Topological structural alerts modulations of mammalian cell mutagenicity for halogenated derivatives

Genotoxicity is a key toxicity endpoint for current regulatory requirements regarding new and existing chemicals. However, genotoxicity testing is time-consuming and costly, and involves the use of laboratory animals. This has motivated the development of computational approaches, designed to predict genotoxicity without the need to conduct laboratory tests. Currently, many existing computational methods, like quantitative structure–activity relationship (QSAR) models, provide limited information about the possible mechanisms involved in mutagenicity or predictions based on structural alerts (SAs) do not take statistical models into account. This paper describes an attempt to address this problem by using the TOPological Substructural MOlecular Design (TOPS-MODE) approach to develop and validate improved QSAR models for predicting the mutagenicity of a range of halogenated derivatives. Our most predictive model has an accuracy of 94.12%, exhibits excellent cross-validation and external set statistics. A reasonable interpretation of the model in term of SAs was achieved by means of bond contributions to activity. The results obtained led to the following conclusions: primary halogenated derivatives are more mutagenic than secondary ones; and substitution of chlorine by bromine increases mutagenicity while polyhalogenation decreases activity. The paper demonstrates the potential of the TOPS-MODE approach in developing QSAR models for identifying structural alerts for mutagenicity, combining high predictivity with relevant mechanistic interpretation.Ciencias AmbientalesCiencias de la AlimentaciónFarmaciaIngeniería, Industria y ConstrucciónMedicin

Bayesian spatio-temporal CPUE standardization: case study of European sardine (Sardina pilchardus) along the western coast of Portugal

Fishery data is one of the most accessible sources of information currently used for ecological studies and stock assessments. Unlike scientific surveys that are usually restricted to a given time of the year, fisheries dependent data is almost continuously available in time. Moreover, the information collected from the fisheries is less expensive and time consuming. However, for use as a relative abundance index, fishery-dependent data requires standardization as catch-per-unit-effort (CPUE) in order to remove the impact of vessel-specific differences and fishing behavior. Understanding the key factors that influence the population dynamics of fish species implies assessment of their spatial distribution and seasonal habitat selection but, spatio-temporal dependence issues are often not explicitly included in the modeling process. This study standardizes sardine fishery-dependent data obtained from the west coast of Portugal as CPUE by means of a Bayesian hierarchical spatio-temporal model using integrated nested Laplace approximation (INLA). This is one of the first studies of the region to provide maps of the relative abundance of this species for all months of the year. The best model included length of the vessel, vessel ID, month, year and location (latitude, longitude), while none of the five environmental covariates (Chl-a, SST, bathymetry, current velocity and direction) were relevant. In terms of spatial distribution, sardines were more abundant in the northern area, especially during the last quarter of the year. The applied methodology has contributed to improve our knowledge of European sardine distribution throughout the year, providing accurate predictive maps and insights into the standardization process of fishery-dependent data that could also be applied to other fish species and areas

Bayesian spatio-temporal CPUE standardization: Case study of European sardine (Sardina pilchardus) along the western coast of Portugal

Understanding the key factors influencing population dynamics of fish stocks requires knowledge of their spatial distribution and seasonal habitat selection, but these spatio-temporal dynamics are often not explicitly included in ecological studies and stock assessment models. This study standardized the data of sardine fishery-dependent catch-per- unit- effort (CPUE) from the west coast of Portugal using Bayesian hierarchical spatio-temporal models (BHSTM) with the integrated nested Laplace approximation (INLA). Sardine CPUE was best explained by length of the vessel, vessel ID, month, year, and location (latitude, longitude). In terms of spatio-temporal distribution, sardine biomass prediction maps showed a constant pattern that changed every quarter of the year. In addition, sardine CPUE index showed a cyclical trend along the year with minimum values in July and maximum peak in November. This approach provided insights on variables and corresponding modelling effects that may be relevant in spatio-temporal fishery-dependent data standardization, and that could be applied to other fish species and areas.En prens

miR-28 regulates the germinal center reaction and blocks tumor growth in preclinical models of non-Hodgkin lymphoma

