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Artículos galardonado con el Premio al Mejor Artículo Científico de 2021 publicado en la revista oficial de la Health Technology Assessment international (HTAi)​. The Monitoring Studies (MS) program, the approach developed by RedETS to generate postlaunch real-world evidence (RWE), is intended to complement and enhance the conventional health technology assessment process to support health policy decision making in Spain, besides informing other interested stakeholders, including clinicians and patients. The MS program is focused on specific uncertainties about the real effect, safety, costs, and routine use of new and insufficiently assessed relevant medical devices carefully selected to ensure the value of the additional research needed, by means of structured, controlled, participative, and transparent procedures. However, despite a clear political commitment and economic support from national and regional health authorities, several difficulties were identified along the development and implementation of the first wave of MS, delaying its execution and final reporting. Resolution of these difficulties at the regional and national levels and a greater collaborative impulse in the European Union, given the availability of an appropriate methodological framework already provided by EUnetHTA, might provide a faster and more efficient comparative RWE of improved quality and reliability at the national and international levels. No specific funding has been required to develop this report. The financial support for the activities of RedETS is provided by the Spanish Ministry of Health. Sí

Addiction management is complex, and it requires a bio-psycho-social perspective, that ought to consider the multiple etiological and developmental factors. Because of this, a large amount of resources has been allocated to assess the vulnerability to dependence, i.e., to identify the processes underlying the transition from substance use to dependence, as well as its course, in order to determine the key points in its prevention, treatment, and recovery. Consequently, knowledge \from neuroscience must be taken into account, which is why different initiatives have emerged with this objective, such as the “Research Domain Criteria” (RDoC), and the “Addiction Neuroclinical Assessment” (ANA). Particularly, neuropsychophysiological measures could be used as markers of cognitive and behavioral attributes or traits in alcohol dependence, and even trace clinical change. In this way, the aim of this narrative review is to provide an overview following ANA clinical framework, to the most robust findings in neuropsychophysiological changes in alcohol dependence, that underlie the main cognitive domains implicated in addiction: incentive salience, negative emotionality, and executive functioning. The most consistent results have been found in event-related potential (ERP) analysis, especially in the P3 component, that could show a wide clinical utility, mainly for the executive functions. The review also shows the usefulness of other components, implicated in affective and substance-related processing (P1, N1, or the late positive potential LPP), as well as event-related oscillations, such as theta power, with a possible use as vulnerability or clinical marker in alcohol dependence. Finally, new tools emerging from psychophysiology research, based on functional connectivity or brain graph analysis could help toward a better understanding of altered circuits in alcohol dependence, as well as communication efficiency and effort during mental operations. This review concludes with an examination of these tools as possible markers in the clinical field and discusses methodological differences, the need for more replicability studies and incipient lines of work. It also uses consistent findings in psychophysiology to draw possible treatment targets and cognitive profiles in alcohol dependence., The preparation of the manuscript was supported by: 'Instituto de Salud Carlos III, Fondos FEDER, Red de Trastornos Adictivos' (RTA, RD16/0017/0014 to JM and RD16/0017/0017 to GR); 'Ministerio de Sanidad, Delegación del Gobierno para el Plan Nacional Sobre Drogas' (PNSD, 2019I012 to JM and PNSD,2016-Rubio to GR, AS, JP-M and RJ-B); 'Ministerio de Ciencia e Innovación, Fondo de Investigaciones Sanitarias' (FIS15/00463 to GR and AM-M; FIS, PI18/00576 to JM); 'Ministerio de Economía y Competitividad' (PSI2015-68851-P to RJ-B and ID).

This article belongs to the Special Issue Bioinformatics and Precision Computational Biology: Selected Papers from the X International Conference on Bioinformatics #SoIBio+10., Mesenchymal Stromal Cells (MSC) are multipotent cells characterized by self-renewal, multilineage differentiation, and immunomodulatory properties. To obtain a gene regulatory profile of human MSCs, we generated a compendium of more than two hundred cell samples with genome-wide expression data, including a homogeneous set of 93 samples of five related primary cell types: bone marrow mesenchymal stem cells (BM-MSC), hematopoietic stem cells (HSC), lymphocytes (LYM), fibroblasts (FIB), and osteoblasts (OSTB). All these samples were integrated to generate a regulatory gene network using the algorithm ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks; based on mutual information), that finds regulons (groups of target genes regulated by transcription factors) and regulators (i.e., transcription factors, TFs). Furtherly, the algorithm VIPER (Algorithm for Virtual Inference of Protein-activity by Enriched Regulon analysis) was used to inference protein activity and to identify the most significant TF regulators, which control the expression profile of the studied cells. Applying these algorithms, a footprint of candidate master regulators of BM-MSCs was defined, including the genes EPAS1, NFE2L1, SNAI2, STAB2, TEAD1, and TULP3, that presented consistent upregulation and hypomethylation in BM-MSCs. These TFs regulate the activation of the genes in the bone marrow MSC lineage and are involved in development, morphogenesis, cell differentiation, regulation of cell adhesion, and cell structure., This research was funded by Fondo de Investigación Sanitaria—Instituto de Salud Carlos III (FIS—ISCIII, Spanish Ministry of Health, project reference PI18/00591) where J.D.L.R. was the PI. The research was also partially funded by Fondo de Investigación Sanitaria (FIS—ISCIII, project reference PI16/01407). The work within these projects was also cofunded by the FEDER program of the European Union. J.D.L.R. lab acknowledges also the support given by the European Project H2020 ArrestAD (Project ID: 737390, H2020-FETOPEN-1-2016-2017).

[Background and Aims]: The synthetic atypical cannabinoid Abn-CBD, a cannabidiol (CBD) derivative, has been recently shown to modulate the immune system in different organs, but its impact in obesity-related meta-inflammation remains unstudied. We investigated the effects of Abn-CBD on metabolic and inflammatory parameters utilizing a diet-induced obese (DIO) mouse model of prediabetes and non-alcoholic fatty liver disease (NAFLD)., [Materials and Methods]: Ten-week-old C57Bl/6J mice were fed a high-fat diet for 15 weeks, following a 2-week treatment of daily intraperitoneal injections with Abn-CBD or vehicle. At week 15 mice were obese, prediabetic and developed NAFLD. Body weight and glucose homeostasis were monitored. Mice were euthanized and blood, liver, adipose tissue and pancreas were collected and processed for metabolic and inflammatory analysis., [Results]: Body weight and triglycerides profiles in blood and liver were comparable between vehicle- and Abn-CBD-treated DIO mice. However, treatment with Abn-CBD reduced hyperinsulinemia and markers of systemic low-grade inflammation in plasma and fat, also promoting white adipose tissue browning. Pancreatic islets from Abn-CBD-treated mice showed lower apoptosis, inflammation and oxidative stress than vehicle-treated DIO mice, and beta cell proliferation was induced. Furthermore, Abn-CBD lowered hepatic fibrosis, inflammation and macrophage infiltration in the liver when compared to vehicle-treated DIO mice. Importantly, the balance between hepatocyte proliferation and apoptosis was improved in Abn-CBD-treated compared to vehicle-treated DIO mice., [Conclusions]: These results suggest that Abn-CBD exerts beneficial immunomodulatory actions in the liver, pancreas and adipose tissue of DIO prediabetic mice with NAFLD, thus protecting tissues. Therefore, Abn-CBD and related compounds could represent novel pharmacological strategies for managing obesity-related metabolic disorders., This work was supported by Consejería de Salud de la Junta de Andalucía Andalucía se mueve con Europa (PI-0574-2012 to SR-Z) and Instituto de Salud Carlos III (ISCIII), Ministerio de Sanidad, Gobierno de España Una manera de hacer Europa (13/00309 and 17/01004 to FB-S, co-funded by FEDER, EU). SR-Z was recipient of a postdoctoral fellowship from Consejeria de Salud de la Junta de Andalucia (RH-0070-2013). AR received a short-term stay fellowship from Banco Santander (Programa Bolsas Iberoamericanas Jovens Professores e Pesquisadores) and was funded by a CNPq research grant (Grant No. 306359/2017-0). IG-M was funded by the European Commission Research & Innovation, Horizon2020 program, call H2020-MSCA-IF-2016 (GA: 748749). FB-S belongs to the regional Nicolás Monardes research program of the Consejería de Salud (C-0070-2012 and RC0005-2016; Junta de Andalucía, Spain). BG was supported by the Ministerio de Economia y Competitividad co-funded by FEDER (PI10/00871, PI13/00593 and BFU2017-83588-P). CIBERDEM is an initiative of the Instituto de Salud Carlos III.

© 2020 by the authors. The aim of this review is to shed light over the most recent advances in Coenzyme Q10 (CoQ10) applications as well as to provide detailed information about the functions of this versatile molecule, which have proven to be of great interest in the medical field. Traditionally, CoQ10 clinical use was based on its antioxidant properties; however, a wide range of highly interesting alternative functions have recently been discovered. In this line, CoQ10 has shown pain-alleviating properties in fibromyalgia patients, a membrane-stabilizing function, immune system enhancing ability, or a fundamental role for insulin sensitivity, apart from potentially beneficial properties for familial hypercholesterolemia patients. In brief, it shows a remarkable amount of functions in addition to those yet to be discovered. Despite its multiple therapeutic applications, CoQ10 is not commonly prescribed as a drug because of its low oral bioavailability, which compromises its efficacy. Hence, several formulations have been developed to face such inconvenience. These were initially designed as lipid nanoparticles for CoQ10 encapsulation and distribution through biological membranes and eventually evolved towards chemical modifications of the molecule to decrease its hydrophobicity. Some of the most promising formulations will also be discussed in this review. This work was supported by FIS PI16/00786 and FIS PI19/00377 grants, Instituto de Salud Carlos III, Ministerio de Sanidad, Spain, and Fondo Europeo de Desarrollo Regional (FEDER Unión Europea), Ayudas para la Formación de Profesorado Universitario (FPU), Ministerio de Ciencia e innovación, AEPMI (Asociación de Enfermos de Patología Mitocondrial), and ENACH (Asociación de enfermos de Neurodegeneración con Acumulación Cerebral de Hierro).

