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62 páginas, 5 figuras, 2 tablas, Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C, The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R21AI160576), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JBP Foundation, the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10- LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANR GenMISC (ANR-21-COVR-039), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the ANR-RHU program (ANR-21-RHUS-08), the European Union’s Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the ANR-RHU Program ANR-21- RHUS-08 (COVIFERON), the Square Foundation, Grandir – Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), and Paris Cité University. We acknowledge support from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award R01AI104887 to R.H.S. and S.R.W. The Laboratory of Human Evolutionary Genetics (Institut Pasteur) is supported by the Institut Pasteur, the Collège de France, the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence “Integrative Biology of Emerging Infectious Diseases” (ANR-10-LABX-62-IBEID) and “Milieu Intérieur” (ANR-10-LABX-69-01), the Fondation de France (no. 00106080), the FRM (Equipe FRM DEQ20180339214 team), and the ANR COVID-19-POPCELL (ANR-21-CO14-0003-01). A.Puj. is supported by ACCI20-759 CIBERER, EasiGenomics H2020 Marató TV3 COVID 2021-31-33, the HORIZON-HLTH-2021-ID: 101057100 (UNDINE), the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342), and the CERCA Program/Generalitat de Catalunya. The Canarian Health System sequencing hub was funded by the Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), Fundación MAPFRE Guanarteme (OA21/131), and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). The CoV-Contact Cohort was funded by the French Ministry of Health and the European Commission (RECOVER project). Our studies are also funded by the Ministry of Health of the Czech Republic Conceptual Development of Research Organization (FNBr, 65269705) and ANID COVID0999 funding in Chile. G. Novelli and A. Novelli are supported by Regione Lazio (Research Group Projects 2020) No. A0375-2020-36663, GecoBiomark. A.M.P., M.L.D., and J.P.-T. are supported by the Inmungen-CoV2 project of CSIC. This work was supported in part by the Intramural Research Program of the NIAID, NIH. The research work of A.M..P, M.L.D., and J.P.-T. was funded by the European Commission –NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). I.M. is a senior clinical investigator at FWO Vlaanderen supported by a VIB GC PID grant, by FWO grants G0B5120N (DADA2) and G0E8420N, and by the Jeffrey Modell Foundation. I.M. holds an ERC-StG MORE2ADA2 grant and is also supported by ERN-RITA. A.Y. is supported by fellowships from the European Academy of Dermatology and Venereology and the Swiss National Science Foundation and by an Early Career Award from the Thrasher Research Fund. Y.-H.C. is supported by an A*STAR International Fellowship (AIF). M.O. was supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society (HNMS), the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the National Cancer Institute (NCI) F99 Award (F99CA274708). A.A.A. was supported by Ministerio de Ciencia Tecnología e Innovación MINCIENCIAS, Colombia (111584467551/CT 415-2020). D.L. is supported by a fellowship from the FRM for medical residents and fellows. E.H. received funding from the Bank of Montreal Chair of Pediatric Immunology, Foundation of CHU Sainte-Justine, CIHR grants PCC-466901 and MM1-181123, and a Canadian Pediatric Society IMPACT study. Q.P.-H. received funding from the European Union’s Horizon 2020 research and innovation program (ATAC, 101003650), the Swedish Research Council, and the Knut and Alice Wallenberg Foundation. Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, R01AI091707-10S1, and R01AI161444; a George Mason University Fast Grant; the G. Harold and Leila Y. Mathers Charitable Foundation; the Meyer Foundation; and the Bawd Foundation. R.P.L. is on the board of directors of both Roche and the Roche subsidiary Genentech. J.L.P. was supported by a Francois Wallace Monahan Postdoctoral Fellowship at the Rockefeller University and by a European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018).

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10-5), especially those, The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH; R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program (UL1 TR001866), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (EQU201903007798), the ANRS-COV05, ANR-RHU program ANR-21-RHUS-08, ANR GENVIR (ANR-20-CE93-003), ANR GenMISC (ANR-21-COVR-0039), and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the Square Foundation, Grandir–Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the Université Paris Cité. This work was partly supported by the Center for Research on Influenza Pathogenesis and Transmission, a National Institute of Allergy and Infectious Diseases (NIAID)–funded Center of Excellence for Influenza Research and Response (contract no. 75N93021C00014), and the FLUOMICS Consortium (NIH-NIAID grant U19AI135972) to both A. García-Sastre and R.A. Medina, and by NIAID grant U19AI142733 and U19AI168631 to A. García-Sastre. Work in the Medina laboratory was also supported by the PIA ACT 1408, FONDECYT 1161971 and 1212023 grants from Agencia Nacional de Investigación y Desarrollo of Chile. The VirPath team is supported by INSERM REACTing (Research & Action Emerging Infectious Diseases), CNRS, and Mérieux Research grants. B. Padey is supported by an ANRT CIFRE PhD scholarship. For the Lyon cohort, specimen collection and study was supported by a grant from the French Ministry of Health PHRC-I 2013 ANTIGRIPPE. C. Rodríguez-Gallego and colleagues were supported by the Instituto de Salud Carlos III (COV20_01333, COV20_01334, and PI12/01565, Spanish Ministry for Science and Innovation RTC-2017-6471-1; AEI/FEDER, UE), Grupo DISA, Fundación MAPFRE Guanarteme, Sociedad Española de Neumología y Cirugía Torácica and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas, científicas del Instituto Tecnológico y de Energías Renovables para colaborar en la lucha contra la COVID-19”). E. Andreakos is supported by the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574). P. Bastard was supported by the French Foundation for Medical Research (EA20170638020) and by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). This study was supported by Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009); cofinanced by European Regional Development Fund “A way to achieve Europe”; Operative Program Intelligence Growth 2014-2020 (CB21/13/00006) also was supported by CIBER-Consorcio Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea–Next Generation EU and Consejería de Economía, Conocimiento, Empresas y Universidad, Secretaría General de Universidades, Investigación y Tecnología, Junta de Andalucía, Spain (P18-RT-3320). I. Meyts is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies, a CSL-Behring Research Grant, KU Leuven C1 grant C16/18/007, a VIB GC PID Grant, Fonds Wetenschappelijk Onderzoek grants G0C8517N, G0B5120N, and G0E8420N, and the Jeffrey Modell Foundation. Open Access funding provided by Rockefeller University.

Vaccines against SARS-CoV-2 have been shown to be safe and effective but their protective efficacy against infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe coronavirus disease 2019 (COVID-19), we report a spatiotemporal description of SARS-CoV-2 infection and replication through the brain. SARS-CoV-2 brain replication occurs primarily in neurons, leading to neuronal loss, signs of glial activation and vascular damage in mice infected with SARS-CoV-2. One or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. These findings further support the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19., We thank the CSIC and the Spanish Ministry of Science and Innovation for continuous support. This research was supported by the Spanish Ministry of Science and Innovation/Spanish Research Agency/10.13039/501100011033 grant nos. PID2019-105995RB-I00 (J.J.T.-A. and J.V.), PID2020-114481RB-I00 (J.G.-A. and M.E.), RTI2018-096629-B-I00 (A.P.) and PID2019-106410RB-I00 (J.L.-B.). Moreover, this research was also funded by Red TerCel ISCIII (no. RD16/0011/0025 to J.J.T.-A.), Consejería de Economía, Conocimiento, Empresas y Universidad US-1380891 (to J.J.T.-A. and J.V.), Consejería de Salud y Familias, Junta de Andalucía grant no. PECOVID-0078-2020 (to R.R.-L. and J.V.), Consejería de Educación y Deporte, Junta de Andalucía grant no. PY20_01312 (to A.P.), Fondo COVID-19 grant no. COV20/00151 (Spanish Health Ministry, Instituto de Salud Carlos III), Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant and CSIC grant no. 202120E079 (J.G.-A.), CSIC grant no. 2020E84, La CaixaImpulse grant no. CF01-00008 and Ferrovial and MAPFRE donations (to M.E.). Additionally, we received funding from the European Commission-NextGenerationEU, through the CSIC’s Global Health Platform (PTI Salud Global) (to J.G.-A. and M.E.) and the European Research Council (ERC Advanced grant no. PRJ201502629) (to J.L.-B.). J.G.-A. and M.E. also acknowledge financial support from the Spanish State Research Agency (no. AEI/10.13039/501100011033) through the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (nos. SEV-2013-0347 and SEV-2017-0712). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