Non-Hodgkin lymphoma comprises a variety of neoplasms, many of which arise from germinal center (GC)-experienced B cells. microRNA-28 (miR-28) is a GC-specific miRNA whose expression is lost in numerous mature B-cell neoplasms. Here we show that miR-28 regulates the GC reaction in primary B cells by impairing class switch recombination and memory B and plasma cell differentiation. Deep quantitative proteomics combined with transcriptome analysis identified miR-28 targets involved in cell-cycle and B-cell receptor signaling. Accordingly, we found that miR-28 expression diminished proliferation in primary and lymphoma cells in vitro. Importantly, miR-28 reexpression in human Burkitt (BL) and diffuse large B-cell lymphoma (DLBCL) xenografts blocked tumor growth, both when delivered in viral vectors or as synthetic, clinically amenable, molecules. Further, the antitumoral effect of miR-28 is conserved in a primary murine in vivo model of BL. Thus, miR-28 replacement is uncovered as a novel therapeutic strategy for DLBCL and BL treatment.This work was supported by a Ministerio de Economia y Competitividad's research training program (Formacion de Personal Investigador [FPI]) fellowship (N.B.-I.); the Ramon y Cajal program (RYC-2009-04503) funded by the Ministerio de Educacion, Cultura y Deporte and the European Research Council Proof of Concept program (HEAL-BY-MIRNA 713728) (V.G.d.Y.); the Centro Nacional de Investigaciones Cardiovaculares (CNIC) (A.F.A.-P., S.M.M., A.R.R.); the Ministerio de Economia y Competitividad (SAF2010-21394, SAF2013-42767-R), the European Research Council Starting Grant program (BCLYM-207844), and Proof of Concept program (HEAL-BY-MIRNA 713728) (A.R.R.); the People Programme-Marie Curie Actions (FP7-PIIF-2012-328177), Spanish Ministry of Economy and Competitiveness (MINECO; SAF2013-45787-R), and Gobierno de Navarra (GN-106/2014) (S.R.); and the Ministerio de Economia y Competitividad (BIO2012-37926 and BIO2015-67580-P), Instituto de Salud Carlos III (Fondo de Investigacion Sanitaria [FIS] grants PRB2 [IPT13/0001, Proteo-Red], the Fundacion La Marato TV3, and Redes tematicas de investigacion cooperativa en salud [RETICS] [RD12/0042/00056, RIC]) (J.V.). This work has been cofunded by Fondo Europeo de Desarrollo Regional (FEDER) funds. The CNIC is supported by the and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).S

Local pig breeds: Nutritional requirements, innovative practices and local feeding resources as challenges in project TREASURE

TREASURE is a research and innovation project of European Union’s Horizon 2020 programme which is devoted to traditional genetic resources in pig production with aim to improve their potentials for enhanced use. Studying and improving management of local pig breeds in their production systems is one of the challenges in which we address their performances and nutrition with special attention on locally available feeding resources and innovative practices aiming to improved welfare. For that purpose 15 experiments on 12 breeds were designed in the project, which are hereafter shortly presented. Their concepts and main objectives with some highlights on already available results are described. © 2017, University of Zagreb. All rights reserved

Engineering of III-Nitride Semiconductors on Low Temperature Co-fired Ceramics

This work presents results in the feld of advanced substrate solutions in order to achieve high crystalline quality group-III nitrides based heterostructures for high frequency and power devices or for sensor applications. With that objective, Low Temperature Co-fred Ceramics has been used, as a noncrystalline substrate. Structures like these have never been developed before, and for economic reasons will represent a groundbreaking material in these felds of Electronic. In this sense, the report presents the characterization through various techniques of three series of specimens where GaN was deposited on this ceramic composite, using diferent bufer layers, and a singular metal-organic chemical vapor deposition related technique for low temperature deposition. Other single crystalline ceramic-based templates were also utilized as substrate materials, for comparison purposes

