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[EN] The high incidence of cardiac arrythmias underlines the need for the assessment of pharmacological therapies. In this field of drug efficacy, as in the field of drug safety highlighted by the Comprehensive in Vitro Proarrhythmia Assay initiative, new pillars for research have become crucial: firstly, the integration of in-silico experiments, and secondly the evaluation of fully integrated biological systems, such as human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). In this study, we therefore aimed to combine in-vitro experiments and in-silico simulations to evaluate the antiarrhythmic effect of L-type calcium current (I-CaL) block in hiPSC-CMs. For this, hiPSC-CM preparations were cultured and an equivalent virtual tissue was modeled. Re-entry patterns of electrical activation were induced and several biomarkers were obtained before and after I-CaL block. The virtual hiPSC-CM simulations were also reproduced using a tissue composed of adult ventricular cardiomyocytes (hAdultV-CMs). The analysis of phases, currents and safety factor for propagation showed an increased size of the re-entry core when I-CaL was blocked as a result of depressed cellular excitability. The bigger wavefront curvature yielded reductions of 12.2%, 6.9%, and 4.2% in the frequency of the re-entry for hiPSC-CM cultures, virtual hiPSC-CM, and hAdultV-CM tissues, respectively. Furthermore, I-CaL block led to a 47.8% shortening of the vulnerable window for re-entry in the virtual hiPSC-CM tissue and to re-entry vanishment in hAdultV-CM tissue. The consistent behavior between in-vitro and in-silico hiPSC-CMs and between in-silico hiPSC-CMs and hAdultV-CMs evidences that virtual hiPSC-CM tissues are suitable for assessing cardiac efficacy, as done in the present study through the analysis of I-CaL block., This work was supported by the "Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2017-2020" of the Ministerio de Ciencia e Innovacion y Universidades (PID2019-104356RB-C41/AEI/10.13039/501100011033) , also by the Direccion General de Politica Cientifica de la Generalitat Valenciana (PROMETEO 2020/043) , by the European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 101016496, and by the Agencia Estatal de Investigacion [RYC2018-024346-I].

Metabolomic assays, combined with other omic technologies, such as transcriptomics and proteomics, have gained relevant importance in clinical research. Significant progress has been made in the identification of biomarkers to detect many diseases in early stages, such as inborn errors of metabolism or different types of cancer. In this way the early diagnosis could lead to adequate management of the treatments for these diseases and, possibly, to improve the prognosis and the survival of the patients. In addition, in the last few years, numerous studies of metabolomics related to nutrition were carried out. Thus the area of nutrigenomics was growing rapidly providing information about changes in the metabolome of an individual after ingesting nutrients. This could lead to the discovery of new bioprotective foods against many diseases. In this review, we emphasize the use and application of metabolomics in clinical and medical research to improve the detection, diagnosis, and treatment of different diseases.

et al., During the High Luminosity LHC, the Drift Tube chambers installed in the CMS detector need to operate with an integrated dose ten times higher than expected at the LHC due to the increase in integrated luminosity from 300 fb-1 to 3000 fb-1. Irradiations have been performed to assess the performance of the detector under such conditions and to characterize the radiation aging of the detector. The presented analysis focuses on the behaviour of the high voltage currents and the dose measurements needed to extrapolate the results to High Luminosity conditions, using data from the photon irradiation campaign at GIF++ in 2016 as well as the efficiency analysis from the irradiation campaign started in 2017. Although the single-wire loss of high voltage gain observed of 70% is very high, the muon reconstruction efficiency is expected to decrease less than 20% during the full duration of High Luminosity LHC in the areas under highest irradiation.