There is evidence that in schizophrenia, imbalances in inflammatory and oxidative processes occur during pregnancy and in the early postnatal period, generating interest in the potential therapeutic efficacy of anti-inflammatory and antioxidant compounds. Mangiferin is a polyphenolic compound abundant in the leaves of Mangifera indica L. that has robust antioxidant and anti-inflammatory properties, making it a potential candidate for preventive or co-adjuvant therapy in schizophrenia. Hence, this study set-out to evaluate the effect of mango leaf extract (MLE) in a model of schizophrenia based on maternal immune activation, in which Poly I:C (4 mg/kg) is administered intravenously to pregnant rats. Young adult (postnatal day 60-70) or adolescent (postnatal day 35-49) male offspring received MLE (50 mg/kg of mangiferin) daily, and the effects of MLE in adolescence were compared to those of risperidone, assessing behavior, brain magnetic resonance imaging (MRI), and oxidative/inflammatory and antioxidant mediators in the adult offspring. MLE treatment in adulthood reversed the deficit in prepulse inhibition (PPI) but it failed to attenuate the sensitivity to amphetamine and the deficit in novel object recognition (NOR) induced. By contrast, adolescent MLE treatment prevented the sensorimotor gating deficit in the PPI test, producing an effect similar to that of risperidone. This MLE treatment also produced a reduction in grooming behavior, but it had no effect on anxiety or novel object recognition memory. MRI studies revealed that adolescent MLE administration partially counteracted the cortical shrinkage, and cerebellum and ventricle enlargement. In addition, MLE administration in adolescence reduced iNOS mediated inflammatory activation and it promoted the expression of biomarkers of compensatory antioxidant activity in the prefrontal cortex and hippocampus, as witnessed through the reduction of Keap1 and the accumulation of NRF2 and HO1. Together, these findings suggest that MLE might be an alternative therapeutic or preventive add-on strategy to improve the clinical expression of schizophrenia in adulthood, while also modifying the time course of this disease at earlier stages in populations at high-risk. EB, JAG-P and ST-S work was supported by the “Fondo Europeo de Desarrollo Regional” (FEDER)-UE “A way to build Europe” from the “Ministerio de Economía y Competitividad” (RTI2018-099778-B-I00); from the “Plan Nacional sobre Drogas, Ministerio de Sanidad, Consumo y Bienestar Social” (2019I041); from the “Ministerio de Salud-Instituto de Salud Carlos III” (PI18/01691); from the “Programa Operativo de Andalucía FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejería Salud y Familias, Junta de Andalucía” (PI-0080- 2017, PI-0009-2017), “Consejería de Salud y Familias, Junta de Andalucía” (PI-0134-2018 and PEMP-0008-2020); from the “Consejería de Transformación Económica, Industria, Conocimiento y Universidad, Junta de Andalucía” (P20_00958 and CTS-510); from the CEIMAR (CEIJ-003); from the “Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz-INiBICA” (LI19/06IN-CO22; IN-C09); from the “CIBERSAM”: CIBER-Consorcio Centro de Investigación Biomédica en Red- (CB07/09/0033), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 955684. CM, LC and MTF-P were supported by the Spanish Ministry of Science and Technology (PID2020- 116229RB-I00) and European Regional Development Fund (ERDF). KM and JCL were supported by the “MICINN” (PID2019-109033RB-I00) and the “CIBERSAM”: CIBERConsorcio Centro de Investigación Biomédica en Red- (CB07/ 09/0026), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación. MLS-M was supported by the “Ministerio de Ciencia, Innovación, Instituto de Salud Carlos III” (PI17/ 01766, BA21/00030), co-financed by European Regional Development Fund (ERDF), “A way to make Europe”; from the “CIBERSAM”: CIBERConsorcio Centro de Investigación Biomédica en Red- (CB07/09/0031), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación; from the “Delegación del Gobierno para el Plan Nacional sobre Drogas” (2017/085); from the “Fundación Mapfre” and “Fundación Alicia Koplowitz.” MD work was supported by the “Ministerio de Ciencia e In review 18/ 28 Innovación” (MCIN) and “Instituto de Salud Carlos III” (ISCIII) (PT20/00044); from the “CIBERSAM” CIBERConsorcio Centro de Investigación Biomédica en Red-(CB07/ 09/0031). The CNIC is supported by the ISCIII, the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí

Various species of the SARS-CoV-2 host cell receptor, the angiotensin-converting enzyme 2 (ACE2), are present in serum, which may result from virus entry and subsequent proteolytic processing of the membrane receptor. We have recently demonstrated changes of particular ACE2 species in virus infected humans, either cleaved fragments or circulating full-length species. Here, we further explore the potential of serum ACE2 as a biomarker to test SARS-CoV-2 infection and vaccine efficacy in virus susceptible transgenic K18-hACE2 mice expressing human ACE2. First, in serum samples derived from K18-hACE2 mice challenged with a lethal dose of SARS-CoV-2, we observed an increase in the levels of cleaved ACE2 fragment at day 2 post-challenge, which may represent the subsequent proteolytic processing through virus entry. These elevated levels were maintained until the death of the animals at day 6 post-challenge. The circulating full-length ACE2 form displayed a sizable peak at day 4, which declined at day 6 post-challenge. Noticeably, immunization with two doses of the MVA-CoV2-S vaccine candidate prevented ACE2 cleaved changes in serum of animals challenged with a lethal dose of SARS-CoV-2. The efficacy of the MVA-CoV2-S was extended to vaccinated mice after virus re-challenge. These findings highlight that ACE2 could be a potential serum biomarker for disease progression and vaccination against SARS-CoV-2., This study was funded in part by the Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL; grant 2020-0308), the Direcció General de Ciència I Investigació, Generalitat Valenciana (AICO/2021/308), and by the Instituto de Salud Carlos III (ISCIII, grants PI19-01359), co-financed by the Fondo Europeo de Desarrollo Regional (FEDER, “Investing in your future”) and through CIBERNED, ISCIII. We also acknowledge financial support from the Spanish Ministerio de Economía y Competitividad, through the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV-2017-0723). This research was also supported by Fondo COVID-19 grant COV20/00151 (Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)), Fondo Supera COVID-19 grant (Crue Universidades-Banco Santander), and Spanish Research Council (CSIC) grant 202120E079 (to JG-A); CSIC grant 2020E84, Ferrovial, and MAPFRE donations (to ME); and Spanish Ministry of Science and Innovation (MCIN)/Spanish Research Agency (AEI)/10.13039/501100011033 grant (PID2020-114481RB-I00; to JG-A and ME). This research work was also funded by the European Commission- NextGenerationEU, through CSIC’s Global Health Platform (PTI Salud Global) (to JG-A and ME). MPL is supported by a BEFPI scholarship from the Generalitat Valenciana. JGA and ME acknowledges financial support from the Spanish State Research Agency, AEI/10.13039/501100011033, through the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV-2013-0347, SEV-2017-0712).

