Ravenscar computational model compliant AADL simulation on LEON2

AADL has been proposed for designing and analyzing SW and HW architectures for real-time mission-critical embedded systems. Although the Behavioral Annex improves its simulation semantics, AADL is a language for analyzing architectures and not for simulating them. AADS-T is an AADL simulation tool that supports the performance analysis of the AADL specification throughout the refinement process from the initial system architecture until the complete, detailed application and execution platform are developed. In this way, AADS-T enables the verification of the initial timing constraints during the complete design process. In this paper we focus on the compatibility of AADS-T with the Ravenscar Computational Model (RCM) as part of the TASTE toolset. Its flexibility enables AADS-T to support different processors. In this work we have focused on performing the simulation on a LEON2 processor.This work has been supported by ESTEC 22810/09/NL/JK HW-SW CODESIGN Project contracted to GMV Aerospace and Defence S.A.U

CD44-high neural crest stem-like cells are associated with tumour aggressiveness and poor survival in neuroblastoma tumours

BACKGROUND: Neuroblastoma is a paediatric tumour originated from sympathoadrenal precursors and characterized by its heterogeneity and poor outcome in advanced stages. Intra-tumoral cellular heterogeneity has emerged as an important feature in neuroblastoma, with a potential major impact on tumour aggressiveness and response to therapy. CD44 is an adhesion protein involved in tumour progression, metastasis and stemness in different cancers; however, there has been controversies about the significance of CD44 expression in neuroblastoma and its relationship with tumour progression. METHODS: We have performed transcriptomic analysis on patient tumour samples studying the outcome of patients with high CD44 expression. Adhesion, invasion and proliferation assays were performed in sorted CD44high neuroblastoma cells. Tumoursphere cultures have been used to enrich in undifferentiated stem-like cells and to asses self-renewal and differentiation potential. We have finally performed in vivo tumorigenic assays on cell line-derived or Patient-derived xenografts. FINDINGS: We show that high CD44 expression is associated with low survival in high-grade human neuroblastoma, independently of MYCN amplification. CD44 is expressed in a cell population with neural crest stem-like features, and with the capacity to generate multipotent, undifferentiated tumourspheres in culture. These cells are more invasive and proliferative in vitro. CD44 positive cells obtained from tumours are more tumorigenic and metastatic, giving rise to aggressive neuroblastic tumours at high frequency upon transplantation. INTERPRETATION: We describe an unexpected intra-tumoural heterogeneity within cellular entities expressing CD44 in neuroblastoma, and propose that CD44 has a role in neural crest stem-like undifferentiated cells, which can contribute to tumorigenesis and malignancy in this type of cancer. FUNDING: Research supported by grants from the "Asociación Española contra el Cáncer" (AECC), the Spanish Ministry of Science and Innovation SAF program (SAF2016-80412-P), and the European Research Council (ERC Starting Grant to RP).Spanish Ministry of Science and Innovation SAF program (SAF2016-80412-P

Study of the Briquetting Process of Walnut Shells for Pyrolysis and Combustion

Walnut shells can be used as fuels in power plants directly or as biochars obtained by pyrolysis or torrefaction. They are an example of clean waste biomass which shows a low ash content and a high Net Calorific Value, making them excellent for energy recovery in industrial and non-industrial applications, such as in bakeries, restaurants, and homes. Their main inconvenience is their low bulk density. Densification is a possible solution that reduces the costs of transportation, handling, and storage. In this work, after the characterization of the walnut shells, briquettes were obtained using a hydraulic piston press briquette machine under different conditions to find the best quality without the need for previous grinding for pelletizing. This method features easy operation and maintenance, and the briquette shape could be adapted as desired. The quality of the briquettes was measured through their density and durability. After fixing a compaction pressure to obtain acceptable briquettes, the factors affecting their quality were studied: operating temperature, moisture content, and the presence of small amounts of walnuts. Good quality briquettes were obtained with a compaction pressure of 66 MPa, with densities around 1040 kg/m3, and durabilities higher than 94% when the process was carried at 140 °C. The greatest increase in durability was observed between briquettes obtained at room temperature and those obtained at 80 °C. The presence of small amounts of walnuts, common after the shelling process, improved the durability. Although water is necessary, briquettes obtained from biomass with only 1% of moisture showed better durabilities. Therefore, walnut shells are suitable for obtaining good quality briquettes according to the specifications of solid biofuels established in the standards, without the need for any pretreatment.This research was funded by the Agencia Estatal de Investigación (Spain) [grant number AEI/10.13039/501100011033], by the University of Alicante [grant number UAUSTI21-03] and by the Spanish Ministerio de Economia y Competividad [Research Project CTQ2016-76608-R]

Metodos no invasivos de medición de la inflamación en las neumonitis por hipersensibilidad : utilidad del esputo inducido