Industry dynamics, technological regimes and the role of demand

In this paper, we propose an industrial dynamics model to analyze the interactions between the price-performance sensitivity of demand, the sources of innovation in a sector, and certain features of the corresponding pattern of industrial transformation. More precisely, we study market concentration in different technological regimes and demand conditions. The computational analysis of our model shows that market demand plays a key role in industrial dynamics. Thus, although for intermediate values of the price-performance sensitivity, our results show the well-known relationships in the literature between technological regimes and industry transformation, we find surprising outcomes when demand is strongly biased either towards price or performance. Hence, for different technological regimes, a high performance sensitivity of demand tends to concentrate the market. On the other hand, under conditions of high price sensitivity, the industry generally tends to atomize. That is to say, for extreme values of the price-performance sensitivity of demand, we find concentrated or atomized market structures no matter the technological regime we are in. These results highlight the importance of considering the role of demand in the analysis of industrial dynamics

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

AbstractThoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.</jats:p

Predictores del uso de la estrategia invasiva precoz en mujeres con síndrome coronario agudo sin elevación de ST

Objetivo: Identificar los determinantes asociados a la estrategia invasiva precoz (EIP) en mujeres con síndrome coronario agudo sin elevación de ST (SCASEST). Diseño: Estudio de cohortes retrospectivo. Análisis crudo y ajustado de la realización de EIP mediante regresión logística no condicional. Ámbito: Unidades coronarias participantes en 2010-2011 en el registro ARIAM-SEMICYUC. Pacientes: Cuatrocientas cuarenta mujeres con SCASEST. Se excluyeron 16 por datos insuficientes y 58 con coronariografía electiva (> 72 h). Variables analizadas: Demográficas, factores de riesgo coronario, medicación previa, comorbilidad. Características clínicas, analíticas, hemodinámicas y electrocardiográficas del episodio. Resultados: Las mujeres tratadas conservadoramente presentaban mayor edad, mayor prevalencia de anticoagulación oral, diabetes, lesiones coronarias previas e insuficiencia cardiaca (p 80 años y el aumento de la frecuencia cardiaca son factores independientes asociados al tratamiento conservador.To identify determinants associated to an early invasive strategy in women with acute coronary syndromes without ST elevation (NSTE-ACS).Design: A retrospective cohort study was made. Crude and adjusted analysis of the performance of the early invasive strategy using logistic regression.Setting: Coronary Units enrolled in 2010 - 2011 in the ARIAM-SEMICYUC registry.Patients: A total of 440 women with NSTE-ACS were studied. Sixteen patients were excluded due to insufficient data, together with 58 patients subjected to elective coronary angiography (> 72 h).Variables analyzed: Demographic parameters, coronary risk factors, previous medication, comorbidity. Clinical, laboratory, hemodynamic and electrocardiographic data of the episode. Results: Women treated conservatively were of older age, had oral anticoagulation, diabetes, previous coronary lesions, and heart failure (p 80 years (OR 0.48, 95% CI 0.27 to 0.82, p=0.009), known coronary lesions (OR 0.47, 95% CI 0.26-0.84, p=0.011), and heart rate (OR 0.98, 95% CI 0.97-0.99, p=0.003) were independently associated to conservative treatment. Smoking (OR 2.50, 95% CI 1.20 to 5.19, p=0.013) and high-risk electrocardiogram (OR 2.96, 95% CI 1.72 to 4.97, p 80 years and increased heart rate were independent factors associated to conservative treatment

Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families

<p>Abstract</p> <p>Background</p> <p>Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the <it>SLX4 </it>gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of <it>SLX4 </it>in German or Byelorussian familial cases of breast cancer without detected mutations in <it>BRCA1 </it>or <it>BRCA2 </it>has been completed, with globally negative results.</p> <p>Methods</p> <p>The genomic region of <it>SLX4</it>, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of <it>BRCA1 </it>or <it>BRCA2 </it>mutations.</p> <p>Results</p> <p>This mutational analysis revealed extensive genetic variation of <it>SLX4</it>, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them.</p> <p>Conclusions</p> <p>Overall, while the results of this study do not identify clearly pathogenic mutations of <it>SLX4 </it>contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease.</p