Deep brain stimulation (DBS) is a powerful neurostimulation therapy proposed for the treatment of several neuropsychiatric disorders. However, DBS mechanism of action remains unclear, being its effects on brain dynamics of particular interest. Specifically, DBS reversibility is a major point of debate. Preclinical studies in obesity showed that the stimulation of the lateral hypothalamus (LH) and nucleus accumbens (NAcc), brain centers involved in satiety and reward circuits, are able to modulate the activity of brain structures impaired in this pathology. Nevertheless, the long-term persistence of this modulation after DBS withdrawal was unexplored. Here we examine the in vivo presence of such changes 1 month after LH- and NAcc-DBS, along with differences in synaptic plasticity, following an exploratory approach. Thus, both stimulated and non-stimulated animals with electrodes in the NAcc showed a common pattern of brain metabolism modulation, presumably derived from the electrodes’ presence. In contrast, animals stimulated in the LH showed a relative metabolic invariance, and a reduction of neuroplasticity molecules, evidencing long-lasting neural changes. Our findings suggest that the reversibility or persistence of DBS modulation in the long-term depends on the selected DBS target. Therefore, the DBS footprint would be influenced by the stability achieved in the neural network involved during the stimulation. This research was supported by the Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III (projects PI14/00860 and PI17/01766, and grant CPII14/00005), co-financed by European Regional Development Fund (ERDF), “A way of making Europe”, CIBERSAM, Delegación del Gobierno para el Plan Nacional sobre Drogas (2017/085), Fundación Mapfre and Fundación Alicia Koplowitz. MCV was supported by Fundación Tatiana Pérez de Guzmán el Bueno as scholarship holder of this institution. DRM was supported by Consejería de Educación e Investigación, Comunidad de Madrid, co-funded by European Social Fund “Investing in your future” (grant, PEJD-2018-PRE/BMD- 7899). NLR was supported by Instituto de Investigación Sanitaria Gregorio Marañón, "Programa Intramural de Impulso a la I+D+I 2019”. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV‐2015‐0505). Support for Nacher’s lab came from Ministry of Economy and Competitiveness (SAF2015- 68436-R), Generalitat Valenciana (PROMETEO2013/069) and Fundación Alicia Koplowitz (FAK2012/01).

Vulnerability to addiction may be given by the individual's risk of developing an addiction during their lifetime. A challenge in the neurobiology of drug addiction is understanding why some people become addicted to drugs. Here, we used positron emission tomography (PET) and statistical parametric mapping (SPM) to evaluate changes in brain glucose metabolism in response to chronic morphine self-administration (MSA) in two rat strains with different vulnerability to drug abuse, Lewis (LEW) and Fischer 344 (F344). Four groups of animals were trained to self-administer morphine or saline for 15 days. 2-deoxy-2-[18F]-fluoro-D-glucose (FDG)-PET studies were performed on the last day of MSA (acquisition phase) and after 15 days of withdrawal. PET data were analyzed using SPM12. LEW-animals self-administered more morphine injections per session than F344-animals. We found significant brain metabolic differences between LEW and F344 strains in the cortex, hypothalamus, brainstem, and cerebellum. In addition, the different brain metabolic patterns observed after the MSA study between these rat strains indicate differences in the efficiency of neural substrates to translate the drug effects, which could explain the differences in predisposition to morphine abuse between one individual and another. These findings have important implications for the use of these rat strains in translational morphine and opiate research. MLS was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (projects PI17/01766, and grant BA21/00030), co-funded by the European Regional Development Fund (ERDF), “A way to make Europe”, CIBERSAM, Delegación del Gobierno para el Plan Nacional sobre Drogas (2017/085), Fundación Mapfre, and Fundación Alicia Koplowitz. EA was supported by grants from Ministerio de Sanidad, Servicios Sociales e Igualdad and Red de Trastornos Adictivos del Instituto de Salud Carlos III (RTA-RD16/020/0022), Delegación del Gobierno para el Plan Nacional sobre Drogas (2016I073), Ministerio de Ciencia e Innovación (PSI2016-80541-P), UNED (Plan de Promoción de la Investigación 2018–2020), and the European Union´s Justice Programme – Drugs Policy Initiatives (JUST-2017-AG-DRUGS- 806996-JUSTSO). NLR was supported by Instituto de Investigación Sanitaria Gregorio Marañón, "Programa Intramural de Impulso a la I + D + I 2019″. MD work was supported by Ministerio de Ciencia e Innovación (MCIN) and Insituto de Salud Carlos III (ISCIII) (PT20/00044). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV‐2015‐0505). Sí

Novel safe, immunogenic, and effective vaccines are needed to control the COVID-19 pandemic, caused by SARS-CoV-2. Here, we describe the safety, robust immunogenicity, and potent efficacy elicited in rhesus macaques by a modified vaccinia virus Ankara (MVA) vector expressing a full-length SARS-CoV-2 spike (S) protein (MVA-S). MVA-S vaccination was well tolerated and induced S and receptor-binding domain (RBD)-binding IgG antibodies and neutralizing antibodies against SARS-CoV-2 and several variants of concern. S-specific IFNγ, but not IL-4, -producing cells were also elicited. After SARS-CoV-2 challenge, vaccinated animals showed a significant strong reduction of virus loads in bronchoalveolar lavages (BAL) and decreased levels in throat and nasal mucosa. Remarkably, MVA-S also protected macaques from fever and infection-induced cytokine storm. Computed tomography and histological examination of the lungs showed reduced lung pathology in MVA-S-vaccinated animals. These findings favor the use of MVA-S as a potential vaccine for SARS-CoV-2 in clinical trials., This research was supported by Fondo COVID-19 grant COV20/00151 (Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)), Fondo Supera COVID-19 grant (Crue Universidades-Banco Santander), and Spanish Research Council (CSIC) grant 202120E079 (to JG-A); CSIC grant 2020E84, la Caixa Banking Foundation grant CF01-00008, Ferrovial, and MAPFRE donations (to ME); a Spanish Ministry of Science and Innovation (MCIN)/Spanish Research Agency (AEI)/10.13039/501100011033 grant (PID2020-114481RB-I00; to JG-A and ME); and internal funding from the BPRC. This research work was also funded by the European Commission-NextGenerationEU, through CSIC’s Global Health Platform (PTI Salud Global) (to JG-A and ME). RD received grants from the European Commission Horizon 2020 Framework Programme (Project VIRUSCAN FETPROACT-2016: 731868 and Project EPIC-CROWN-2: 101046084), and Fundación Caixa-Health Research HR18-00469 (Project StopEbola).