Incluye: PDF y EPUB Este documento ha sido realizado por la Agencia de Evaluación de Tecnologías Sanitarias del Instituto de Salud Carlos III en el marco de la financiación del Ministerio de Sanidad para el desarrollo de las actividades del Plan anual de Trabajo de la Red Española de Agencias de Evaluación de Tecnologías Sanitarias y Prestaciones del SNS, aprobado en el Pleno del Consejo Interterritorial del SNS del 28 de octubre de 2020 (conforme al Acuerdo del Consejo de Ministros de 9 de diciembre de 2020). El contenido del presente informe es responsabilidad exclusiva de la Agencia de Evaluación de Tecnologías Sanitarias del Instituto de Salud Carlos III sin que la colaboración de los revisores presuponga por su parte la completa aceptación del mismo. Los revisores del documento no suscriben necesariamente todas y cada una de las conclusiones y recomendaciones finales, que son responsabilidad exclusiva de las autoras. No

This article belongs to the Special Issue Bioinformatics and Precision Computational Biology: Selected Papers from the X International Conference on Bioinformatics #SoIBio+10., Cancer is a complex disease affecting millions of people worldwide, with over a hundred clinically approved drugs available. In order to improve therapy, treatment, and response, it is essential to draw better maps of the targets of cancer drugs and possible side interactors. This study presents a large-scale screening method to find associations of cancer drugs with human genes. The analysis is focused on the current collection of Food and Drug Administration (FDA)-approved drugs (which includes about one hundred chemicals). The approach integrates global gene-expression transcriptomic profiles with drug-activity profiles of a set of 60 human cell lines obtained for a collection of chemical compounds (small bioactive molecules). Using a standardized expression for each gene versus standardized activity for each drug, Pearson and Spearman correlations were calculated for all possible pairwise gene-drug combinations. These correlations were used to build a global bipartite network that includes 1007 gene-drug significant associations. The data are integrated into an open web-tool called GEDA (Gene Expression and Drug Activity) which includes a relational view of cancer drugs and genes, disclosing the putative indirect interactions found for FDA-approved drugs as well as the known targets of these drugs. The results also provide insight into the complex action of pharmaceuticals, presenting an alternative view to address predicted pleiotropic effects of the drugs., This research was funded by Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (FIS-ISCIII, Spanish Ministry of Health, project reference PI18/00591) where J.D.L.R. was the PI. The work within this project was also co-funded by the FEDER program of the European Union. J.D.L.R. lab acknowledges the support given by the EU COST Action Stratagem (reference: CA17104, https://www.cost.eu/actions/CA17104/). J.D.L.R. lab also acknowledges the support given by the European Project H2020 ArrestAD (Project ID: 737390, H2020-FETOPEN-1-2016-2017).

Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor and autism-associated gene that exerts an important influence over neuronal structure and function during development. In addition, it participates in synaptic plasticity processes in adulthood. As an attempt to assess synaptic and developmental mechanisms by which PTEN can modulate cognitive function, we studied the consequences of 2 different genetic manipulations in mice: presence of additional genomic copies of the Pten gene (Ptentg) and knock-in of a truncated Pten gene lacking its PDZ motif (Pten-ΔPDZ), which is required for interaction with synaptic proteins. Ptentg mice exhibit substantial microcephaly, structural hypoconnectivity, enhanced synaptic depression at cortico-amygdala synapses, reduced anxiety, and intensified social interactions. In contrast, Pten-ΔPDZ mice have a much more restricted phenotype, with normal synaptic connectivity, but impaired synaptic depression at cortico-amygdala synapses and virtually abolished social interactions. These results suggest that synaptic actions of PTEN in the amygdala contribute to specific behavioral traits, such as sociability. Also, PTEN appears to function as a bidirectional rheostat in the amygdala: reduction in PTEN activity at synapses is associated with less sociability, whereas enhanced PTEN activity accompanies hypersocial behavior. Spanish Ministry of Economy and Competitiveness (SAF2016-78071-R and SAF2015-62540-ERC to S.K.; PCIN-2016-095 and SAF2017-86983-R to J.A.E.; BFU201563769-R to R.L.; SAF2014-58598-JIN and RYC-2016-20414 to M.N.); Basque Ministry of Health (RIS3 and ELKARTEK to S.K.); University of the BasqueCountry (EHUrOPE14/03 to S.K.); Junta de Comunidades de Castilla–La Mancha (PPII2014-005-P to R.L.); Spanish Ministry of Economy and Competitiveness (BES-2011-043464 to C.S.-P.).

36 p.-3 fig.-4 tab.-6 appendix tab. AIM: To evaluate the safety and efficacy of autologous periodontal ligament-derived mesenchymal stem cells (PDL-MSCs) embedded in a xenogeneic bone substitute (XBS) for the regenerative treatment of intra-bony periodontal defects. MATERIAL AND METHODS: This quasi-randomized controlled pilot phase II clinical trial included patients requiring a tooth extraction and presence of one intra-bony lesion (1-2 walls). Patients were allocated to either the experimental (XBS + 10x106 PDL-MSCs/100mg) or the control group (XBS). Clinical and radiographical parameters were recorded at baseline, 6, 9 and 12 months. The presence of adverse events was also evaluated. Chi-square, Student`s t-test, U-Mann Whitney, repeated-measures ANOVA and regression models were used. RESULTS: Twenty patients were included. No serious adverse events were reported. Patients in the experimental group (n=9) showed greater clinical attachment level (CAL) gain [1.44, standard deviation (SD)=1.87] and probing pocket depth (PPD) reduction (2.33, SD=1.32) than the control group (n=10; CAL gain=0.88, SD=1.68, and PPD reduction=2.10, SD=2.46), without statistically significant differences. CONCLUSION: The application of PDL-MSCs to XBS for the treatment of one-two wall intra-bony lesions was safe and resulted in low postoperative morbidity and appropriate healing, although its additional benefit, when compared with the XBS alone, was not demonstrated. This study received funding from the Spanish Ministry of Health (EC10-095) to MS.

The high heterogeneity of psychiatric disorders leads to a lack of diagnostic precision. Therefore, the search of biomarkers is a fundamental aspect in psychiatry to reach a more personalized medicine. The endocannabinoid system (ECS) has gained increasing interest due to its involvement in many different functional processes in the brain, including the regulation of emotions, motivation, and cognition. This article reviews the role of the main components of the ECS as biomarkers in certain psychiatric disorders. Studies carried out in rodents evaluating the effects of pharmacological and genetic manipulation of cannabinoid receptors or endocannabinoids (eCBs) degrading enzymes were included. Likewise, the ECS-related alterations occurring at the molecular level in animal models reproducing some behavioral and/or neuropathological aspects of psychiatric disorders were reviewed. Furthermore, clinical studies evaluating gene or protein alterations in post-mortem brain tissue or in vivo blood, plasma, and cerebrospinal fluid (CSF) samples were analyzed. Also, the results from neuroimaging studies using positron emission tomography (PET) or functional magnetic resonance (fMRI) were included. This review shows the close involvement of cannabinoid receptor 1 (CB1r) in stress regulation and the development of mood disorders [anxiety, depression, bipolar disorder (BD)], in post-traumatic stress disorder (PTSD), as well as in the etiopathogenesis of schizophrenia, attention deficit hyperactivity disorder (ADHD), or eating disorders (i.e. anorexia and bulimia nervosa). On the other hand, recent results reveal the potential therapeutic action of the endocannabinoid tone manipulation by inhibition of eCBs degrading enzymes, as well as by the modulation of cannabinoid receptor 2 (CB2r) activity on anxiolytic, antidepressive, or antipsychotic associated effects. Further clinical research studies are needed; however, current evidence suggests that the components of the ECS may become promising biomarkers in psychiatry to improve, at least in part, the diagnosis and pharmacological treatment of psychiatric disorders., The preparation of the manuscript was supported by ‘Instituto de Salud Carlos III, Fondos FEDER, Red de Trastornos Adictivos’ (RTA, RD16/0017/0014 to J.M. and RD16/0017/0017 to G.R.) and ‘Ministerio de Sanidad, Delegación del Gobierno para el Plan Nacional Sobre Drogas’ (PNSD, 2019/012 to J.M.).

Mitochondrial diseases are considered rare genetic disorders characterized by defects in oxidative phosphorylation (OXPHOS). They can be provoked by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most frequent mitochondrial diseases, principally caused by the m.8344A>G mutation in mtDNA, which affects the translation of all mtDNA-encoded proteins and therefore impairs mitochondrial function. In the present work, we evaluated autophagy and mitophagy flux in transmitochondrial cybrids and fibroblasts derived from a MERRF patient, reporting that Parkin-mediated mitophagy is increased in MERRF cell cultures. Our results suggest that supplementation with coenzyme Q10 (CoQ), a component of the electron transport chain (ETC) and lipid antioxidant, prevents Parkin translocation to the mitochondria. In addition, CoQ acts as an enhancer of autophagy and mitophagy flux, which partially improves cell pathophysiology. The significance of Parkin-mediated mitophagy in cell survival was evaluated by silencing the expression of Parkin in MERRF cybrids. Our results show that mitophagy acts as a cell survival mechanism in mutant cells. To confirm these results in one of the main affected cell types in MERRF syndrome, mutant induced neurons (iNs) were generated by direct reprogramming of patients-derived skin fibroblasts. The treatment of MERRF iNs with Guttaquinon CoQ10 (GuttaQ), a water-soluble derivative of CoQ, revealed a significant improvement in cell bioenergetics. These results indicate that iNs, along with fibroblasts and cybrids, can be utilized as reliable cellular models to shed light on disease pathomechanisms as well as for drug screening., This work was supported by FIS PI16/00786 grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Spanish Ministry of Education, Culture and Sports, “Ayudas para la Formación de Profesorado Universitario” (FPU) and AEPMI (Asociación de Enfermos de Patología Mitocondrial) and ENACH (Asociación de enfermos de Neurodegeneración con Acumulación Cerebral de Hierro).