Aquatic organisms, including important cultured species, are forced to contend with acute changes in water temperature as the frequency and intensity of extreme weather events worsen. Acute temperature spikes are likely to threaten aquaculture species, but dietary intervention may play an important protective role. Increasing the concentration of macronutrients, for example dietary fat content, may improve the thermal resilience of aquaculture species, however, this remains unexplored. To evaluate this hypothesis, we used two commercially available diets (20% versus 10% crude fat) to examine if dietary fat content improves the growth performance of juvenile barramundi (Lates calcarifer) while increasing their resilience to acute thermal stress. Fish were fed their assigned diets for 28-days before assessing the upper thermal tolerance (CTMAX) and the thermal sensitivity of swimming performance (UCRIT) and metabolism. We found that feeding fish a high fat diet resulted in heavier fish, but did not affect the thermal sensitivity of swimming performance or metabolism over an 18 °C temperature range (from 20 to 38 °C). Thermal tolerance was compromised in fish fed the high fat diet by 0.48 °C, showing significantly lower CTMAX. Together, these results suggest that while a high fat diet increases juvenile L. calcarifer growth, it does not benefit physiological performance across a range of relevant water temperatures and may even reduce fish tolerance of extreme water temperatures. These data may have implications for aquaculture production in a warming world, where episodic extremes of temperature are likely to become more frequent.

[EN] Potassium levels in the plasma, [Kþ]o, are regulated precisely under physiological conditions. However, increases (from approx. 4.5 to 8.0 mM) can occur as a consequence of, e.g., endurance exercise, ischemic insult or kidney failure. This hyperkalemic modulation of ventricular electrophysiology has been studied extensively. Hypokalemia is also common. It can occur in response to diuretic therapy, following renal dialysis, or during recovery from endurance exercise. In the human ventricle, clinical hypokalemia (e.g., [Kþ]o levels of approx. 3.0 mM) can cause marked changes in both the resting potential and the action potential waveform, and these may promote arrhythmias. Here, we provide essential background information concerning the main Kþ-sensitive ion channel mechanisms that act in concert to produce prominent short-term ventricular electrophysiological changes, and illustrate these by implementing recent mathematical models of the human ventricular action potential. Even small changes (~1 mM) in [Kþ]o result in significant alterations in two different Kþ currents, IK1 and HERG. These changes can markedly alter in resting membrane potential and/or action potential waveform in human ventricle. Specifically, a reduction in net outward transmembrane Kþ currents (repolarization reserve) and an increased substrate input resistance contribute to electrophysiological instability during the plateau of the action potential and may promote pro-arrhythmic early after-depolarizations (EADs). Translational settings where these insights apply include: optimal diuretic therapy, and the interpretation of data from Phase II and III trials for anti-arrhythmic drug candidates., In Valencia, this work was supported by: (i) the “Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016” from the Ministerio de Economía, Industria y Competitividad of Spain (DPI2016-75799-R) and AEI/FEDER, UE, and by the “Programa Prometeu (PROMETEU/2016/088) de la Conselleria d'Educació, Formació I Ocupació, Generalitat Valenciana”. and (v) GileadSciences, Ltd. Wayne Giles acknowledges receipt of financial support in the form of a salary award (Medical Scientist) from Alberta Innovates-Health Solutions, and operating funding from the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Alberta.

[EN] The effect of the direction of the meat fiber on the diffusion of sodium nitrate and water in Semimembranosus pork muscle during curing was studied at different temperatures. Nitrate and water diffusion were modelled based on Fick's second law. The nitrate diffusion coefficients ranged from 0.007·10¿10 to 0.034·10¿10 m2/s (parallel) and 0.89·10¿10 to 1.41·10¿10 m2/s (perpendicular), while for water the values ranged from 9.87·10¿9 to 12.46·10¿9 m2/s (parallel) and 5.22·10¿10 to 9.29·10¿10 m2/s (perpendicular). In every case, these values increased as the temperature rose. The activation energy for water diffusion perpendicular to the meat fiber (31.86 kJ/mol) was greater than when the diffusion was parallel (15.06 kJ/mol). The opposite was observed for nitrate diffusion (96.44 kJ/mol when parallel vs. 24.71 kJ/mol when perpendicular), which implies that nitrate needs more energy for parallel diffusion and, consequently, curing is slower in that direction., The authors of this paper acknowledge the financial support from Spanish Government ("Ministerio de Educacion y Cultura", CONSOLIDER INGENIO 2010, CSD2007-00016) and from the Valencian Government ("Generalitat Valenciana", Valencia, Spain, PROMETEOII/2014/0005).