We generated an optimized COVID-19 vaccine candidate based on the modified vaccinia virus Ankara (MVA) vector expressing a full-length prefusion-stabilized SARS-CoV-2 spike (S) protein, termed MVA-CoV2-S(3P). The S(3P) protein was expressed at higher levels (2-fold) than the non-stabilized S in cells infected with the corresponding recombinant MVA viruses. One single dose of MVA-CoV2-S(3P) induced higher IgG and neutralizing antibody titers against parental SARS-CoV-2 and variants of concern than MVA-CoV2-S in wild-type C57BL/6 and in transgenic K18-hACE2 mice. In immunized C57BL/6 mice, two doses of MVA-CoV2-S or MVA-CoV2-S(3P) induced similar levels of SARS-CoV-2-specific B- and T-cell immune responses. Remarkably, a single administration of MVA-CoV2-S(3P) protected all K18-hACE2 mice from morbidity and mortality caused by SARS-CoV-2 infection, reducing SARS-CoV-2 viral loads, histopathological lesions, and levels of pro-inflammatory cytokines in the lungs. These results demonstrated that expression of a novel full-length prefusion-stabilized SARS-CoV-2 S protein by the MVA poxvirus vector enhanced immunogenicity and efficacy against SARS-CoV-2 in animal models, further supporting MVA-CoV2-S(3P) as an optimized vaccine candidate for clinical trials., This research was supported by Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII), Fondo COVID-19 grant COV20/00151, Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant and Spanish Research Council (CSIC) grant 202120E079 (to JG-A), CSIC grant 2020E84, La CaixaImpulse grant CF01-00008, Ferrovial and MAPFRE donations (to ME), and Spanish Ministry of Science and Innovation (MICINN), Spanish Research Agency grant PID2020-114481RB-I00 (to JG-A and ME). This research work was also funded by the European Commission-NextGenerationEU, through CSIC’s Global Health Platform (PTI Salud Global) (to JG-A and ME). JC acknowledges MICINN and CSIC support (project number 202020E079). RD received grants from the European Commission Horizon 2020 Framework Programme: Project VIRUSCAN FETPROACT-2016: 731868 and EPIC-CROWN-2-2021:101046084, and Fundación Caixa-Health Research HR18-00469 (Project StopEbola).

Two doses of the MVA-CoV2-S vaccine candidate expressing the SARS-CoV-2 spike (S) protein protected K18-hACE2 transgenic mice from a lethal dose of SARS-CoV-2. This vaccination regimen prevented virus replication in the lungs, reduced lung pathology, and diminished levels of pro-inflammatory cytokines. High titers of IgG antibodies against S and receptor-binding domain (RBD) proteins and of neutralizing antibodies were induced against parental virus and variants of concern, markers that correlated with protection. Similar SARS-CoV-2-specific antibody responses were observed at prechallenge and postchallenge in the two-dose regimen, while the single-dose treatment does not avoid vaccine breakthrough infection. All vaccinated animals survived infection and were also protected to SARS-CoV-2 reinfection. Furthermore, two MVA-CoV2-S doses induced long-term memory S-specific humoral and cellular immune responses in C57BL/6 mice, 6 months after immunization. The efficacy and immunological benefits of the MVA-CoV2-S vaccine candidate against COVID-19 supports its consideration for human clinical trials., This research was supported by Fondo COVID-19 grant COV20/00151 (Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)), Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant and CSIC grant 202120E079 (to J.G.-A.), CSIC grant 2020E84, La CaixaImpulse grant CF01-00008, Ferrovial and MAPFRE donations (to M.E.) and MICINN, Spanish Research Agency grant PID2020-114481RB-I00 (to J.G.-A. and M.E.). This research work was also funded by the European Commission-NextGenerationEU, through CSIC’s Global Health Platform (PTI Salud Global) (to J.G.-A. and M.E.). J.M.C. acknowledges MICINN and CSIC support (project number 202020E079). R.D. received grants from the European Commission Horizon 2020 Framework Programme: Project VIRUSCAN FETPROACT-2016: 731868 and EPIC-CROWN-2-2021:101046084, and Fundación Caixa-Health Research HR18-00469 (Project StopEbola). We thank the Spanish Research Council (CSIC) and the Spanish Ministry of Science and Innovation (MICINN) for continuous support. We thank Centro de Investigación en Sanidad Animal (CISA)-Instituto Nacional de Investigaciones Agrarias (INIA-CSIC) (Valdeolmos, Madrid, Spain) for the BSL-3 facilities. SARS-CoV-2 MAD6 virus isolate was kindly provided by José M. Honrubia and Dr. Luis Enjuanes (CNB-CSIC, Madrid, Spain). We thank Carlos Óscar Sánchez Sorzano (CNB-CSIC, Madrid, Spain) for help with the statistical analysis. We thank the Histology Facility at CNB-CSIC for the histological preparation of biological samples.

The protective efficacy of vaccines against SARS-CoV-2 infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe COVID-19 disease, we report a detailed spatiotemporal description of the SARS-CoV-2 infection and replication in different areas of the brain. Remarkably, SARS-CoV-2 brain replication occurs primarily in neurons, producing important neuropathological alterations such as neuronal loss, incipient signs of neuroinflammation, and vascular damage in SARS-CoV-2 infected mice. Notably, one or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. To our knowledge, this is the first study of a COVID-19 vaccine candidate showing 100% efficacy against SARS-CoV-2 brain infection and damage, reinforcing the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19, worth to move forward into clinical trials., The authors thank the Centro de Investigación en Sanidad Animal (CISA)-Instituto Nacional de Investigaciones Agrarias (INIA-CSIC) (Valdeolmos, Madrid, Spain) for the BSL-3 facilities. SARS-CoV-2 MAD6 virus isolate was kindly provided by José M. Honrubia and Dr. Luis Enjuanes (CNB-CSIC, Madrid, Spain). We also thank to Dr. Konstantin L. Levitsky for excellent technical assistance with the confocal acquisition. We thank the Spanish Research Council (CSIC) and the Spanish Ministry of Science and Innovation (MICINN) for continuous support. This research was supported by MCIN/Spanish Research Agency (AEI)/ 10.13039/501100011033 grants: PID2019-105995RB-I00 (J.T.-A. and J.V.), PID2020- 114481RB-I00 (J.G.-A. and M.E.), and PID2019-106410RB-I00 (J.L.-B.). Moreover, this research work was also funded by Red TerCel ISCIII, RD16/0011/0025 (J.T.-A.); Consejería de Salud y Familias, Junta de Andalucía Grant, PECOVID-0078-2020 (R.R.-L. and J.V.); Fondo COVID-19 grant COV20/00151 [Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)], Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant and CSIC grant 202120E079 (J.G.-A.); and CSIC grant 2020E84, La CaixaImpulse grant CF01-00008, Ferrovial and MAPFRE donations (M.E.). Additionally, we have also funding from the European Commission-NextGenerationEU, through CSIC's Global Health Platform (PTI Salud Global) (J.G.-A. and M.E.) and the European Research Council (ERC Advanced Grant PRJ201502629) (J.L.-B.).

[Purpose]: There is no consensus on the best exercise recommendation for women affected by severe obesity while they are waiting for bariatric surgery. For this reason, the effects of a combination of aerobic exercise performed at the intensity at which maximal fat oxidation is reached (Fatmax) with low-intensity resistance training were studied., [Materials and Methods]: Twenty sedentary middle-aged Caucasian women (43.2 ± 7.5 years, BMI = 46.5 ± 5.9 kg·m−2) were allocated to a control group (CG, n = 10) that followed solely the conventional preoperative care or to an experimental group (EG, n = 10) that, in addition, performed a 12-week individualized and supervised physical activity program (PAP) that combined aerobic training at Fatmax with low-intensity resistance training., [Results]: After the PAP, maximal fat oxidation during exercise increased in the EG (0.187 ± 0.068 vs 0.239 ± 0.080 g·min-1, p = 0.025, pre vs. post, respectively), but resting fat oxidation did not (0.088 ± 0.034 vs 0.092 ± 0.029 g·min-1, p = 0.685, pre vs. post, respectively). Additionally, the resting metabolic rate in the EG was also unchanged (1869 ± 406 vs. 1894 ± 336 kcal; p = 0.827, pre vs. post, respectively), probably because of the effects of resistance training on the maintenance of fat-free mass. No significant changes were observed in the CG., [Conclusion]: A PAP that combines aerobic exercise at Fatmax with low resistance training may counteract some of the deleterious side effects of the standard presurgical care of women waiting for bariatric surgery and increase maximal fat oxidation during exercise., Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature., This work has been carried out under the agreement for scientific cooperation among the Hospital Vinalopó, the Hospital General Universitario de Elche, and the Universidad Miguel Hernández de Elche (FISABIO3.l5X), and has been funded by the following research projects: “Physical and psychological effects of an exercise program in bariatric patients”(UEM2.11X; Escuela de Estudios Universitarios Real Madrid-Universidad Europea de Madrid) and “Physiological and psychological effects of a physical activity program on bariatric patients” (Fundación MAPFRE).