[Introduction]: Massive hemorrhage continues to be a treatable cause of death. Its management varies from prefixed ratio-driven administration of blood components to goal-directed therapy based on point-of-care testing and administration of coagulation factor concentrates. [Areas covered]: . We review the current role of fibrinogen concentrate (FC) for the management of massive hemorrhage, either administered without coagulation testing in life-threatening hemorrhage, or within an algorithm based on viscoelastic hemostatic assays and plasma fibrinogen level. We identified relevant guidelines, meta-analyzes, randomized controlled trials, and observational studies that included indications, dosage, and adverse effects of FC, especially thromboembolic events. [Expert opinion]: Moderate- to high-grade evidence supports the use of FC for the treatment of severe hemorrhage in trauma and cardiac surgery; a lower grade of evidence is available for its use in postpartum hemorrhage and end-stage liver disease. Pre-emptive FC administration in non-bleeding patients is not recommended. FC should be administered early, in a goal-directed manner, guided by early amplitude of clot firmness parameters (A5- or A10-FIBTEM) or hypofibrinogenemia. Further investigation is required into the early use of FC, as well as its potential advantages over cryoprecipitate, and whether or not its administration at high doses leads to a greater risk of adverse events. This study was partially supported by Fondo de Investigación Sanitaria (FIS) PI 15/00512, Instituto de Salud Carlos III, Ministry of Health, Government of Spain, and European Regional Development Fund (ERDF).

Ras GTPases convey signals from different types of membranes. At these locations, different Ras isoforms, interactors and regulators generate different biochemical signals and biological outputs. The study of Ras localisation-specific signal transduction networks has been hampered by our inability to specifically activate each of these Ras pools. Here, we describe a new set of site-specific tethered exchange factors, engineered by fusing the RasGRF1 CDC25 domain to sub-localisation-defining cues, whereby Ras pools at specific locations can be precisely activated. We show that the CDC25 domain has a high specificity for activating HRas but not NRas and KRas. This unexpected finding means that our constructs mainly activate endogenous HRas. Hence, their use enabled us to identify distinct pathways regulated by HRas in endomembranes and plasma membrane microdomains. Importantly, these new constructs unveil different patterns of HRas activity specified by their subcellular localisation. Overall, the targeted GEFs described herein constitute ideal tools for dissecting spatially-defined HRas biochemical and biological functions., This work was supported by the Science Foundation Ireland under grant no. 06/CE/B1129 (AH, CD, DM and WK) and grant no. 15/CDA/3495 (DM, MRC); and PC lab is supported by grant BFU2011-23807 from the Spanish Ministry of Economy–Fondos FEDER; and by the Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD/12/0036/0033);and Spanish Ministry of Health; and by Asociación Española Contra el Cáncer (AECC), grant GCB141423113.

The atypical cannabinoid Abn-CBD improves the inflammatory status in preclinical models of several pathologies, including autoimmune diseases. However, its potential for modulating inflammation in autoimmune type 1 diabetes (T1D) is unknown. Herein we investigate whether Abn-CBD can modulate the inflammatory response during T1D onset using a mouse model of T1D (non-obese diabetic- (NOD)-mice) and of beta cell damage (streptozotocin (STZ)-injected mice). Six-week-old female NOD mice were treated with Abn-CBD (0.1–1 mg/kg) or vehicle during 12 weeks and then euthanized. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1 mg/kg of body weight) or vehicle for 1 week, following STZ challenge, and euthanized 1 week later. Blood, pancreas, pancreatic lymph nodes (PLNs) and T cells were collected and processed for analysis. Glycemia was also monitored. In NOD mice, treatment with Abn-CBD significantly reduced the severity of insulitis and reduced the pro-inflammatory profile of CD4 T cells compared to vehicle. Concomitantly, Abn-CBD significantly reduced islet cell apoptosis and improved glucose tolerance. In STZ-injected mice, Abn-CBD decreased circulating proinflammatory cytokines and ameliorated islet inflammation reducing intra-islet phospho-NF-κB and TXNIP. Abn-CBD significantly reduced 2 folds intra-islet CD8 T cells and reduced Th1/non-Th1 ratio in PLNs of STZ-injected mice. Islet cell apoptosis and intra-islet fibrosis were also significantly reduced in Abn-CBD pre-treated mice compared to vehicle. Altogether, Abn-CBD reduces circulating and intra-islet inflammation, preserving islets, thus delaying the progression of insulitis. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat the early stages of T1D., H2020-MSCA-IF-2016, Grant Agreement number: 748749, EU. Consejeria de Salud y Familias, Junta de Andalucia, Spain (PI-0318-2018). Instituto de Salud Carlos III, Ministerio de Sanidad, Gobierno de España, Spain (PI17/01004). Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional, Spain (BFU2017-83588-P to BRG). We thank all the staff of the animal facility at IBIMA (ECAI de Experimentación Animal) and especially its coordinator Dr. Ricardo González Carrascosa for his excellent work. The authors also gratefully acknowledge all the staff of the bioimaging facility at IBIMA (ECAI de Imagen) and the proteomic (ECAI de Proteómica) facility, especially Dra. Carolina Lobo-García for excellent technical assistance. FJBS and IGM belong to the regional "Nicolás Monardes" research program from Consejería de Salud y Familias (C-0070-2012, RC0005-2016, RC-0001-2021 and C1-0018-2019; Junta de Andalucía, Spain). FJBS, NCV and BRG are members of the pancreatic islets study group from the Spanish Society for Diabetes (SED), Spain. CIBERDEM is an initiative of the Instituto de Salud Carlos III, Spain.

Mitochondria are key in the metabolism of aerobic organisms and in ageing progression and age-related diseases. Mitochondria are essential for obtaining ATP from glucose and fatty acids but also in many other essential functions in cells including aminoacids metabolism, pyridine synthesis, phospholipid modifications and calcium regulation. On the other hand, the activity of mitochondria is also the principal source of reactive oxygen species in cells. Ageing and chronic age-related diseases are associated with the deregulation of cell metabolism and dysfunction of mitochondria. Cell metabolism is controlled by three major nutritional sensors: mTOR, AMPK and Sirtuins. These factors control mitochondrial biogenesis and dynamics by regulating fusion, fission and turnover through mito- and autophagy. A complex interaction between the activity of these nutritional sensors, mitochondrial biogenesis rate and dynamics exists and affect ageing, age-related diseases including metabolic disease. Further, mitochondria maintain a constant communication with nucleus modulating gene expression and modifying epigenetics. In this review we highlight the importance of mitochondria in ageing and the repercussion in the progression of age-related diseases and metabolic disease., The research group is funded by the Andalusian Government Grant BIO177 (FEDER funds of European Commission). Research has been funded by the Spanish Ministry of Economy and Competitiveness Grant DEP2012-39985 and Instituto de Salud Carlos III FIS Grant PI14/01962. Authors are also members of the CIBERER, Instituto Carlos III, of the Spanish Ministry of Health.

Background: Adolescent girls’ family context and psychological characteristics play important roles in their sexual behavior, including the use of the emergency contraceptive pill (ECP). This study aims to (1) determine the prevalence of ECP use among girls who have had sexual intercourse and (2) comparatively analyze their family and psychological profiles according to whether they have used ECPs. Methods: The sample of 1735 Spanish girls aged 15 to 18 came from a representative sample of the 2014 edition of the Health Behaviour in School-aged Children (HBSC) study. Of this sample, 398 girls had sexual intercourse and reported their ECP use. Data collection for the HBSC study was performed through an online questionnaire to which adolescents responded anonymously in school. Data analyses were descriptive and bivariate and were performed with the statistical program IBM SPSS Statistics 23. Results: The results demonstrated that 30.65% of girls who had sexual intercourse used ECPs. Noticeable differences in paternal knowledge and communication with the father were observed between girls who used the ECP at least once and those who did not use it. In contrast, differences between girls who used the ECP once and those who used it twice or more were pronounced with regard to parental knowledge, communication with parents, maternal affection, life satisfaction, sense of coherence and depression. Conclusions: This work demonstrates a high prevalence of ECP use and a more positive family and psychological profile for girls who used ECP once compared with those who used it twice or more.

Hypoxia, a hallmark of solid tumors, determines the selection of invasive and aggressive malignant clones displaying resistance to radiotherapy, conventional chemotherapy or targeted therapy. The recent introduction of immunotherapy, based on immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cells, has markedly transformed the prognosis in some tumors but also revealed the existence of intrinsic or acquired drug resistance. In the current review we highlight hypoxia as a culprit of immunotherapy failure. Indeed, multiple metabolic cross talks between tumor and stromal cells determine the prevalence of immunosuppressive populations within the hypoxic tumor microenvironment and confer upon tumor cells resistance to ICPIs and CAR T-cells. Notably, hypoxia-triggered angiogenesis causes immunosuppression, adding another piece to the puzzle of hypoxia-induced immunoresistance. If these factors concurrently contribute to the resistance to immunotherapy, they also unveil an unexpected Achille’s heel of hypoxic tumors, providing the basis for innovative combination therapies that may rescue the efficacy of ICPIs and CAR T-cells. Although these treatments reveal both a bright side and a dark side in terms of efficacy and safety in clinical trials, they represent the future solution to enhance the efficacy of immunotherapy against hypoxic and therapy-resistant solid tumors., CR unit receives funding from the Italian Association of Cancer Research (AIRC; IG21408). ABSR unit is supported by Foundation for Science and Technology (FCT), Portugal (UID/NEU/04539/2019, UIDB/ 04539/2020 and UIDP/04539/2020). J.D.L.R. unit is funded by Fondo de Investigación Sanitaria—Instituto de Salud Carlos III (FIS—ISCIII, Ministry of Health of Spain; PI18/00591 and PT17/0009/0008) and by the FEDER European Union’s program. J.D.L.R. and C. R. are Vice-Chair and Chair of the COST-Action STRATAGEM (CA17104). All authors are members of STRATAGEM (CA17104).