Resumen: Introducción: El deterioro intelectual y neurológico progresivo (DINP) en la infancia tiene una incidencia de 0,5 por mil nacimientos. Su impacto en lo que a morbimortalidad se refiere es importante. Los objetivos de este trabajo son conocer datos demográficos del DINP, su mortalidad y las principales causas que lo originan. Material y métodos: Se trata de un estudio retrospectivo y multicéntrico llevado a cabo en diferentes hospitales de la Comunidad Valenciana (España). Definición de caso: edad inferior a 18 años con pérdida de habilidades intelectuales o del desarrollo previamente adquiridas de al menos 3 meses de duración. Resultados: Participaron 9 hospitales y se reclutaron un total de 85 casos. La edad media al inicio de los síntomas fue de 1,8 años y al diagnóstico de 3,6. En el 68% de los casos existía un retraso previo al inicio de los síntomas. La mortalidad fue del 16,4%. Se llegó a un diagnóstico en el 74% de los casos. La causa más frecuentemente encontrada fue el síndrome de Rett. El 68% de los casos diagnosticados eran debidos a una metabolopatía. Discusión: La existencia de un retraso del desarrollo previo, así como el inicio tan precoz del proceso, puede dificultar la identificación de un DINP. Al igual que el resto de series, el mayor número de casos diagnosticados corresponde a metabolopatías. Conclusiones: El DINP en la infancia tiene un inicio precoz, con un amplio porcentaje de casos que permanecen sin diagnóstico etiológico y una mortalidad elevada. Abstract: Background: Progressive intellectual and neurological deterioration (PIND) in childhood has an incidence of 0.5 per thousand live births. Its impact on morbimortality is important. The aim of this work is to study the epidemiology of PIND and the most important causes of this process. Methods: A retrospective and multicentre study was carried out in different hospitals of the Valencian Community (Spain). Case definition: age less than 18 years with a progressive loss of intellectual or development abilities, previously acquired for at least 3 months. Results: Nine hospitals participated in the study and a total of 85 cases were included. The mean age at the onset of symptoms was 1.8 years, and the mean age at diagnosis was 3.6 years. In 68% of cases there was an intellectual or developmental delay before the onset of symptoms. The mortality rate was 16.4%. A diagnosis was achieved in 74% of the cases. The most frequently found cause was Rett syndrome. More than two-thirds (68%) of diagnosed cases were due to a metabolic disease. Discussion: The existence of a previous development delay and the early onset of the PIND can make it difficult to identify. Like the rest of the series, the largest number of diagnosed cases involved a metabolic disease. Conclusions: PIND has an early onset, and in a large percentage of cases the origin remains unknown and with a high mortality rate.

Heart failure (HF) claims 250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. QT interval and action potential (AP) prolongation are hallmark proarrhythmic changes in the failing myocardium, which potentially result from alterations in repolarizing potassium currents. Thus,we aimed to examinewhether decreased expression of the rapid delayed rectifier potassiumcurrent, IKr, contributes to repolarization abnormalities in human HF. Tomap functional IKr expression across the left ventricle (LV), we optically imaged coronary-perfused LV free wall from donor and end-stage failing human hearts. The LV wedge preparation was used to examine transmural AP durations at 80% repolarization (APD80), and treatment with the IKr-blocking drug, E-4031, was utilized to interrogate functional expression. We assessed the percent change in APD80 post-IKr blockade relative to baseline APD80 (ΔAPD80) and found that ΔAPD80s are reduced in failing versus donor hearts in each transmural region, with 0.35-, 0.43-, and 0.41-fold reductions in endo-, mid-, and epicardium, respectively (p = 0.008, 0.037, and 0.022). We then assessed hERG1 isoform gene and protein expression levels using qPCR and Western blot. While we did not observe differences in hERG1a or hERG1b gene expression between donor and failing hearts, we found a shift in the hERG1a:hERG1b isoform stoichiometry at the protein level. Computer simulations were then conducted to assess IKr block under E-4031 influence in failing and nonfailing conditions. Our results confirmed the experimental observations and E-4031-induced relative APD80 prolongationwas greater in normal conditions than in failing conditions, provided that the cellularmodel of HF included a significant downregulation of IKr. In humanHF, the response to IKr blockade is reduced, suggesting decreased functional IKr expression. This attenuated functional response is associated with altered hERG1a:hERG1b protein stoichiometry in the failing human LV, and failing cardiomyoctye simulations support the experimental findings. Thus, of IKr protein and functional expression may be important determinants of repolarization remodeling in the failing human LV., We thank the Translational Cardiovascular Biobank & Repository (TCBR) at Washington University for provision of donor/patient records. The TCBR is supported by the NIH/CTSA (UL1 TR000448), Children's Discovery Institute, and Richard J. Wilkinson Trust. We also thank the laboratory of Dr. Sakiyama-Elbert for the use of the StepOnePlus equipment We appreciate the critical feedback on the manuscript by Dr. Jeanne Nerbonne. This work has been supported by the National Heart, Lung & Blood Institute (NHLBI, R01 HL114395). K. Holzem has been supported by the American Heart Association (12PRE12050315) and the NHLBI (F30 HL114310).