High-throughput metabolomics using liquid chromatography and mass spectrometry (LC/MS) provides a useful method to identify biomarkers of disease and explore biological systems. However, the majority of metabolic features detected from untargeted metabolomics experiments have unknown ion signatures, making it critical that data should be thoroughly quality controlled to avoid analyzing false signals. Here, we present a postalignment method relying on intermittent pooled study samples to separate genuine metabolic features from potential measurement artifacts. We apply the method to lipid metabolite data from the PREDIMED (PREvención con DIeta MEDi-terránea) study to demonstrate clear removal of measurement artifacts. The method is publicly available as the R package MetProc, available on CRAN under the GPL-v2 license., This work was supported by NIH research Grant HL118264. The PREDIMED trial was supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140 to R.E.; RTIC RD 06/0045 to M.A.M.-G.; and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición [CIBEROBN]), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, and PI13/01090), Ministerio de Ciencia e Innovación (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA-COMP2010-181, GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011).

This article is made available via the PMC Open Access Subset for unrestricted noncommercial re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic., Vaccines against SARS-CoV-2, the causative agent of the COVID-19 pandemic, are urgently needed. We developed two COVID-19 vaccines based on modified vaccinia virus Ankara (MVA) vectors expressing the entire SARS-CoV-2 spike (S) protein (MVA-CoV2-S); their immunogenicity was evaluated in mice using DNA/MVA or MVA/MVA prime/boost immunizations. Both vaccines induced robust, broad and polyfunctional S-specific CD4+ (mainly Th1) and CD8+ T-cell responses, with a T effector memory phenotype. DNA/MVA immunizations elicited higher T-cell responses. All vaccine regimens triggered high titers of IgG antibodies specific for the S, as well as for the receptor-binding domain; the predominance of the IgG2c isotype was indicative of Th1 immunity. Notably, serum samples from vaccinated mice neutralized SARS-CoV-2 in cell cultures, and those from MVA/MVA immunizations showed a higher neutralizing capacity. Remarkably, one or two doses of MVA-CoV2-S protect humanized K18-hACE2 mice from a lethal dose of SARS-CoV-2. In addition, two doses of MVA-CoV2-S confer full inhibition of virus replication in the lungs. These results demonstrate the robust immunogenicity and full efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic., This research was supported by Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII), Fondo COVID-19 grant COV20/00151 and Fondo Supera COVID-19 (Crue Universidades-Banco Santander) (to J.G.-A.), CSIC grant 2020E84, Ferrovial and Mapfre donations (to M.E.) and Fondo Solidario Juntos, Banco de Santander (to D.S.). This publication was supported by the European Virus Archive GLOBAL (EVA-GLOBAL) project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 871029.

Given the widespread use of bisphenols and parabens in consumer products, the assessment of their intake is crucial and represents the first step towards the assessment of the potential risks that these compounds may pose to human health. In the present study, a total of 98 samples of food items commonly consumed by the Spanish population were collected from different national supermarkets and grocery stores for the determination of parabens and bisphenols. Our analysis demonstrated that 56 of the 98 food samples contained detectable levels of parabens with limits of quantification (LOQ) between 0.4 and 0.9 ng g&minus, 1. The total concentration of parabens (sum of four parabens: &sum, parabens) ranged from below the LOQ to 281.7 ng g&minus, 1, with a mean value of 73.86 ng g⁻1. A total of 52% of the samples showed detectable concentrations of bisphenols. Bisphenol A (BPA) was the most frequently detected bisphenol in the food samples analysed, followed by bisphenol S (BPS) and bisphenol E (BPE). Bisphenol AF (BPAF), bisphenol B (BPB) and bisphenol P (BPP) were not found in any of the analysed samples. LOQ for these bisphenols were between 0.4 and 4.0 ng g&minus, 1.

The effect of fire severity and recurrence on the recovery of enzymatic activities (β-glucosidase, urease, acid phosphatase) and bacterial activity was monitored. Unburned and burned soil samples from soil affected by a high severity wildfire and by a low severity experimental fire were subjected in laboratory to a temperature gradient to simulate different fire severities. These samples were subjected to a second laboratory heat treatment to simulate the effect of recurrence. Soil temperature was measured and used to calculate the degree-hours reached by the soil. The results showed: a) a strong effect of repeated soil heating at different temperatures on soil microbial activity; b) a different sensitivity of enzymatic activities and bacterial activity to fire, c) the magnitude of changes in these biochemical properties was related to the extent of heat supplied to samples and the previous fire/heat history, and d) degree-hours are adequate to quantify the severity of heat treatments and to examine their effects on soil microbial activity. The relationships between degree-hours and the different biochemical properties analyzed clearly demonstrate that the usefulness of these biochemical properties to detect the soil microbial community response to the heat stress followed the order: urease activity > acid phosphatase activity >β-glucosidase activity ≫ bacterial activity., This study was supported by the Ministerio Español de Economía y Competitividad (AGL2012-39686-C02-01), the National Institute of Agricultural Research of Spain (INIA) through project RTA2017-00042- C05-02 cofunded by FEDER, and by Fundación MAPFRE. A. Barreiro and A. Lombao were recipients of FPU grants from the Ministerio Español de Educación (AP2010-2284, AP2010-1900).

Obesogenic endocrine-disrupting chemicals, such as bisphenol A (BPA) and its analogue bisphenol S (BPS), seem to play an important role in the development of obesity, although contradictory results have been reported. The aim of the present study was to conduct a gender analysis of the factors associated with exposure to dietary bisphenols in 585 Spanish adolescents. Dietary BPA and BPS exposure was assessed using a food frequency questionnaire. Foods and macronutrients accounting for more than 95% of energy intake were selected for analysis. Stepwise regression was used to estimate the foods that most contributed to dietary bisphenol exposure in the sample. Gender-related factors associated with greater dietary bisphenol exposure were evaluated using multivariate logistic regression models. Canned tuna was the main dietary source of BPA and BPS in both adolescent boys and girls. Overweight/obese girls showed a higher risk of high dietary exposure to BPA (odds ratio (OR): 3.38, 95% confidence interval (CI): 1.25–9.07) and total bisphenols (OR: 2.81, 95% CI: 1.03–7.67) in comparison with girls with a BMI lower than 25 kg/m2 . Present results indicate a positive association of dietary exposure to both total bisphenols and BPA with being overweight/obese in adolescent girls., GP/EFSA/ENCO/380 2018/03/G04: OBEMIRISK: Knowledge platform for assessing the risk of bisphenol on gut microbiota and its role in obesogenic phenotypes: looking for biomarkers’ framework, Plan Estatal de I + D + I 2013–2016, FEDER-ISCIII PI17/01758, FEDER-Consejería de Salud y Familias, Junta de Andalucía PE-0250–2019, FEDER-Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y Universidades/ Proyecto P18-RT-4247, Fundación Mapfre MAPFRE2018