The objectives were to determine the impact of frailty and disability on 30-day mortality and whether the addition of these variables to HFRSS EFFECT risk score (FBI-EFFECT model) improves the short-term mortality predictive capacity of both HFRSS EFFECT and BI-EFFECT models in older patients with acute decompensated heart failure (ADHF) atended in the emergency department. We performed a retrospective analysis of OAK Registry including all consecutive patients ≥65 years old with ADHF attended in 3 Spanish emergency departments over 4 months. FBI-EFFECT model was developed by adjusting probabilities of HFRSS EFFECT risk categories according to the 6 groups (G1: non frail, no or mildly dependent; G2: frail, no or mildly dependent; G3: non frail, moderately dependent; G4: frail, moderately dependent; G5: severely dependent; G6: very severely dependent).We included 596 patients (mean age: 83 [SD7]; 61.2% females). The 30-day mortality was 11.6% with statistically significant differences in the 6 groups (p

Heritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology. Pharmacological inhibition of Nos2 rapidly reversed aortic dilation and medial degeneration in young Adamts1-deficient mice and in young or old MFS mice. Patients with MFS showed elevated NOS2 and decreased ADAMTS1 protein levels in the aorta. These findings uncover a possible causative role for the ADAMTS1-NOS2 axis in human TAAD and warrant evaluation of NOS2 inhibitors for therapy., CNIC is supported by the Spanish Ministerio de Economía, Industria y Competitividad (MINECO) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Support was also provided by grants from MINECO (grants SAF2013-45258P (M.R.C.), SAF2012-34296 (J.M.R.) and SAF2015-636333R (J.M.R.)), Fundacion La Marato (TV3 grants 20151331 (J.M.R.) and 20151330 (A.E.)), CSIC (M.R.C.), the CIBERCV of Ministerio de Sanidad (grant CB16/11/00264; J.M.R.) and the Red de Investigación Cardiovascular (RIC) of Ministerio de Sanidad (grants RD12/0042/0022 (J.M.R.), RD12/0042/0021 (A.E.), RD12/0042/0024 (M.S.), RD12/0042/0056 (J.L.J.-B.) and RD12/0042/0018 (J.F.N.)), and by a Marie Skłodowska-Curie fellowship (E.J.R.) and FPI fellowships BES 2010-034552 (J.O.) and SVP-2013-067777 (S.V.).

In recent decades, cases of autochthonous hepatitis E (HE) have sharply increased in European countries where foodborne transmission is considered the main route of HE virus (HEV) transmission. Although rabbits are considered the main reservoir of the zoonotic HEV‐3ra subtype, information on the role of wild lagomorphs in the epidemiology of HEV remains scarce. The aim of this study therefore was to assess the circulation of HEV in European wild rabbits (Oryctolagus cuniculus) and Iberian hares (Lepus granatensis), the most important lagomorph species in Spanish Mediterranean ecosystems. Liver samples from 372 wild rabbits and 78 Iberian hares were analysed using a broad‐spectrum RT‐PCR that detects HEV genotypes 1–8. None of the 450 lagomorphs tested were positive for HEV infection. To the best of our knowledge, this is the first study to assess HEV circulation in wild rabbits in Spain and the first to evaluate HEV infection in Iberian hares. Our results indicate absence of HEV circulation in wild rabbits and Iberian hares in southern Spain during the study period, which suggests that the risk of transmission of HEV from wild lagomorphs to other species, including humans, is low., This work was supported by the Ministerio de Sanidad (RD12/0017/0012) integrated in the Plan Nacional de I+D+I and cofinanced by the ISCIII‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), Fundación para la Investigación en Salud (FIS) del Instituto Carlos III (PI16/01297) and Fundación Progreso y Salud de la Junta de Andalucía (PIN‐0477‐2017). J. Caballero‐Gómez is supported by an FPU grant from the Spanish Ministry of Education, Culture and Sport (FPU17/01319) and S. Jiménez‐Ruiz holds a PhD contract from the UCLM co‐supported by the European Social Fund (2018/12504). A. Rivero Juárez and M. Frías are the recipient of a Miguel Servet and Sara Borrell postdoctoral perfection grants by the Ministerio de Ciencia, Innovación y Universidades of Spain (CP18/00111) and (CD18/00091), respectively.

© 2019 by the authors., Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics–metabolomics). The data showed that Adck2+/− mice exhibited impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in Coenzyme Q (CoQ) biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation., This research was supported by grants from the Spanish Ministry of Health, Instituto de Salud Carlos III (ISCIII), PI17/01286 and Andalussian Government Excellence grant P12-CTS-943 to P.N., FIS PI17/00190 to R.A., by grants from Istituto di Ricerca Pediatrica Città della Speranza and Telethon Italy (GGP13222 and GGP14187c) to L.S., and the Intramural Research Program of National Institute on Aging, National Institutes of Health (NIA/NIH) (M.A.A., M.B. and R.d.C.). L.V.-F. doctoral thesis was directed by C.S.-O. I.N.-E. and A.d.F. were postdoctoral fellows at National Institute on Aging, National Institutes of Health (NIA/NIH).

[Abstract] BACKGROUND: Ectopic pregnancy is a life-threatening condition for which novel screening tools that would enable early accurate diagnosis would improve clinical outcomes. Kisspeptins, encoded by KISS1, play an essential role in human reproduction, at least partially by regulating placental function and possibly embryo implantation. Kisspeptin levels are elevated massively in normal pregnancy and reportedly altered in various gestational pathologic diseases. Yet, the pathophysiologic role of KISS1/kisspeptin in ectopic pregnancy has not been investigated previously. OBJECTIVE: The purpose of this study was to evaluate changes of KISS1/kisspeptin levels in ectopic pregnancy and their underlaying molecular mechanisms and to ascertain the diagnostic implications of these changes. STUDY DESIGN: A total of 122 women with normal pregnancy who underwent voluntary termination of pregnancy and 84 patients who experienced tubal ectopic pregnancy were recruited. Measurements of plasma kisspeptins and KISS1 expression analyses in human embryonic/placental tissue were conducted in ectopic pregnancy and voluntary termination of pregnancy control subjects during the early gestational window (

Certain host genetic variants, especially in the human leucocyte antigen (HLA) region, are associated with different progression of HIV-1-induced diseases and AIDS. Long term non progressors (LTNP) represent only the 2% of infected patients but are especially relevant because of their efficient HIV control. In this work we present a global analysis of genetic data in the large national multicenter cohort of Spanish LTNP, which is compared with sero-negative individuals and HIV-positive patients. We have analyzed whether several single-nucleotide polymorphisms (SNPs) including in key genes and certain HLA-A and B alleles could be associated with a specific HIV phenotype. A total of 846 individuals, 398 HIV-1positive patients (213 typical progressors, 55 AIDS patients, and 130 LTNPs) and 448 HIV-negative controls, were genotyped for 15 polymorphisms and HLA-A and B alleles. Significant differences in the allele frequencies among the studied populations identified 16 LTNP-associated genetic factors, 5 of which were defined for the first time as related to LTNP phenotype: the protective effect of HLA-B39, and the detrimental impact of HLA-B18, -A24, -B08 and –A29. The remaining eleven polymorphisms confirmed previous publications, including the protective alleles HLA-B57, rs2395029 (HCP5), HLA bw4 homozygosity, HLA-B52, HLA-B27, CCR2 V64I, rs9264942 (HLA-C) and HLA-A03; and the risk allele HLA bw6 homozygosity. Notably, individual Spanish HIV-negative individuals had an average of 0.12 protective HLA alleles and SNPs, compared with an average of 1.43 protective alleles per LTNP patient, strongly suggesting positive selection of LTNP. Finally, stratification of LTNP according to viral load showed a proportional relationship between the frequency of protective alleles with control of viral load. Interestingly, no differences in the frequency of protection/risk polymorphisms were found between elite controllers and LTNPs maintaining viral loads, Instituto de Salud Carlos III from the Spanish Ministry of Health, through Red Temática de Investigación Cooperativa en SIDA (RIS) [G03/173(2), PI050528 and RD06/0006/0033 to MDV, RD06/0006/0035 and RD12/0017/0037 to the HIV BioBank, and C03/173 and RD12/0017/0018 to CoRIS], cofinanced by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER), and also financed by Plan Nacional I+D+I from the Spanish Ministry of Science and Technology [SAF2007-60934, SAF2010-18917 and SAF2013-48754-C2-1-R to MDV], by Instituto de Salud Carlos III [Intrasalud PI12/0056 to JA] and by Fundación para la Investigación y Prevención del SIDA en España (FIPSE) [to HIV Biobank]. Institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO

Hepatitis E virus (HEV) is an emerging zoonotic pathogen that has been detected in different animal species. A survey study was carried out to assess HEV infection in non‐human primates (NHPs) housed in zoos in Spain. Anti‐HEV antibodies were detected in eight of the 181 NHPs tested (4.4%; 95%CI: 1.4–7.4). At least one seropositive animal was detected in five of the 33 species sampled (15.2%). This is the first report of seropositivity in black‐and‐white ruffed lemurs (Varecia variegata ), common chimpanzees (Pan troglodytes ), and Barbary macaques (Macaca sylvanus ). Anti‐HEV antibodies were found in six of the eight zoos included in the study (75.0%). Seroconversion was detected in one chimpanzee, which confirms HEV circulation in one zoo between 2015 and 2016. Seropositivity was significantly higher in hominids than in other NHP families. HEV RNA was not detected in any of the serum samples tested. The results indicate susceptibility of NHPs to HEV infection. Further studies are required to elucidate the role of these species in the epidemiology of HEV., This work was partially supported by the Ministerio de Sanidad (RD12/0017/0012) included in the Plan Nacional de I+D+I and cofinanced by the Fundación para la Investigación en Salud (FIS) del Instituto Carlos III (PI16/01297) and the ISCIII‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). J. Caballero‐Gómez is supported by the FPU grant of the Spanish Ministry of Education, Culture and Sport (FPU17/01319). A. Rivero Juarez and M. Frias are the recipients of a Miguel Servet and Sara Borrell post‐doctoral perfection grants by the Ministerio de Ciencia, Innovación y Universidades of Spain (CP18/00111 and CD18/00091, respectively).