El diagnòstic de la pneumonitis per hipersensibilitat requereix en ocasions la realització de tècniques diagnòstiques invasives que de vegades no són possibles de practicar donat el deteriorament de la capacitat funcional que presenta el pacient. L'ús de noves tècniques d'estudi de la inflamació pulmonar, a través de mètodes no invasius, podrien ser d'utilitat en el diagnòstic i seguiment d'aquesta entitat. En el present estudi, plantegem el valor de l'estudi de l'esput induït en el diagnòstic de la pneumonitis per hipersensibilitat, així com la seva possible utilitat en el context de les proves de provocació bronquial específiques.El diagnóstico de la neumonitis por hipersensibilidad requiere en ocasiones la realización de técnicas diagnósticas invasivas que en ocasiones no son posibles de practicar dado el deterioro de la capacidad funcional que presenta el paciente. El empleo de nuevas técnicas de estudio de la inflamación pulmonar, a través de métodos no invasivos, podrían ser de utilidad en el diagnóstico y seguimiento de esta entidad. En el presente estudio, planteamos el valor del estudio del esputo inducido en el diagnóstico de la neumonitis por hipersensibilidad, así como su posible utilidad en el contexto de las pruebas de provocación bronquial específica

Sex-Specific Regulation of miR-29b in the Myocardium Under Pressure Overload is Associated with Differential Molecular, Structural and Functional Remodeling Patterns in Mice and Patients with Aortic Stenosis

Pressure overload in patients with aortic stenosis (AS) induces an adverse remodeling of the left ventricle (LV) in a sex-specific manner. We assessed whether a sex-specific miR-29b dysregulation underlies this sex-biased remodeling pattern, as has been described in liver fibrosis. We studied mice with transverse aortic constriction (TAC) and patients with AS. miR-29b was determined in the LV (mice, patients) and plasma (patients). Expression of remodeling-related markers and histological fibrosis were determined in mouse LV. Echocardiographic morpho-functional parameters were evaluated at baseline and post-TAC in mice, and preoperatively and 1 year after aortic valve replacement (AVR) in patients with AS. In mice, miR-29b LV regulation was opposite in TAC-males (down-regulation) and TAC-females (up-regulation). The subsequent changes in miR-29b targets (collagens and GSK-3?) revealed a remodeling pattern that was more fibrotic in males but more hypertrophic in females. Both systolic and diastolic cardiac functions deteriorated more in TAC-females, thus suggesting a detrimental role of miR-29b in females, but was protective in the LV under pressure overload in males. Clinically, miR-29b in controls and patients with AS reproduced most of the sexually dimorphic features observed in mice. In women with AS, the preoperative plasma expression of miR-29b paralleled the severity of hypertrophy and was a significant negative predictor of reverse remodeling after AVR; therefore, it may have potential value as a prognostic biomarker

O Eixo Atlántico: un territorio educador, unha comunidade educativa

Eixo Atlântico do Noroeste PeninsularEixo Atlântico do Noroeste Peninsularinfo:eu-repo/semantics/publishedVersio

Soluble endoglin antagonizes Met signaling in spindle carcinoma cells

Increased levels of soluble endoglin (Sol-Eng) correlate with poor outcome in human cancer. We have previously shown that shedding of membrane endoglin, and concomitant release of Sol-Eng is a late event in chemical mouse skin carcinogenesis associated with the development of undifferentiated spindle cell carcinomas (SpCCs). In this report, we show that mouse skin SpCCs exhibit a high expression of hepatocyte growth factor (HGF) and an elevated ratio of its active tyrosine kinase receptor Met versus total Met levels. We have evaluated the effect of Sol-Eng in spindle carcinoma cells by transfection of a cDNA encoding most of the endoglin ectodomain or by using purified recombinant Sol-Eng. We found that Sol-Eng inhibited both mitogen-activated protein kinase (MAPK) activity and cell growth in vitro and in vivo. Sol-Eng also blocked MAPK activation by transforming growth factor-β1 (TGF-β1) and impaired both basal and HGF-induced activation of Met and downstream MAPK. Moreover, Sol-Eng strongly reduced basal and HGF-stimulated spindle cell migration and invasion. Both Sol-Eng and full-length endoglin were shown to interact with Met by coimmunoprecipitation experiments. However, full-length endoglin expressed at the plasma membrane of spindle carcinoma cells had no effect on Met signaling activity, and was unable to inhibit HGF-induced cell migration/invasion. These results point to a paradoxical suppressor role for Sol-Eng in carcinogenesis.Ministerio de Economía y Competitividad (SAF2010-19152, SAF2013-46183-R to M.Q., and SAF2010-19222, SAF2013-43421-R to C.B.), Comunidad Autónoma de Madrid (S2010/BMD-2359, SkinModel, to M.Q.). GdC was the recipient of a Juan de la Cierva postdoctoral research contract. EP-G and EM-V are the recipients of a postdoctoral research contract from the scientific foundation of Asociación Española Contra el Cáncer (AECC).Peer reviewe

Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients

[Background] Von Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumors: hemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma, pheochromocytomas, pancreatic serous cystadenoma, and endolymphatic sac tumors. These tumors do not express VHL protein (pVHL). pVHL ubiquitinates hypoxia inducible factor (HIF) protein for degradation by the proteasome; in the absence of VHL, HIF translocates to the nucleus to activate the expression of its target genes. Targeting VHL-derived tumors with drugs that have reduced side effects is urgent to avoid repeat CNS surgeries. Recent reports have shown that propranolol, a β-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control hemangioblastoma growth in VHL disease because of its antiangiogenic effects demonstrated in IH and the hypothetical impact on HIF levels.[Methods] HeLa 9X (HRE) hypoxia responsive element cell line and primary hemangioblastoma-derived cells were subjected to propranolol treatment and cell viability and apoptosis were evaluated. HIF1-α and Hif-2α expression after propranolol treatment was analyzed by western blotting. Quantitative PCR was performed to study the mRNA expression of HIF target genes. Vascular endothelial growth factor (VEGF) was measured in culture supernatants by immunoassay.[Results] Propranolol downregulated HIF-dependent transcription in HeLa 9XHRE cells. Under hypoxic conditions, propranolol decreased the expression of HIF target genes in hemangioblastoma cells, which stopped proliferating and died following long-term treatment. These results suggests that propranolol treatment promoted reduced HIF protein expression and corresponding downregulation of HIF target genes, and inhibited cell proliferation in parallel with induction of cell death by apoptosis.[Conclusions] Our results suggest that propranolol could reduce the growth of HIF-dependent tumors and may thus be a promising treatment to delay surgery in VHL patients.This work was supported by grants from Ministerio de Economia y Competitividad SAF2011-23475 and from Alianza VHL Spain& Fundación Iberdrola to LMB. Virginia Albiñana was supported by Alianza VHL Spain, Fundación Iberdrola and Fundación Divina Pastora.Peer reviewe

Cooperativity of stress-responsive transcription factors in core hypoxia-inducible factor binding regions

The transcriptional response driven by Hypoxia-inducible factor (HIF) is central to the adaptation to oxygen restriction. Despite recent characterization of genome-wide HIF DNA binding locations and hypoxia-regulated transcripts in different cell types, the molecular bases of HIF target selection remain unresolved. Herein, we combined multi-level experimental data and computational predictions to identify sequence motifs that may contribute to HIF target selectivity. We obtained a core set of bona fide HIF binding regions by integrating multiple HIF1 DNA binding and hypoxia expression profiling datasets. This core set exhibits evolutionarily conserved binding regions and is enriched in functional responses to hypoxia. Computational prediction of enriched transcription factor binding sites identified sequence motifs corresponding to several stress-responsive transcription factors, such as activator protein 1 (AP1), cAMP response element-binding (CREB), or CCAAT-enhancer binding protein (CEBP). Experimental validations on HIF-regulated promoters suggest a functional role of the identified motifs in modulating HIF-mediated transcription. Accordingly, transcriptional targets of these factors are over-represented in a sorted list of hypoxia-regulated genes. Altogether, our results implicate cooperativity among stress-responsive transcription factors in fine-tuning the HIF transcriptional responseThis work was supported by Ministerio de Ciencia e Innovación (Spanish Ministry of Science and Innovation, MICINN) [grant number SAF2008-03147 to L. del P.], Comunidad Autónoma de Madrid [grant number S-SAL-0311_2006 to L. del P.] and the 7th Research Framework Programme of the European Union [grant number METOXIA project ref. HEALTH-F2-2009-222741] to L. del P. D.V. was a recipient of PhD funding from the Spanish Ministry of Science and Innovation [FPU programme] and the European Molecular Biology Organization [Short-Term Fellowships

Successful pregnancy in a high-risk catecholaminergic polymorphic ventricular tachycardia patient

Objective: To report the case of a successful pregnancy outcome in a severely symptomatic woman affected by catecholaminergic polymorphic ventricular tachycardia (CPVT) carrier of a novel variant in ryanodine receptor 2 (RYR2) followed by a review of the current literature. Case(s): A 27-year-old primigravida affected by CPVT was referred to our tertiary care hospital after an implantable cardioverter defibrillator (ICD) shock. The patient also received medical treatment with metoprolol and flecainide. A healthy baby was born by Cesarean section at 31 weeks after the onset of preterm labor and premature rupture of membranes. CPVT is a rare inherited cardiac condition characterized by episodic polymorphic ventricular arrhythmias with a structurally normal heart. These are usually triggered by exercise or emotional stress and can lead to syncope or even sudden cardiac death. Treatment of this condition comprises betablockers in isolation or in addition to other antiarrhythmics, left cardiac sympathetic denervation and/or ICD. Conclusion: This case illustrates the importance of a multidisciplinary approach in this clinical scenario and the benefits of an optimization of the medical treatment, and demonstrates that, even in severely affected patients, a successful pregnancy is possible under close control. However, the risk of arrhythmic events and the course of pregnancy remain largely unknown in patients with CPVT, and further investigation is needed