The continuous dissemination of the novel emerging SARS-CoV-2 virus, with more than 78 million infected cases worldwide and higher than 1,700,000 deaths as of 23 December 2020, highlights the urgent need for the development of novel vaccines against COVID-19. With this aim, we have developed novel vaccine candidates based on the poxvirus modified vaccinia virus Ankara (MVA) strain expressing the full-length SARS-CoV-2 spike (S) protein, and we have evaluated their immunogenicity in mice using DNA/MVA or MVA/MVA prime/boost immunization protocols., Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, are urgently needed. We developed two COVID-19 vaccines based on modified vaccinia virus Ankara (MVA) vectors expressing the entire SARS-CoV-2 spike (S) protein (MVA-CoV2-S); their immunogenicity was evaluated in mice using DNA/MVA or MVA/MVA prime/boost immunizations. Both vaccines induced robust, broad, and polyfunctional S-specific CD4+ (mainly Th1) and CD8+ T-cell responses, with a T effector memory phenotype. DNA/MVA immunizations elicited higher T-cell responses. All vaccine regimens triggered high titers of IgG antibodies specific for the S, as well as for the receptor-binding domain; the predominance of the IgG2c isotype was indicative of Th1 immunity. Notably, serum samples from vaccinated mice neutralized SARS-CoV-2 in cell cultures, and those from MVA/MVA immunizations showed a higher neutralizing capacity. Remarkably, one or two doses of MVA-CoV2-S protect humanized K18-hACE2 mice from a lethal dose of SARS-CoV-2. In addition, two doses of MVA-CoV2-S confer full inhibition of virus replication in the lungs. These results demonstrate the robust immunogenicity and full efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic. IMPORTANCE The continuous dissemination of the novel emerging SARS-CoV-2 virus, with more than 78 million infected cases worldwide and higher than 1,700,000 deaths as of 23 December 2020, highlights the urgent need for the development of novel vaccines against COVID-19. With this aim, we have developed novel vaccine candidates based on the poxvirus modified vaccinia virus Ankara (MVA) strain expressing the full-length SARS-CoV-2 spike (S) protein, and we have evaluated their immunogenicity in mice using DNA/MVA or MVA/MVA prime/boost immunization protocols. The results showed the induction of a potent S-specific T-cell response and high titers of neutralizing antibodies. Remarkably, humanized K18-hACE2 mice immunized with one or two doses of the MVA-based vaccine were 100% protected from SARS-CoV-2 lethality. Moreover, two doses of the vaccine prevented virus replication in lungs. Our findings prove the robust immunogenicity and efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic.

Endocrine disruptors (EDCs) have been associated with the increased incidence of metabolic disorders. In this work, we conducted a systematic review of the literature in order to identify the current knowledge of the interactions between EDCs in food, the gut microbiota, and metabolic disorders in order to shed light on this complex triad. Exposure to EDCs induces a series of changes including microbial dysbiosis and the induction of xenobiotic pathways and associated genes, enzymes, and metabolites involved in EDC metabolism. The products and by-products released following the microbial metabolism of EDCs can be taken up by the host; therefore, changes in the composition of the microbiota and in the production of microbial metabolites could have a major impact on host metabolism and the development of diseases. The remediation of EDC-induced changes in the gut microbiota might represent an alternative course for the treatment and prevention of metabolic diseases. Yes

[EN] Introduction and objectives The Life's Simple 7 strategy of the American Heart Association proposes 7 metrics of ideal cardiovascular health: body mass index (BMI) < 25 mg/m2, not smoking, healthy diet, moderate physical activity ≥ 150 min/wk, total blood cholesterol < 200 mg/dL, systolic and diastolic blood pressures < 120 and < 80 mmHg, respectively, and fasting blood glucose < 100 mg/dL. It is important to assess the combined effect of these 7 metrics in the Spanish population. We prospectively analyzed the impact of baseline Life's Simple 7 metrics on the incidence of major cardiovascular events in the PREDIMED cohort (57.5% women, average baseline age, 67 years). Methods The healthy diet metric was defined as attaining ≥ 9 points on a validated 14-item Mediterranean diet adherence screener. An incident major cardiovascular event was defined as a composite of myocardial infarction, stroke, or cardiovascular death. Cox regression was used to calculate multivariable adjusted hazard ratios (HR) and their 95% confidence intervals (95%CI) for successive categories of health metrics. Results After a median follow-up of 4.8 years in 7447 participants, there were 288 major cardiovascular events. After adjustment for age, sex, center, and intervention group, HRs (95%CI) were 0.73 (0.54-0.99), 0.57 (0.41-0.78), and 0.34 (0.21-0.53) for participants with 2, 3, and ≥ 4 metrics, respectively, compared with participants with only 0 to 1 metrics. Conclusions In an elderly Spanish population at high cardiovascular risk, better adherence to Life's Simple 7 metrics was progressively associated with a substantially lower rate of major cardiovascular events., [ES] Introducción y objetivos La estrategia Life's Simple 7 de la American Heart Association propuso 7 métricas de salud cardiovascular ideal: índice de masa corporal (IMC) < 25, no fumar, dieta saludable, actividad física moderada ≥ 150 min a la semana, colesterol total < 200 mg/dl, presión arterial sistólica < 120 mmHg y diastólica < 80 mmHg y glucemia basal < 100 mg/dl. Resulta de gran interés valorar el efecto combinado de estas 7 metas. Se analizó prospectivamente el impacto de las métricas basales Life's Simple 7 en la incidencia de eventos cardiovasculares mayores en la cohorte PREDIMED (el 57,5% mujeres; media de edad inicial, 67 años). Métodos La métrica de dieta saludable se definió como alcanzar al menos 9 puntos en una escala validada de 14 puntos de adhesión a dieta mediterránea. Se definió evento cardiovascular mayor incidente como infarto de miocardio, ictus o muerte de causa cardiovascular. Se usó regresión de Cox para estimar hazard ratios (HR) ajustadas multivariables con intervalos de confianza del 95% (IC95%) para categorías sucesivas de métricas de salud cardiovascular. Resultados Tras seguir a 7.447 participantes durante una mediana de 4,8 años, se registraron 288 eventos. Respecto a los participantes con solo 0-1 métricas, tras ajustar por edad, sexo, centro y grupo de intervención, se observaron HR (IC95%) 0,73 (0,54-0,99), 0,57 (0,41-0,78) y 0,34 (0,21-0,53), para 2, 3 y 4 o más métricas respectivamente. Conclusiones En una población española con alto riesgo cardiovascular, la presencia de un mayor número de métricas se asoció progresivamente con una reducción sustancial en la tasa de eventos cardiovasculares mayores., This study was funded by the Instituto de Salud Carlos III, Spanish Ministry of Health through the support provided to research networks especially developed for the study (RTIC G03/140, to R. Estruch and RTIC RD 06/0045 to M.Á. Martínez González), the Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition, the Spanish National Center for Cardiovascular Research (CNIC 06/2007), Spanish Health Research Fund-European Fund for Regional Development (PI04-2239, PI05/2584, CP06/00100, PI06/00100, PI07/0240,PI07/1138, PI07/0473, PI10/01407, PI10/02658, PI11/02505), Ministry of Science and Innovation (AGL-2009-13906-C02 and AGL-2010-22319-C03), Mapfre Foundation 2010, Regional Health Ministry of Andalusia (PI0105/2007), Public Health Division of the Department of Health of the Generalitat of Catalonia and Generalitat of Valencia (ACOMP06109, GVACOMP201-181,GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), and the Regional Government of Navarre (P27/2011).