Wild boar (Sus scrofa ) is considered as the main wildlife reservoir of zoonotic hepatitis E virus (HEV) genotypes. The aim of this study was to evaluate the circulation of HEV in free‐ranging wild boar in the Doñana National Park (DNP), Spain. Blood samples were collected from 99 wild boar in the DNP during 2015. Sera were analysed in parallel using indirect ELISA and real‐time RT‐PCR. A total of 57 of the 99 tested animals (57.6%; 95%CI: 47.8%–67.3%) had anti‐HEV antibodies, indicating that this virus is widespread in wild boar in the DNP. HEV RNA was detected in one animal and phylogenetic analysis showed that the sequence isolated belonged to subtype 3r. The results suggest a potential risk of zoonotic transmission of this novel HEV‐3 subtype, which could be of public health concern. Further studies are required to assess the role of wild boar in the epidemiology of HEV‐3r and to determine the infectivity of this emergent HEV subtype in other species, including humans., This work was partially supported by the Ministerio de Sanidad (RD12/0017/0012) included in the Plan Nacional de I+D+I and co‐financed by the Fundación para la Investigación en Salud (FIS) del Instituto Carlos III (PI16/01297), the ISCIII‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER) and the Spanish Ministry of Economy and Competitiveness (MINECO) (AGL2016‐76358‐R). J. Caballero‐Gómez is supported by the FPU grant of the Spanish Ministry of Education, Culture and Sport (FPU17/01319). J.A. Barasona is supported by MINECO‐UCM through a “Juan de la Cierva” contract (FJCI‐2015‐23643). A. Rivero‐Juarez is the recipient of a Miguel Servet Research Contract by the Ministerio de Ciencia, Promoción y Universidades of Spain (CP18/00111).

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series., The authors would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Fundacion bancaria La Caixa, Grifols SA, Fundacio ACE, and ISCIII (Ministry of Health, Spain). They also want to thank the private sponsors who support the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A., and Fundacio ACE). They are indebted to the Trinitat Port-Carbo legacy and her family for their support of Fundacio ACE research programs. Fundacio ACE is a participating center in the Dementia Genetics Spanish Consortium (DEGESCO). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, and PI17/01474. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de Hacer Europa). L.M.R. is supported by Consejeria de Salud de la Junta de Andalucia (grant PI-0001/2017). Control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed after standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. The present work was performed as part of the Biochemistry, Molecular Biology, and Biomedicine doctoral program of S. MorenoGrau at Universitat Autonoma de Barcelona (Barcelona, Spain).r Data collection and sharing for this project was partially funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie; the Alzheimer's Association; the Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study was coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California.; r The AddNeuroMed data are from a public-private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an integrated project funded by the European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5. Clinical leads responsible for data collection are Iwona K1oszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse). Imaging leads are Andy Simmons (London), Lars-Olad Wahlund (Stockholm), and Christian Spenger (Zurich). Bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London).r Funding support for the Alzheimer's Disease Genetics Consortium (ADGC) was provided through the NIA Division of Neuroscience (U01-AG032984).r The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Ertekin-Taner and Dr. Steven G. Younkin at the Mayo Clinic in Jacksonville, FL, used samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949, NINDS grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation.r The Neocodex-Murcia study was funded by the Fundacion Alzheimur (Murcia), the Ministerio de Educacion y Ciencia (Gobierno de Espana), Corporacion Tecnologica de Andalucia, Agencia IDEA (Consejeria de Innovacion, Junta de Andalucia), the Diabetes Research Laboratory, and the Biomedical Research Foundation. University Hospital Clinico San Carlos has been supported by CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM); CIBERDEM is an ISCIII Project.r The ROS/MAP study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984 and U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute.r The TGEN study was supported by Kronos Life Science Laboratories, the National Institute on Aging (Arizona Alzheimer's Disease Center grants P30 AG19610 and RO1 AG023193, the Mayo Clinic Alzheimer's Disease Center grant P50 AG16574, and the Intramural Research Program), the National Alzheimer's Coordinating Center (U01 AG016976), and the state of Arizona.r The authors thank the International Genomics of Alzheimer's Project (IGAP) for providing summary result data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chip was funded by the French National Foundation on Alzheimer's disease and related disorders. European Alzheimer's Disease Initiative (EADI) was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universite de Lille 2, and the Lille University Hospital. GERAD was supported by the Medical Research Council (grant no. 503480), Alzheimer's Research UK (grant no. 503176), the Wellcome Trust (grant no. 082604/2/07/Z), and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no.; 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC-10-196728.

Infeccions pel VIH; Factors de risc mèdics; Profilaxi preexposició Infecciones por VIH; Factores de riesgo médicos; Profilaxis preexposición HIV infections; Medical risk factors; Pre-exposure prophylaxis Background Pre-exposure prophylaxis (PrEP) is an effective and cost-effective strategy for HIV prevention. Spain carried out an implementation study in order to assess the feasibility of implementing PrEP programmes within its heterogeneous health system. Methods Observational longitudinal study conducted on four different types of health-care setting: a community centre (CC), a sexually transmitted infections clinic (STIC), a hospital-based HIV unit (HBHIVU) and a hospital-based STI unit (HBSTIU). We recruited gay, bisexual and other men who have sex with men (GBSM) and transgender women at risk of HIV infections, gave them PrEP and monitored clinical, behavioural PrEP-related and satisfaction information for 52 weeks. We collected perceptions on PrEP implementation feasibility from health-care professionals participating in the study. Results A total of 321 participants were recruited, with 99.1% being GBMSM. Overall retention was 87.2% and it was highest at the CC (92.6%). Condom use decreased during the study period, while STIs did not increase consistently. The percentage of people who did not miss any doses of PrEP during the previous week remained at over 93%. No HIV seroconversions occurred. We observed overall decreases in GHB (32.5% to 21.8%), cocaine (27.5% to 21.4%), MDMA (25.7% to 14.3%), speed (11.4% to 5.7%) and mephedrone use (10.7% to 5.0%). The overall participant satisfaction with PrEP was 98.6%. Health-care professionals’ perceptions of PrEP feasibility were positive, except for the lack of personnel. Conclusions PrEP implementation is feasible in four types of health-care settings. Local specificities have to be taken into consideration while implementing PrEP. This study has been conducted with the resources from the National AIDS Programme ant those from the participating study centers. Gilead donated the drug administered in the study. Donors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Some authors are employed by BCN Checkpoint. BCN Checkpoint is a Community Centre run by an NGO. BCN Checkpoint did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of author PC. The specific roles of this author is articulated in the ‘author contributions’ section.

© 2020 by the authors., The aim of this review is to shed light over the most recent advances in Coenzyme Q10 (CoQ10) applications as well as to provide detailed information about the functions of this versatile molecule, which have proven to be of great interest in the medical field. Traditionally, CoQ10 clinical use was based on its antioxidant properties; however, a wide range of highly interesting alternative functions have recently been discovered. In this line, CoQ10 has shown pain-alleviating properties in fibromyalgia patients, a membrane-stabilizing function, immune system enhancing ability, or a fundamental role for insulin sensitivity, apart from potentially beneficial properties for familial hypercholesterolemia patients. In brief, it shows a remarkable amount of functions in addition to those yet to be discovered. Despite its multiple therapeutic applications, CoQ10 is not commonly prescribed as a drug because of its low oral bioavailability, which compromises its efficacy. Hence, several formulations have been developed to face such inconvenience. These were initially designed as lipid nanoparticles for CoQ10 encapsulation and distribution through biological membranes and eventually evolved towards chemical modifications of the molecule to decrease its hydrophobicity. Some of the most promising formulations will also be discussed in this review., This work was supported by FIS PI16/00786 and FIS PI19/00377 grants, Instituto de Salud Carlos III, Ministerio de Sanidad, Spain, and Fondo Europeo de Desarrollo Regional (FEDER Unión Europea), Ayudas para la Formación de Profesorado Universitario (FPU), Ministerio de Ciencia e innovación, AEPMI (Asociación de Enfermos de Patología Mitocondrial), and ENACH (Asociación de enfermos de Neurodegeneración con Acumulación Cerebral de Hierro).

[Objectives]: Our objective was to identify patient factors associated with being untreated for hepatitis C virus (HCV) infection in HIV-coinfected patients., [Methods]: A prospective longitudinal study was carried out. HIV-infected patients with active chronic HCV infection included in the HERACLES cohort (NCT02511496) constituted the study population. The main study outcome was receipt of HCV direct-acting antiviral (DAA) treatment from 1 May 2015 to 1 May 2017. The population was divided into patients who were receiving HCV treatment during follow-up and those who were not., [Results]: Of the 15 556 HIV-infected patients in care, 3075 (19.7%) presented with chronic HCV infection and constituted the study population. At the end of the follow-up, 1957 patients initiated HCV therapy (63.6%). Age < 50 years, absence of or minimal liver fibrosis, being treatment-naïve, HCV genotype 3 infection, being in the category of people who inject drugs using opioid substitutive therapy (OST-PWID), and being in the category of recent PWID were identified as significant independent risk factors associated with low odds of DAA implementation. When a multivariate analysis was performed including only the PWID population, both OST-PWID [odds ratio (OR) 0.552; 95% confidence interval (CI) 0.409–0.746) and recent PWID (OR 0.019; 95% CI 0.004–0.087) were identified as independent factors associated with low odds of treatment implementation., [Conclusions]: We identified factors, which did not include prioritization of a DAA uptake strategy, that limited access to HCV therapy. The low treatment uptake in several populations seriously jeopardizes the elimination of HCV infection in the coming years., This work was supported by the Ministerio de Sanidad (RD12/0017/0012) integrated in the Plan Nacional de I+D+I, and cofinanced by the ISCIII‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), the Fundación para la Investigación en Salud (FIS) del Instituto Carlos III (PI15/01017), and the Red de Investigación en SIDA de España ISCIII‐RETIC (grant number: RD16/0025/0034).

© 2018 Hernández-Camacho, Bernier, López-Lluch and Navas., Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility., This work has been partially funded by the Spanish Ministry of Health, Instituto de Salud Carlos III (ISCIII), FIS PI14-01962, and the Andalusian Government grant BIO177 (FEDER funds of European Commission). JH-C has been awarded by CIBERER, Instituto de Salud Carlos III. This work was also supported, in part, by the Intramural Research Program of the National Institute on Aging, NIH.

BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand crosslinking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency, Surrallés laboratory is supported by the ICREA-Academia program, the Marató de TV3 (project 464/C/2012), the Spanish Ministry of Health (projects FANCOSTEM and FANCOLEN), the Spanish Ministry of Economy and Competiveness (projects CB06/07/0023, SAF2012-31881, SAF2013-45836-R and SAF2015-64152-R), the European Commission (EUROFANCOLEN project HEALTH-F5-2012-305421 and P-SPHERE COFUND project), the Fanconi Anemia Research Fund Inc., and the “Fondo Europeo de Desarrollo Regional, una manera de hacer Europa” (FEDER). CIBERER is an initiative of the Instituto de Salud Carlos III, Spain. This work was also supported by grants from the Asociación Española Contra el Cáncer (AECC, Hereditary Cancer group, 2010), the Generalitat de Catalunya (SGR 2014-364 and 2014-338), and the Instituto de Salud Carlos III (PIE13/00022-ONCOPROFILE, CP10/00617, PI10/01422, PI12/02585, PI13/00285, PI15/00854, PI16/00563, PI16/01218, and RTICC RD12/0036/0008). S.G.-E. is funded by a Miguel Servet contract from the Instituto de Salud Carlos III.

Recent studies point to the cannabinoid CB2 receptors (CB2r) and the non-cannabinoid receptor GPR55 as potential key targets involved in the response to stress, anxiety, and depression. Considering the close relationship between neuropsychiatric disorders and suicide, the purpose of this study was to evaluate the potential alterations of CB2r and GPR55 in suicide victims. We analyzed gene and protein expression of both receptors by real-time PCR and western blot, respectively, in the dorsolateral prefrontal cortex (DLPFC) of 18 suicide victims with no clinical psychiatric history or treatment with anxiolytics or antidepressants, and 15 corresponding controls. We used in situ proximity ligation assay to evaluate whether the receptors formed heteromeric complexes and to determine the expression level of these heteromers, also assessing the co-expression of heteromers in neurons, astroglia, or microglia cells. CB2r and GPR55 gene expressions were significantly lower (by 33 and 41%, respectively) in the DLPFC of suicide cases. CB2r protein expression was higher, as were CB2-GPR55 heteroreceptor complexes. The results also revealed the presence of CB2-GPR55 receptor heteromers in both neurons and astrocytes, whereas microglial cells showed no expression. We did not observe any significant alterations of GPR55 protein expression. Additional studies will be necessary to evaluate if these alterations are reproducible in suicide victims diagnosed with different psychiatric disorders. Taken together, the results suggest that CB2r and GPR55 may play a relevant role in the neurobiology of suicide., This research was supported by grants from the Ministry of Science and Innovation (RETICS16/0017/0014) and Ministry of Health (PNSD 2015IO16, FIS PI14/00438) to JM, grants 2014-SGR-1236 from Generalitat de Catalunya and 201413-30 from the Fundació La Marató de TV3 to RF, and grants from Ministry of Science and Innovation (BFU2012-37907), Fundació La Marató TV3 (grant numbers 201413330 and 201441331) to JL.

© 2018 Hernández-Camacho, Bernier, López-Lluch and Navas. Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility. This work has been partially funded by the Spanish Ministry of Health, Instituto de Salud Carlos III (ISCIII), FIS PI14-01962, and the Andalusian Government grant BIO177 (FEDER funds of European Commission). JH-C has been awarded by CIBERER, Instituto de Salud Carlos III. This work was also supported, in part, by the Intramural Research Program of the National Institute on Aging, NIH.

On behalf of the HELENA Study Group., [Background and aims]: The ideal cardiovascular health (iCVH) construct consists of 4 health behaviors (smoking status, body mass index, physical activity and diet) and 3 health factors (total cholesterol, blood pressure and fasting glucose). A greater number of iCVH components in adolescence are related to better cardiovascular health, but little is known about the correlates of iCVH in adolescents. Thus, the aim of the study was to examine correlates of iCVH in European adolescents., [Methods and results]: The study comprised 637 European adolescents with complete iCVH data. Participants were part of the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study, a cross-sectional, multicenter study conducted in 9 different European countries. Correlates investigated were sex and age, family affluence scale, maternal education, geographic location, sleep time, television viewing, duration of pregnancy, birth weight and breastfeeding. Younger adolescents, those whose mothers had medium/high education or those who watched television less than 2 h per day had a greater number of iCVH components compared to those who were older, had a mother with low education or watched television 2 h or more daily (P ≤ 0.01)., [Conclusion]: Since in our study older adolescents had worse iCVH than younger adolescents, early promotion of cardiovascular health may be important. Future studies may also investigate the usefulness of limiting television viewing to promote iCVH. Finally, since adolescents of mothers with low education had poorer iCVH, it may be of special interest to tailor public health promotion to adolescents from families with low socioeconomic status., The HELENA project was supported by the European Community Sixth RTD Framework Programme (contract FOOD-CT-2005-007034). The data for this study was gathered under the aegis of the HELENA project, and further analysis was additionally supported by the Spanish Ministry of Economy and Competitiveness (grants RYC-2010-05957 and RYC-2011-09011), the Spanish Ministry of Health: Maternal, Child Health and Development Network (grant RD16/0022), the Fondo Europeo de Desarrollo Regional (MICINN-FEDER) and by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES). Pontus Henriksson was supported by a grant from Henning and Johan Throne-Holst Foundation. Hanna Henriksson was supported by grants from the Swedish Society of Medicine and the County Council of Östergötland, Sweden. Dr. Gracia-Marco acknowledges “Programa de Captación de Talento - UGR Fellows” as part of “Plan Propio” of the University of Granada (Spain).

There is evidence that endogenous cannabinoids (eCBs) play a role in the control of the hypothalamic–pituitary–adrenal (HPA) axis, although they appear to have dual, stimulatory and inhibitory, effects. Recent data in rats suggest that eCBs, acting through CB1 receptors (CB1R), may be involved in adaptation of the HPA axis to daily repeated stress. In the present study we analyze this issue in male mice and rats. Using a knock-out mice for the CB1 receptor (CB1−/−) we showed that mutant mice presented similar adrenocorticotropic hormone (ACTH) response to the first IMO as wild-type mice. Daily repeated exposure to 1 h of immobilization reduced the ACTH response to the stressor, regardless of the genotype, demonstrating that adaptation occurred to the same extent in absence of CB1R. Prototypical changes observed after repeated stress such as enhanced corticotropin releasing factor (CRH) gene expression in the paraventricular nucleus of the hypothalamus, impaired body weight gain and reduced thymus weight were similarly observed in both genotypes. The lack of effect of CB1R in the expression of HPA adaptation to another similar stressor (restraint) was confirmed in wild-type CD1 mice by the lack of effect of the CB1R antagonist AM251 just before the last exposure to stress. Finally, the latter drug did not blunt the HPA, glucose and behavioral adaptation to daily repeated forced swim in rats. Thus, the present results indicate that CB1R is not critical for overall effects of daily repeated stress or proper adaptation of the HPA axis in mice and rats., Supported by grants SAF2011-28313, RD06/0001/0015 (Instituto de Salud Carlos III, Redes temáticas de Investigación Cooperativa en Salud) and SGR2009-16 to A.A. and supported by grants from the Ministry of Science and Innovation (SAF 2008-01106) and Ministry of Health (RETICS-FEDER RD06/0001/1004 and PNSD 2007/061) to J.M. C.R., R.D-M and M.S.G-G were predoctoral fellows of the Ministry of Science and Innovation (MICINN). A.R was supported by RETICS.

[Objectives]: Previous research showed that low concentration of biomarkers in the blood during adolescence (i.e., iron status; retinol; and vitamins B6, B12, C, and D) may be involved in the early stages of development of many chronic diseases, such as hypertension. The aim was to evaluate if iron biomarkers and vitamins in the blood are associated with blood pressure in European adolescents., [Methods]: Participants from the Healthy Lifestyle in Europe by Nutrition in Adolescence cross-sectional study (N = 1089; 12.5–17.5 y; 580 girls) were selected by complex sampling. Multilevel linear regression models examined the associations between iron biomarkers and vitamins in the blood and blood pressure; the analyses were stratified by sex and adjusted for contextual and individual potential confounders., [Results]: A positive association was found in girls between RBC folate concentration and systolic blood pressure (SBP) (β = 3.19; 95% confidence interval [CI], 0.61–5.77), although no association between the vitamin serum biomarkers concentrations and diastolic blood pressure (DBP) was found. In boys, retinol was positively associated with DBP (β = 3.84; 95% CI, 0.51–7.17) and vitamin B6 was positively associated with SBP (β = 3.82; 95% CI, 1.46–6.18). In contrast, holotranscobalamin was inversely associated with SBP (β = −3.74; 95% CI, −7.28 to −0.21)., [Conclusions]: Levels of RBC folate and vitamin B6 in blood may affect BP in adolescents. In this context, programs aimed at avoiding high BP levels should promote healthy eating behavior by focusing on the promotion of vegetable proteins and foods rich in vitamin B12 (i.e., white meat and eggs), which may help to achieve BP blood control in adolescents., The HELENA Study was financially support by the European Community SixthRTD Framework Programme (contract FOOD-CT-2005-007034). The writing group takes sole responsibility for the content of this article. This study was also supported by a grant from the Spanish Ministry of Health: Maternal, Child Health and Development Network (number RD08/0072), grant from the Spanish Ministry of Education (EX-2008-0641; AP-2008-03806) and the Swedish Heart-Lung Foundation (20090635). ACdeM received scholarship from S~ao PauloResearch FoundationdFAPESP (proc. 2011/11137-1 and 2011/20662-2). LAM received scholarship of visiting professor from the Brazilian government by Science without Borders Program by CNPq (National Counsel of Technological and Scientific Development) and CAPES (Coordination of Improvement of Higher Education Personnel) (proc. 007/2012). The GENUD Research Group cofinancedby the European Regional Development Fund (MICINN-FEDER)

Recent studies have associated alterations of neuronal plasticity in specific brain areas with suicidal behavior. The Notch signaling pathway plays a relevant role in the control of stem cell maintenance, cell migration, and neuronal plasticity. In the present study, the gene expression of the four Notch receptors (NOTCH1-4), the five canonical ligands (DLL1, DLL3, DLL4, JAGGED1, and JAGGED2), the two non-canonical ligands (DLK1 and DLK2), and the transcription factors (HES1, HEY1, and HEY2) were measured in the dorsolateral prefrontal cortex (DLPFC) and amygdala (AMY) of suicide victims (S; n = 13 males, with no clinical psychiatric history and non-treated with anxiolytic or antidepressant drugs) and their corresponding controls (C; n = 13 males) by real-time PCR. The results revealed a reduction of NOTCH2 and NOTCH1, NOTCH3, and NOTCH4 gene expression in the DLPFC and AMY of S compared with C, respectively. DLL1 levels were increased in the DLPFC and decreased in the AMY, whereas DLL4, JAGGED1, and JAGGED2 were significantly decreased in the regions analyzed. DLK1 was reduced in the AMY, whereas no changes were observed in the DLPFC and in DLK2 expression levels in any of the regions analyzed. HES1 was significantly reduced in both brain regions from S, whereas there were no significant changes in HEY1 and HEY2. This study provides evidence suggesting that the Notch signaling pathway could be a potential key target in the treatment of suicidal behaviors., This research was supported by grants from Ministry of Science and Innovation (SAF 2008–01106, RETICS RD12/0028/0019, and FEDER) and Ministry of Health (PNSD 2007/061). FN is a postdoctoral fellow of the RETICS RD12/0028/0019.