At present, there are many applications of metabolomics, together with proteomics and genomics in different areas such as pharmacology, toxicology, plant biotechnology, systems biology, biochemistry, microbiology, food technology, and human diseases. Particularly in the context of human disease, metabolomics has been used to better understand the molecular mechanisms of several diseases. Moreover, the identification of new biomarker molecules is very useful for the early diagnosis of the diseases and thus to design or improve therapeutic strategies.

[EN] Nitrites are important food additives. The nitrite movement in meat is assumed to occur by means of a diffusion process. The objective of this study was to investigate the effect of temperature on nitrite and water diffusion mechanisms in meat samples during the curing of pork meat. For this purpose, cylinders of Semimembranosus muscle were salted with sodium nitrite (NaNO2) at 2 degrees C, 7 degrees C and 12 degrees C. Experimental curing and water loss kinetics were modelled by means of a diffusion model. As the curing time lengthened, the water content fell and the nitrite content increased. The values for the nitrite and water diffusion were estimated to be in the range of 4.58 . 10(-12)-1.02 10(-12) m(2)/s and 5.96 . 10(-9)-9.82 . 10(-9) m(2)/s respectively, and they increased as the temperature went up. The activation energy was 32.24 kJ/mol for water diffusion and 60.32 kJ/mol for nitrite diffusion. (C) 2014 Elsevier Ltd. All rights reserved., The authors of this paper acknowledge the financial support from CONSOLIDER INGENIO 2010 (CSD2007-00016), Spain.

Co/MgAl2O4 catalysts modified with La, Pr or Ce were prepared, characterized by differenttechniques and tested in ethanol steam reforming reaction to produce hydrogen. Thecatalytic behavior at 650 C depended on the nature of rare earth. The amount of carbon onpromoted catalysts was significantly lower than that on unpromoted one. The Pr and Lacontaining catalysts produced a high acetaldehyde selectivity which decreased thehydrogen production. The superior performance of the catalyst promoted with 7.8% Cecould be partially explained by a higher dispersion and a high reduction of Co species. Fil: Barroso, Mariana Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Gomez, Manuel Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Arrua, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Abello, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina

Ni catalysts supported on ZnxMg1xAl2O4 spinel oxide have been prepared by the wet impregnation method with 8 wt.% Ni. The samples were characterized by XRD, BET area, TPR, CO2–TPD, SEM–EDX and TPO and tested in the ethanol steam reforming reaction. The XRD patterns of Ni catalysts supported on ZnxMg1xAl2O4 with x = 1 or 0.5 revealed a highly crystalline spinel phase (ZnAl2O4 type) and different size particles of NiO. MgAl2O4 with a poorer crystallinity and NiO were observed for the catalyst supported with x = 0. The presence of Mg into the support composition decreased the Ni2+ reducibility and increased the basicity and the specific surface area, allowing a high dispersion of metallic particles and an improved resistance to carbon deposition in the ethanol steam reforming reaction. Under the experimental conditions used in this work, Ni/MgAl2O4 was the most active catalyst but showed deactivation by graphitic carbon deposition. Fil: Barroso, Mariana Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina; Fil: Galetti, Agustin Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina; Fil: Gomez, Manuel Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina; Fil: Arrua, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina; Fil: Abello, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina

Pressure overload activates cardiac fibroblasts leading to excessive production of extracellular matrix which may contribute to compromised heart function. The activated fibroblast acquires smooth muscle-like features such as expression of smooth muscle alpha-actin (SMA) and SM22 and is therefore referred to as myofibroblast. The molecular mechanisms underlying mechanical stress-induced myofibroblast differentiation are poorly defined. The objective of this study was to examine the potential roles of the transmembrane proteoglycan syndecan-4 and the calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) in myofibroblast differentiation. Aortic banding resulted in elevated collagen land III, fibronectin, SMA and SM22 mRNA in the left ventricles of wild-type mice, whereas this response was markedly reduced in syndecan-4(-/-) mice. Myofibroblast differentiation in vitro was associated with increased SMA, collagen I and III expression and NFAT-luciferase activity, all of which were reduced in fibroblasts from syndecan-4(-/-) mice or after treatment with calcineurin/NFAT blockers. Following cyclic stretch, NFATc4 was activated in cardiac fibroblasts in a syndecan-4- and calcineurin-dependent manner. Syndecan-4 and calcineurin co-localized and mechanical stress resulted in dephosphorylation of serine179 of syndecan-4, an intracellular residue critical for calcineurin interaction. Over-expression of NFATc4 up-regulated collagen III, MRTF-A (a transcriptional regulator of SMA) and the NFAT-target regulator of calcineurin 1.4 (RCAN1.4). Our data demonstrate that syndecan-4 is important for the differentiation of cardiac fibroblasts into myofibroblasts in the pressure-overloaded heart and that the calcineurin/NFAT pathway is engaged upon mechanical stress in a syndecan-4-dependent manner, playing an active role in myofibroblast differentiation and extracellular matrix production. This article is part of a Special Issue entitled 'Possible Editorial'. (c) 2012 Elsevier Ltd. All rights reserved.

Ample evidence shows the role of cytoskeleton mainly in cell division, cell form, and general orientation by the perception of physical forces such as gravity and mechanical ones in plant cells. However, the problem of how cytoskeleton organization and its dynamics at the cellular level in turn affects main metabolic pathways of gene expression and cellular energetics is yet unsolved. The response given by cells to environmental challenges such as stress responses is crucially dependent on the organization of their architecture. Drought, high salinity, and low temperature are sensed by plants as a water stress condition. The latter is known to entrain a series of physiological and metabolic changes at the cellular level. This review hypothesizes that the cytoskeletal network of plant cells and tissues may transduce environmental stress into changes in the organization and dynamics of metabolism and gene expression. Accordingly, experimental evidence concerning the current models of cytoplasmic architecture that have emerged in recent years and the effects of stress on the cytostructure are analyzed.

Publisher Summary This chapter discusses the involvement of nucleic acids in bacterial injury. The involvement of ribonucleic acid (RNA) in sublethal stress of bacteria has been widely studied. It is noted that the degradation of ribosomes and ribosomal RNA (rRNA) was a generally observed lesion following sublethal stress. The rRNA comprises approximately 63% of the weight of a ribosome. In mature ribosomes, rRNA causes ribosomal proteins to maintain the proper configuration that permits the ribosome to perform its function during protein biosynthesis. The involvement of RNA in injury was first recognized when investigators found that bacterial cells lost 260 nm-absorbing materials when the cells were submitted to temperatures slightly above their maximum growth temperature. The rRNA and ribosome degradation occur during heat-injury. The type and extent of degradation of 16 S and 23 S rRNA, and 50 S and 30 S ribosome subunits is not the same, but the 16 S rRNA and 30 S subunit appear to be affected more readily than 23 S rRNA and 50 S subunit. There appears to be synthesis of both 50 S and 30 S ribosomes and 23 S and 16 S rRNA during recovery.

Background The Mediterranean diet serves as a proxy of a high-quality diet. Although several factors are known to affect a child's ability to follow a high-quality diet, no prospective data are available on factors that influence adherence to a Mediterranean diet among children. Our objective was to investigate the association of Mediterranean diet adherence with eating behaviors, lifestyle habits, and maternal education in a prospective cohort of children. Methods The present prospective cohort analysis included 1639 children aged 8–10 years. The study was carried out during two academic years, 2012/2014, with an average follow-up of 15 months. Eating behaviors, physical activity, and adherence to Mediterranean diet were estimated by the Dutch Eating Behavior Questionnaire for Children, the Physical Activity Questionnaire for Children, and the KIDMED index, respectively. Results Multivariate linear regression analysis adjusted for sex, age, maternal education, baseline adherence to the Mediterranean diet, and intervention group revealed a significant (p