Wildfires are a major problem in Mediterranean forest ecosystems, affecting the same area year after year. Their severity is increasing, partly due to climate change and hence, every now and then, virulent fires of high severity spread ravage this region. The aim of this study was to evaluate the influence of fire regime (recurrence, severity) in soil microbial community structure analyzing the phospholipid fatty acid (PLFA) and the microbial functional diversity assessing the level physiological profiling technique (CLPP). Samples of a soil affected by a high severities wildfire and a soil affected by a low severity experimental fire were heated under laboratory conditions at different temperatures to simulate different fire severity. To simulate fire recurrence, the heating treatment was repeated after one month of incubation. The fire severity was estimated as the amount of heat supplied to samples by degree-hour methodology. A marked impact of fire regime on soil microorganisms was detected; the microbial community response varied depending on previous history of fire and the magnitude of changes in PLFA pattern and CLPP, was related to the amount of heat supplied to the samples. Wildfires had a greater impact on microbial community structure than subsequent soil heating in the laboratory. The total biomass and the biomass of specific groups of microorganisms decreased notably as a consequence of wildfire and minor changes were detected due to the experimental fire and soil heating under laboratory conditions. The results clearly showed the usefulness of PLFA pattern to study the effect of fire regimes and associated direct and indirect changes in soil microorganisms and in soil quality. The data also indicated that the degree-hour methodology rather than maximum temperature is adequate to simulate fire severity and evaluate the impact of thermal shock on soil ecosystems., This study was supported by the Ministerio Español de Economía y Competitividad (AGL2012-39686-C02-01), the National Institute of Agricultural Research of Spain (INIA) through project RTA2017-00042-C05-02, cofunded by FEDER and by Fundación Mapfre. A. Barreiro and A. Lombao were recipients of FPU grants from the Ministerio Español de Educación (AP2010-2284, AP2010-1900).

© 2020 by the authors., Soil properties determining the thermal transmissivity, the heat duration and temperatures reached during soil heating are key factors driving the fire-induced changes in soil microbial communities. The aim of the present study is to analyze, under laboratory conditions, the impact of the thermal shock (infrared lamps reaching temperatures of 100 °C, 200 °C and 400 °C) and moisture level (0%, 25% and 50% per soil volume) on the microbial properties of three soil mixtures from different sites. The results demonstrated that the initial water content was a determinant factor in the response of the microbial communities to soil heating treatments. Measures of fire impact included intensity and severity (temperature, duration), using the degree-hours method. Heating temperatures produced varying thermal shock and impacts on biomass, bacterial activity and microbial community structure., This research was funded by Spanish Ministry of Economy and Competitiveness (AGL2012-39686-C02-01) and for the for the MAPFRE foundation. A. Barreiro and A. Lombao are recipients of FPU grant from Spanish Ministry of Education. The authors thank S.J. González-Prieto for his valuable help with the statistical analyses.

Resumen del póster presentado al 6th Symposium on Biomedical Research: Advances and Perspectives in Molecular Endocrinology "In Homage to Gabriella Morreale", celebrado en el Instituto de Investigaciones Biomédicas Alberto Sols (IIBM-CSIC) el 31 de mayo de 2019., Changes in the body composition such as high adiposity and sarcopeny occur during aging. These changes are usually associated to metabolic alterations like insulin resistance, type 2 diabetes and metabolic syndrome. Adipose tissue is not homogeneous and dysfunction of white adipose tissue (WAT) and brown adipose tissue (BAT) can develop differently during aging. Our aim is to study different WAT and BAT depots at middle-age to detect the initial signals of alteration. Moreover, we have studied the effect of the long-term caloric restriction (CR) and its benefits. Sv129 mice 3 and 12-month-old mice fed ad libitum and 12-month-old mice fed with a 20% CR (3m, 12m and 12mCR, respectively) have been used. RT-PCR has been employed to study lipid metabolism gene expression in eWAT, scWAT and BAT. Moreover, circulating serum and BAT thyroid hormones levels were measured by radioimmunoassay (RIA). 12m animals showed insulin resistance and lower adiponectin levels in plasma compared with 3m. Expression of insulin pathway (Glut4, Irs1), lipogenesis (Fas, Scd1) and lipolysis (Hsl, Atgl, Pparα) genes was decreased in scWAT of 12m animals, but not in eWAT. Furthermore, UCP-1 expression was significantly lower in scWAT of aged mice compared with younger mice, suggesting a decrease in beige adipose tissue associated to aging. On the other hand, we found decreased expression of some BAT-selective genes12m animals such as Ucp1, βAr. CR recovered the expression levels to those of 3m mice. Thyroxine (T4) in plasma did not reach significance among middle-aged and young animals, however triiodothyronine (T3) levels were lower in 12m than 3m and 12mCR mice. Dio2 expression, T4 and T3 concentrations in BAT followed a similar pattern, a decrease in 12m mice and an increase in CR mice. Although eWAT has been described as the most dangerous tissue from the metabolic point of view, our data could suggest an earlier metabolic alteration in scWAT than in eWAT. Our findings prompt that CR could revert the initial agerelated alterations in scWAT. In agreement, we point to alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction at middle-age, which can be ameliorated by CR., BFU2016-78951-R, B2017BMD-3684, BFU2017-90578-REDT, Fundacion Mapfre, CAMS210/BMD-2433.

This project works with the risk model developed by [6] and quests modelling, estimating and pricing insurance for risks brought in by innovative technologies, or other emerging or latent risks. The model considers two different risk streams that arise together, however not clearly separated or observed. Specifically, we consider a risk surplus process where premia are adjusted according to past claim frequencies, like in a Bonus-Malus (BM) system, when we consider a classical or historical risk stream and an unforeseeable risk one. These are unknown risks which can be of high uncertainty that, when pricing insurance (ratemaking and experience rating), suggest a sensitive premium adjustment strategy. It is not clear for the actuary to observe which claim comes from one or the other stream. When modelling such risks it is crucial to estimate the behaviour of such claims, occurrence and their severity. Premium calculation must fairly reflect the nature of these two kinds of risk streams. We start proposing a model, separating claim counts and severities, then propose a premium calculation method, and finally a parameter estimation procedure. In the modelling we assume a Bayesian approach as used in credibility theory, a credibility approach for premium calculation and the use of the Expectation-Maximization (EM) algorithm in the estimation procedure info:eu-repo/semantics/publishedVersion

[Background]: Inflammation is known to be related to the leading causes of death including cardiovascular disease, several types of cancer, obesity, type 2 diabetes, depression-suicide and other chronic diseases. In the context of whole dietary patterns, the Dietary Inflammatory Index (DII®) was developed to appraise the inflammatory potential of the diet. [Objective]: We prospectively assessed the association between DII scores and all-cause mortality in two large Spanish cohorts and valuated the consistency of findings across these two cohorts and results published based on other cohorts., [Design]: We assessed 18,566 participants in the “Seguimiento Universidad de Navarra” (SUN) cohort followed-up during 188,891 person-years and 6790 participants in the “PREvencion con DIeta MEDiterránea” (PREDIMED) randomized trial representing 30,233 person-years of follow-up. DII scores were calculated in both cohorts from validated FFQs. Higher DII scores corresponded to more proinflammatory diets. A total of 230 and 302 deaths occurred in SUN and PREDIMED, respectively. In a random-effect meta-analysis we included 12 prospective studies (SUN, PREDIMED and 10 additional studies) that assessed the association between DII scores and all-cause mortality., [Results]: After adjusting for a wide array of potential confounders, the comparison between extreme quartiles of the DII showed a positive and significant association with all-cause mortality in both the SUN (hazard ratio [HR] = 1.85; 95% CI: 1.15, 2.98; P-trend = 0.004) and the PREDIMED cohort (HR = 1.42; 95% CI: 1.00, 2.02; P-trend = 0.009). In the meta-analysis of 12 cohorts, the DII was significantly associated with an increase of 23% in all-cause mortality (95% CI: 16%–32%, for the highest vs lowest category of DII)., [Conclusion]: Our results provide strong and consistent support for the hypothesis that a pro-inflammatory diet is associated with increased all-cause mortality. The SUN cohort and PREDIMED trial were registered at clinicaltrials.gov as NCT02669602 and at isrctn.com as ISRCTN35739639, respectively., Supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140, to R.E.; RTIC RD 06/0045, to Miguel A. Martínez-González) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (Proyecto de Investigación (PI) 04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, PI13/00615, PI13/01090, PI14/01668, PI14/01798, PI14/01764), Ministerio de Ciencia e Innovación (Recursos y teconologia agroalimentarias(AGL)-2009-13906-C02 and AGL2010-22319-C03 and AGL2013-49083-C3-1- R), Fundación Mapfre 2010, the Consejería de Salud de la Junta de Andalucía (PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (Generalitat Valenciana Ayuda Complementaria (GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151), Conselleria de Sanitat y, PI14/01764 AP; Atención Primaria (CS) 2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011).). Drs. Shivappa and Hébert were supported by grant number R44DK103377 from the United States National Institute of Diabetes and Digestive and Kidney Diseases.