Recent reports suggest that FKBP5 gene and its corresponding FKBP5 protein play a relevant role in the regulation of anxiety and depression in animal models and human stress-related disorders. In the present study, FKBP5 and glucocorticoid receptor (GR) gene and protein expression were analyzed in the amygdala (AMY) of suicide victims (n = 13 males, without clinical psychiatric history and non-treated with anxiolytic or antidepressant drugs) and its corresponding controls (n = 13 males) by real-time PCR and Western blotting. The results revealed that FKBP5 and GR gene expression were significantly reduced in the AMY (−38% and −48%, respectively) of suicide victims compared with controls. Interestingly, FKBP5 and GR protein expression were also significantly decreased (−41% and −42%, respectively) in the AMY of suicide victims compared with controls. These results suggest that the FKBP5 plays a relevant role in human emotional responses and suggest this receptor as a new promising target in the treatment of suicide behavior., This research was supported by grants from Ministry of Science and Innovation (SAF 2008-01106 and RETICS RD06/0001/1004), Ministry of Health (PNSD 2007/061) and “Red Temática de Investigación Cooperativa en Salud” (RETICS, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain, “Red de Trastornos Adictivos”, RD06/0001/1004). JMP-O is a postdoctoral fellow supported by FISCAM (Fundación para la investigación sanitaria en Castilla La Mancha). FN is a predoctoral fellow of the Ministry of Education.

Adult hippocampal neurogenesis (AHN) is a key process for certain types of hippocampal-dependent learning. Alzheimer’s disease (AD) is accompanied by memory deficits related to alterations in AHN. Given that the increased activity of GSK-3β has been related to alterations in the population of hippocampal granule neurons in AD patients, we designed a novel methodology by which to induce selective GSK-3β overexpression exclusively in newborn granule neurons. To this end, we injected an rtTA-IRES-EGFP-expressing retrovirus into the hippocampus of tTO-GSK-3β mice. Using this novel retroviral strategy, we found that GSK-3β caused a cell-autonomous impairment of the morphological and synaptic maturation of newborn neurons. In addition, we examined whether GSK-3β overexpression in newborn neurons limits the effects of physical activity. While physical exercise increased the number of dendritic spines, the percentage of mushroom spines, and the head diameter of the same in tet-OFF cells, these effects were not triggered in tet-ON cells. This observation suggests that GSK-3β blocks the stimulatory actions of exercise. Given that the activity of GSK-3β is increased in the brains of individuals with AD, these data may be relevant for non-pharmacological therapies for AD., Spanish Ministry of Health (SAF-2014-5040-P), and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII) (J. A ´ vila); the Japan Society for the promotion of Science (post-doctoral fellowship to M. Llorens-Martín); and the Alzheimer’s Association (2015-NIRG-340709

The purpose of this study was to evaluate the effects of early life stress on the vulnerability to ethanol consumption in adolescence. To this aim, mice were separated from their mothers for 12 hours/day on postnatal days 8 and 12. Emotional behavior (light-dark box, elevated plus maze and tail suspension tests) and pre-attentional deficit (pre-pulse inhibition) were evaluated in adolescent maternal separated (MS) mice. Alterations of the corticotropin-releasing factor (CRF), glucocorticoid receptor (NR3C1), tyrosine hydroxylase (TH), mu-opioid receptor (MOr), brain-derived neurotrophic factor (BDNF), neuronal nuclei (NeuN), microtubule-associated protein 2 (MAP2) and neurofilament heavy (NF200)-immunoreactive fibers were studied in the paraventricular nucleus of the hypothalamus (PVN), ventral tegmental area (VTA), nucleus accumbens (NAc) or hippocampus (HIP). The effects of maternal separation (alone or in combination with additional stressful stimuli) on ethanol consumption during adolescence were evaluated using the oral ethanol self-administration paradigm. MS mice presented mood-related alterations and pre-attentional deficit. Increased CRF, MOr and TH, and reduced BDNF, NR3C1, NeuN, MAP2 and NF200-immunoreactive fibers were observed in the PVN, NAc and HIP of adolescent MS mice. In the oral ethanol self-administration test, adolescent MS mice presented higher ethanol consumption and motivation. Exposure to additional new stressful stimuli during adolescence significantly increased the vulnerability to ethanol consumption induced by maternal separation. These results clearly demonstrated that exposure to early life stress increased the vulnerability to ethanol consumption, potentiated the effects of stressful stimuli exposure during adolescence on ethanol consumption and modified the expression of key targets involved in the response to stress, ethanol reinforcing properties and cognitive processes., This research was supported by grants from the Ministry of Health (PNSD 2011/043) and ‘Red Temática de Investigación Cooperativa en Salud’ (RETICS, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain, ‘Red de Trastornos Adictivos’, RD06/0001/1004) to J.M.

13 pags, 6 figs, 1 tab. -- Supplementary information is available at the Publisher's web, Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists., This work was funded by the Spanish Ministry of Economy and Competitiveness (BFU2013-44763 to S.V., BFU2012-37116 to D.R., RTC-2014-1931-1 to R.I. and BFU2013-47064-P to A.V.-C.), by SUDOE INTERREG IV B (SOE4/P1/E831 to S.V. and A.V.-C.), by the Spanish Ministry of Science and Innovation (BFU2010-19451 to A.V.-C.), by Diputacion General de Aragon (Protein Targets Group B89 to A. V.-C.) and by the National Institutes of Health (NIA, AG-032285 to N. Reixach). S.V. has been granted an ICREA ACADEMIA award. SOM Biotech was funded by the Spanish Ministry of Health DIN 10-13 grant and the Catalan Competitiveness Agency FINEBT10-2-0037 grant. N. Reig and R.I. were funded by a Torres Quevedo grant by the Spanish Ministry of Economy and Competitiveness. R.S. was supported by CAPES-Science without Borders and S.E. by Consejo Nacional de Promocion Cientifica y Tecnologica (CONICET). We also thank Dr. Debora Foguel for the WT-TTR plasmid used in this study to produce recombinant WT-TTR and Dr Antoni Planas and Dr Ellen Cotrina for technical work. The human cardiac AC16 cell line was developed by Mercy M Davidson at Columbia University46. X-ray experiments were performed at the BL-13 beamline at the ALBA synchrotron in collaboration with the ALBA staff.

The strong association of CD4 count at start of combination therapy with subsequent survival in HIV-infected patients diminished during the first 5 years of treatment. After 5 years, lower baseline CD4 counts were not associated with higher mortality., Background. CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. Methods. We estimated mortality rates (MRs) by time since start of ART (

PTTG1, also known as securin, is an inactivating partner of separase, the major effector for chromosome segregation during mitosis. At the metaphase-to-anaphase transition, securin is targeted for proteasomal destruction by the anaphase-promoting complex or cyclosome, allowing activation of separase. In addition, securin is overexpressed in metastatic or genomically instable tumors, suggesting a relevant role for securin in tumor progression. Stability of securin is regulated by phosphorylation; some phosphorylated forms are degraded out of mitosis, by the action of the SKP1-CUL1-F-box protein (SCF) complex. The kinases targeting securin for proteolysis have not been identified, and mechanistic insight into the cause of securin accumulation in human cancers is lacking. Here, we demonstrate that glycogen synthase kinase-3β (GSK3β) phosphorylates securin to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase. Importantly, a strong correlation between securin accumulation and GSK3β inactivation was observed in breast cancer tissues, indicating that GSK3β inactivation may account for securin accumulation in breast cancers. Ministerio de Ciencia e Innovación de España SAF2008-03095 y SAF2008-05046 Ministerio de Sanidad de España y Fondo Europeo de Desarrollo Regional (FEDER) ISCIII-RETIC-RD06/0020-FEDER Dirección General de Investigación, Tecnología y Empresa, Junta de Andalucía P08-CVI-03603 y PI09-0589

It was recently suggested that tau protein released as a result of neuronal death is toxic to neighbouring cells, an effect that is mediated through the activation of muscarinic M1 and/or M3 receptors. Nevertheless, why tau protein and not other native muscarinic agonists, like ACh, can induce this neurotoxicity remains unknown. To clarify this issue, we analysed the different responses and properties of muscarinic receptors in response to stimulation by tau or ACh. The results revealed that the tau protein has an affinity for muscarinic receptors of around one order of magnitude higher than that of ACh. Furthermore, while the repeated stimulation with ACh induces desensitization of the muscarinic receptors, reiterate stimulation with tau failed to produce this phenomenon. Finally, we found the tau protein to be very stable in the extracellular milieu. These studies provide valuable information to help understand tau toxicity on neural cells bearing M1 or M3 muscarinic receptors and its contribution to neurodegenerative progression in tauopathies., This study was funded by grants from the Spanish Ministry of Health (SAF 2006-02424), Ciberned (CB06/05/0035), Noscira (2008/285), Comunidad de Madrid (SAL/0202/2006), Fundación M. Botín and Fundación R. Areces.

