propertis

The Safety Certification of Software-Intensive Systems with Reusable Components project, in short SafeCer (www.safecer.eu),is targeting increased efficiency and reduced time-to-market by composable safety certification of safety- relevant embedded systems. The industrial domains targeted are within automotive and construction equipment, avionics, and rail. Some of the companies involved are: Volvo Tech- nology, Thales, TTTech, and Intecs among others. SafeCer includes more than 30 partners in six different countries and has a budget of e25.7 millions. A primary objective is to provide support for system safety arguments based on arguments and properties of system components as well as to provide support for generation of corresponding evidence in a similar compositional way. By providing support for efficient reuse of certification and stronger links between certification and development, compo- nent reuse will be facilitated, and by providing support for reuse across domains the amount of components available for reuse will increase dramatically. The resulting efficiency and reduced time to market will, together with increased quality and reduced risk, increase competitiveness and pave the way for a cross-domain market for software components qualified for certification

Revealing the Therapeutic Potential of Botulinum Neurotoxin Type A in Counteracting Paralysis and Neuropathic Pain in Spinally Injured Mice

Botulinum neurotoxin type A (BoNT/A) is a major therapeutic agent that has been proven to be a successful treatment for different neurological disorders, with emerging novel therapeutic indications each year. BoNT/A exerts its action by blocking SNARE complex formation and vesicle release through the specific cleavage of SNAP-25 protein; the toxin is able to block the release of pro-inflammatory molecules for months after its administration. Here we demonstrate the extraordinary capacity of BoNT/A to neutralize the complete paralysis and pain insensitivity induced in a murine model of severe spinal cord injury (SCI). We show that the toxin, spinally administered within one hour from spinal trauma, exerts a long-lasting proteolytic action, up to 60 days after its administration, and induces a complete recovery of muscle and motor function. BoNT/A modulates SCI-induced neuroglia hyperreactivity, facilitating axonal restoration, and preventing secondary cells death and damage. Moreover, we demonstrate that BoNT/A affects SCI-induced neuropathic pain after moderate spinal contusion, confirming its anti-nociceptive action in this kind of pain, as well. Our results provide the intriguing and real possibility to identify in BoNT/A a therapeutic tool in counteracting SCI-induced detrimental effects. Because of the well-documented BoNT/A pharmacology, safety, and toxicity, these findings strongly encourage clinical translation

Transboundary aquifers

This chapter gives an overview of the status of transboundary aquifers and the cooperation related to shared groundwater resources, highlighting the complexity of the assessment, analysis and management of these systems. It summarizes the main challenges regarding transboundary aquifers and the need for more comprehensive and integrated management, which would include technical, legal and organizational aspects as well as training and cooperation

Proton Magnetic Resonance Spectroscopic Changes of the Primary Motor Cortex and Supplementary Motor Area in Hemiparetic Patients with Corticospinal Tract Injury due to Deep Intracerebral Hematoma

This study was conducted to investigate the metabolic changes in the motor and motor association cortices following axonal injury in the internal capsule that was caused by deep intracerebral hematoma. Using proton magnetic resonance spectroscopy (1H MRS), the authors studied the primary motor cortices (M-1) and sup-plementary motor areas (SMA) of 9 hemiparetic patients with documentable hemi-paresis of varying severity, and we studied 10 normal volunteers as controls. To measure the M-1 and SMA biochemical changes, 4 separate single volumes of inter-est(VOIs) were located bilaterally in the affected and unaffected hemisphere (AH and UH). 1H MRS provided a neuronal and axonal viability index by measuring levels of N-acetylaspartate (NAA) and creatine/phosphocreatine (Cr). The M-1/SMA NAA/Cr ratios of the AH and UH in patients, and the AH and normal volunteers were com-pared. The NAA/Cr ratios of the M-1 and SMA in AH, and the SMA in UH were sig-nificantly lower than those of normal volunteers. These 1H MRS findings indicate that axonal injury in the descending motor pathway at the level of internal capsule could induce metabolic changes in the higher centers of the motor pathway

Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma

[Abstract] Long noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of blunt-ended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability.[Significance] This study characterizes the role of lncRNA NIHCOLE in DNA repair and cellular fitness in HCC, thus implicating it as a therapeutic target.This work was supported by the European FEDER funding (to the activities of the groups directed by P. Fortes, O. Llorca, and F. Moreno-Herrero) and grants from the Ministry of Economy and Competitiveness [SAF2015-70971-R to P. Fortes and BFU2017-83794-P (AEI/FEDER, UE) to F. Moreno-Herrero)]; MCIU/AEI/FEDER/UE (RTI2018-101759-B-I00 to P. Fortes), NIH program (CA92584 to S.P. Lees-Miller), Ligue National Contre le Cancer, Équipe Labellisée and ITMO Cancer: Consortium HETCOLI (to J. Zucman-Rossi), NIH program (P01CA092584 to G. Williams), NSERC (RGPIN-2018-04327 to G. Williams), and CFI (RCP-18-023-SEG to G. Williams), Gobierno de Navarra (33/2015 to P. Fortes), Scientific Foundation of the Spanish Association Against Cancer (AECC IDEAS20169FORT to P. Fortes); Fondo de Investigación Sanitaria (PI19/00742 to B. Sangro), financed by the National Institute of Health Carlos III and FEDER. CNIO and CIBERehd are funded by the National Institute of Health Carlos III. J.P. Unfried was a recipient of a University of Navarra's Asociación de Amigos fellowship. L. Prats-Mari is a recipient of a PFIS fellowship (FI20/00074) by the National Institute of Health Carlos III and FSE "Investing in Your Future." This work was also funded by grants from the Autonomous Region of Madrid (Tec4Bio—S2018/NMT-4443 and NanoBioCancer—Y2018/BIO-4747 to O. Llorca and F. Moreno-Herrero) and co-funded by the European Social Fund. F. Moreno-Herrero acknowledges support from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 681299). The GTEx Project was supported by the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.Peer reviewe

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Measurement of the W-boson mass in pp collisions at √s=7 TeV with the ATLAS detector

A measurement of the mass of the W boson is presented based on proton–proton collision data recorded in 2011 at a centre-of-mass energy of 7 TeV with the ATLAS detector at the LHC, and corresponding to 4.6 fb−1 of integrated luminosity. The selected data sample consists of 7.8×106 candidates in the W→μν channel and 5.9×106 candidates in the W→eν channel. The W-boson mass is obtained from template fits to the reconstructed distributions of the charged lepton transverse momentum and of the W boson transverse mass in the electron and muon decay channels, yielding mW=80370±7 (stat.)±11(exp. syst.) ±14(mod. syst.) MeV =80370±19MeV, where the first uncertainty is statistical, the second corresponds to the experimental systematic uncertainty, and the third to the physics-modelling systematic uncertainty. A measurement of the mass difference between the W+ and W−bosons yields mW+−mW−=−29±28 MeV