Alzheimer's disease (AD) is a complex disease, with no definitive biomarkers available that allow clinical diagnosis; this represents a major problem for the advance of efficient drug discovery programs. A successful approach towards the understanding and treatment of AD should take into consideration this complex nature. In this sense, metabolic networks are subject to severe stoichiometric restrictions. Metabolomics amplifies changes both in the proteome and the genome, and represents a more accurate approximation to the phenotype of an organism in health and disease. In this article, we will examine the current rationale for metabolomics in AD, its basic methodology and the available data in animal models and human studies. The discussed topics will highlight the importance of being able to use the metabolomic information in order to understand disease mechanisms from a systems biology perspective as a non-invasive approach to diagnose and grade AD. This could allow the assessment of new therapies during clinical trials, the identification of patients at risk to develop adverse effects during treatment and the final implementation of new tools towards a more personalized medicine., This work was supported by grants from the SpanishMinistry of Health (PI052056; PI061641 to D.P) and the Spanish Ministryof Science (SAF2007–29418-E to D.P). DP's laboratory is part of thenational cooperative research network in multiple sclerosis RETIC-REEM,Spanish Ministry of Health. IB's and DGD's laboratory is part of the nationalcooperative research network in cardiovascular diseases RETIC-RECAVA,Spanish Ministry of Health.

Recent experimental data suggest that mood disorders are related to inflammatory phenomena and have led to the "inflammatory hypothesis of depression". Given that the hippocampus is one of the most affected areas in these disorders, we used a model of acute stress (the Porsolt test) to evaluate the consequences of forced swimming on two crucial events related to the pathophysiology of major depression: the functional maturation of newborn granule neurons; and the hippocampal inflammatory milieu. Using PSD95:GFP-expressing retroviruses, we found that forced swimming selectively alters the dendritic morphology of newborn neurons and impairs their connectivity by reducing the number and volume of their postsynaptic densities. In addition, acute stress triggered a series of morphological changes in microglial cells, together with an increase in microglial CD68 expression, thus suggesting the functional and morphological activation of this cell population. Furthermore, we observed an intriguing change in the hippocampal inflammatory milieu in response to forced swimming. Importantly, the levels of several molecules affected by acute stress (such as Interleukin-6 and eotaxin) have been described to also be altered in patients with depression and other mood disorders., Spanish Ministry of Health (SAF-2014-5040-P), and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII) (J. Ávila); and the Alzheimer’s Association (2015-NIRG-340709) (M. Llorens-Martín).

[Objectives]: This study aimed to explore the associations of liver biomarkers with cardiometabolic risk factors and their clustering, and to provide reference values (percentiles) and cut-off points for liver biomarkers associated with high cardiometabolic risk in European adolescents., [Methods]: Alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), aspartate aminotransferase to ALT ratio (AST/ALT), waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol and insulin were measured in 1084 adolescents. We computed a continuous cardiometabolic risk score and defined the high cardiometabolic risk., [Results]: Higher ALT and GGT and lower AST/ALT were associated with adiposity and with the number of adverse cardiometabolic risk factors (Ps, [Conclusions]: Higher GGT and lower AST/ALT are associated with higher cardiometabolic risk factors and their clustering in male and female European adolescents, whereas the associations of ALT were gender dependent. Our results suggest the usefulness of AST/ALT as a screening test in the assessment of adolescents with high cardiometabolic risk and provide gender- and age-specific thresholds that might be of clinical interest., The HELENA study was carried out with the financial support of the European Community Sixth RTD Framework Programme (contract FOODCT-2005-007034). This work was also supported by grants from Spanish Ministry of Economy and Competitiveness (RYC-2010-05957; RYC-2011-09011) and the Spanish Ministry of Health: Maternal, Child Health and Development Network (no. RD08/0072).

A channel open on the membrane can be formed by palytoxin (PTX). Ten nanomolar PTX caused an irreversible increase in the cytosolic calcium concentration ([Ca2+]c), which was abolished in the absence of external calcium. The increase was eliminated by saxitoxin (STX) and nifedipine (NIF). Calcium rise is secondary to the membrane depolarization. PTX effect on calcium was dependent on extracellular Na+. Li+ decreased the PTX-evoked rise in [Ca2+]c; replacement of Na+ by N-methyl-D-glucamine (NMDG) abolished PTX-induced calcium increase. [Ca2+]c increase by PTX was strongly reduced after inhibition of the reverse operation of the Na+/Ca2+ exchanger, in the presence of antagonists of excitatory amino acid (EAA) receptors, and by inhibition of neurotransmitter release. PTX did not modify calcium extrusion by the plasma membrane Ca2+-ATPase (PMCA), because blockade of the calcium pump increased rather than decreased the PTX-induced calcium influx. Extracellular levels of glutamate and aspartate were measured by HPLC and exocytotic neurotransmitter release by determination of synaptic vesicle exocytosis using total internal reflection fluorescence microscopy (TIRFM). PTX caused a concentration-dependent increase in EAA release to the culture medium. Ten nanomolar PTX decreased cell viability by 30% within 5 min. PTX-induced calcium influx involves three pathways: Na+-dependent activation of voltage-dependent sodium channels (VDSC) and voltage-dependent calcium channels (VDCC), reverse operation of the Na+/Ca2+ exchanger, and indirect activation of EAA receptors through glutamate release. The neuronal injury produced by the toxin could be partially mediated by the PTX-induced overactivation of EAA receptors, VDSC, VDCC and the glutamate efflux into the extracellular space. © 2006 Wiley-Liss, Inc., This work was funded with grants SAF2003-08765-C03-02, SAF-FEDER 2003-04930, REN2001-2959-C04-03, REN2003-06598-C02-01, INIA CAL01-068 (Ministerio de Ciencia y Technología), AGL2004-08268-02-O2/ALI, PGIDT99INN26101, PGIDIT03AL26101PR (Xunta de Galicia, Spain), FISS REMA-G03-007 (Fondo de Investigaciones Sanitarias), EU VIth Frame Program FOOD-CT-2004-06988 (BIOCOP), and FOOD-CT-2004-514055 (DETECTOX).

We reexamined tyrosine-kinase receptor EphA7 RNA signal in embryonic chicken forebrain, to clarify its topographic relationships with early regionalization processes, such as establishment of prosomeric boundaries. After neurulation, uniform alar expression appears across prospective prosomeres prosomere 1, prosomere 2 and prosomere 3 (prethalamus, thalamus and pretectum). This pattern soon changes by differential downregulation at or in between some of the prosomeric boundaries in an individual pattern for each limit, and by expansion of expression into the rostral midbrain. The secondary distribution highlights various transversal and longitudinal domains, notably the zona limitans intrathalamica and the pretectum limits, as well as two longitudinal bands in the basal plate, termed paramedian and parabasal. Strong expression of EphA7 appears at the mammillary pouch and a supramammillary tegmental arch from stage Hamburger and Hamilton stages 14–15 onwards. At the end of the developmental period examined, expression of EphA7 in the ventricular zone decreases generally (with some exceptions) and novel expression domains start to appear in the mantle layer, initiating a third phase of differential expression. Thus, while the expression of EphA7 does not show a fixed functional or topographic relationship to prosomeric boundaries, sequential transcription changes during chicken development are consistent with a differential involvement of the diverse interprosomeric boundaries, as well as dorsoventral patterning organizers, in the regulation of EphA7 expression., The present study was supported by grants from Spanish Ministry of Science and Technology (PB2002-03668, BFU2005-09378-C02-01/BFI to L.P.) and Spanish Ministry of Health (FIS C3/06 Red CIEN) to L.P., and doctoral fellowship of E.G.C. We thank M.A.Nieto, J. R. L. Rubenstein, C. M. Fan, P. Bovolenta and A. McMahon for plasmids. The anti-Pax7 monoclonal antibody developed by A. Kawakami was obtained from the Developmental Studies Hybridoma Bank (developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA 52242, USA).

Changes in intracellular pH (pHi) and cytosolic calcium concentration ([Ca2+]c) caused by the glutamate agonist domoate (DOM) were studied in single cultured mouse cerebellar granule cells (CGC) by using the fluorescent probes 2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM) and simultaneous evaluation of cytosolic calcium concentration with the fluorescent dye Fura-2 acetoxymethyl ester (Fura-2 AM). DOM caused a concentration-dependent increase in [Ca2+]c and a concentration-dependent intracellular acidification of CGC. DOM-induced intracellular acidification was completely abolished by the use of Ca2+-free medium, suggesting that it was due mostly to an influx of extracellular calcium. The pHi decrease caused by DOM was also completely blocked in the presence of the AMPA/kainate receptor antagonist CNQX, indicating that the DOM-induced intracellular acidification was caused by DOM activation of the AMPA/kainate subtype of glutamate receptors. Different mechanisms that could be involved in DOM-induced pHi decrease, such as displacement of H+ by Ca2+ from a common intracellular binding site, DOM-induced alteration of pHi regulation mechanisms, and a possible acidification caused by DOM-induced increase of mitochondrial Ca2+ uptake, were excluded. DOM-induced intracellular acidification was completely prevented by inhibitors of the plasma membrane calcium adenosine triphosphatase (ATPase) (PMCA), including orthovanadate, lanthanum extracellular pH of 8.5, and the specific PMCA inhibitor caloxin 2A1. Our results therefore indicate that PMCA is involved in DOM-induced intracellular acidification in primary cultures of CGC. Simultaneous recording of [Ca2+]c and pHi indicates that the increase in intracellular calcium evoked by DOM will activate the calcium extrusion mechanisms through the calcium pump, which, in turn, will decrease intracellular pH by countertransport of H+ ions., Ministerio de Ciencia y Tecnologı´a, Spain; Contract grant number: SAF2003-08765-C03-02; Contract grant number: REN2001-2959-C04-03; Contract grant number: REN2003-06598- C02-01; Contract grant number: AGL2004-08268-02-O2/ALI; Contract grant number: INIA CAL01-068; Contract grant number: SAF-FEDER 2003-0493; Contract grant sponsor: Xunta de Galicia, Spain; Contract grant number: PGIDT99INN26101; Contract grant number: PGIDIT03AL26101PR; Contract grant sponsor: Fondo de Investigaciones Sanitarias, Spain; Contract grant number: FISS REMA-G03-007; Contract grant sponsor: EU VIth Frame Program; Contract grant number: FOOD-CT-2004-06988 (BIOCOP); Contract grant number: FOODCT-2004-514055 (DETECTOX).