Although, for decades, increased serum bilirubin concentrations were considered a threatening sign of underlying liver disease and had been associated with neonatal jaundice, data from recent years show that bilirubin is a powerful antioxidant and suggest that slightly increased serum bilirubin concentrations are protective against oxidative stress-related diseases, such as cardiovascular diseases. Therefore, a better understanding of the gene-diet interactions in determining serum bilirubin concentrations is needed. None of the previous genome-wide association studies (GWAS) on bilirubin concentrations has been stratified by sex. Therefore, considering the increasing interest in incorporating the gender perspective into nutritional genomics, our main aim was to carry out a GWAS on total serum bilirubin concentrations in a Mediterranean population with metabolic syndrome, stratified by sex. Our secondary aim was to explore, as a pilot study, the presence of gene-diet interactions at the GWAS level. We included 430 participants (188 men and 242 women, aged 55&ndash, 75 years, and with metabolic syndrome) in the PREDIMED Plus-Valencia study. Global and sex-specific GWAS were undertaken to analyze associations and gene-diet interaction on total serum bilirubin. Adherence (low and high) to the Mediterranean diet (MedDiet) was analyzed as the dietary modulator. In the GWAS, we detected more than 55 SNPs associated with serum bilirubin at p &lt, 5 &times, 10&minus, 8 (GWAS level). The top-ranked were four SNPs (rs4148325 (p = 9.25 &times, 24), rs4148324 (p = 9.48 &times, 24), rs6742078 (p = 1.29 &times, 23), rs887829 (p = 1.39 &times, 23), and the rs4148324 (p = 9.48 &times, 24)) in the UGT1A1 (UDP glucuronosyltransferase family 1 member A1) gene, which replicated previous findings revealing the UGT1A1 as the major locus. In the sex-specific GWAS, the top-ranked SNPs at the GWAS level were similar in men and women (the lead SNP was the rs4148324-UGT1A1 in both men (p = 4.77 &times, 11) and women (p = 2.15 &times, 14), which shows homogeneous genetic results for the major locus. There was more sex-specific heterogeneity for other minor genes associated at the suggestive level of GWAS significance (p &lt, 1 &times, 5). We did not detect any gene-MedDiet interaction at p &lt, 5 for the major genetic locus, but we detected some gene-MedDiet interactions with other genes at p &lt, 5, and even at the GWAS level for the IL17B gene (p = 3.14 &times, 8). These interaction results, however, should be interpreted with caution due to our small sample size. In conclusion, our study provides new data, with a gender perspective, on genes associated with total serum bilirubin concentrations in men and women, and suggests possible additional modulations by adherence to MedDiet.

Purpose The nucleus accumbens (NAcc) has been suggested as a possible target for deep brain stimulation (DBS) in the treatment of obesity. Our hypothesis was that NAcc-DBS would modulate brain regions related to reward and food intake regulation, consequently reducing the food intake and, finally, the weight gain. Therefore, we examined changes in brain glucose metabolism, weight gain and food intake after NAcc-DBS in a rat model of obesity. Procedures Electrodes were bilaterally implanted in 2 groups of obese Zucker rats targeting the NAcc. One group received stimulation one hour daily during 15 days, while the other remained as control. Weight and daily consumption of food and water were everyday registered the days of stimulation, and twice per week during the following month. Positron emission tomography (PET) studies with 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) were performed 1 day after the end of DBS. PET data was assessed by statistical parametric mapping (SPM12) software and region of interest (ROI) analyses. Results NAcc-DBS lead to increased metabolism in the cingulate-retrosplenial-parietal association cortices, and decreased metabolism in the NAcc, thalamic and pretectal nuclei. Furthermore, ROIs analyses confirmed these results by showing a significant striatal and thalamic hypometabolism, and a cortical hypermetabolic region. However, NAcc-DBS did not induce a decrease in either weight gain or food intake. Conclusions NAcc-DBS led to changes in the metabolism of regions associated with cognitive and reward systems, whose impairment has been described in obesity. This research was supported by the Ministry of Economy and Competitiveness ISCIII grants (PI14/00860, CPII14/00005), Ministry of Economy, Industry and Competitiveness (PI17/01766), cofunded by ERDF (FEDER) Funds from the European Commission ``A way of making Europe´´, Fundacion Mapfre, Fundacion Alicia Koplowitz (FAK2016/01), `Delegacion de Gobierno para el Plan Nacional sobre Drogas' (PNSD 2017/085), Comunidad de Madrid (BRADE-CM S2013/ICE-2958) and Fundacion Tatiana Perez de Guzman el Bueno. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

Deep brain stimulation (DBS) is a neurosurgery technique widely used in movement disorders, although its mechanism of action remains unclear. In fact, apart from the stimulation itself, the mechanical insertion of the electrode may play a crucial role. Here we aimed to distinguish between the insertional and the DBS effects on brain glucose metabolism. To this end, electrodes were implanted targeting the medial prefrontal cortex in five adult male Wistar rats. Positron Emission Tomography (PET) studies were performed before surgery (D0) and seven (D7) and nine days (D9) after that. DBS was applied during the (18)FDG uptake of the D9 study. PET data were analysed with statistical parametric mapping. We found an electrode insertional effect in cortical areas, while DBS resulted in a more widespread metabolic pattern. The consequences of simultaneous electrode and DBS factors revealed a combination of both effects. Therefore, the insertion metabolic effects differed from the stimulation ones, which should be considered when assessing DBS protocols. The authors thank Kenia Martinez for her help in performing the statistical analyses and the interpretation of the results; Alexandra de Francisco and Yolanda Sierra for their support in stereotaxic surgery, animal handling, and acquisition of imaging studies. This research was supported by Fundacion Mapfre, Alicia Koplowitz [FAK16/01], CIBER de Salud Mental (CIBERSAM), the Ministry of Economy and Competitiveness ISCIII-FIS Grants [PI14/00860, CPII14/00005, and PI17/01766], and Delegacion del Gobierno para el Plan Nacional sobre Drogas [PNSD 2017/085] and cofinanced by ERDF (FEDER) Funds from the European Commission, ``A way of Making Europe,´´ and Comunidad de Madrid [BRADE-CMS2013/ICE-2958]. Sí

[Background] Gastrointestinal adverse effects occurring during cancer chemotherapy are well known and feared; those persisting once treatment has finished are relatively unknown. We characterized the alterations occurring in the rat small intestine, after repeated treatment with cisplatin., [Methods] Male Wistar rats received saline or cisplatin (2 mg kg−1 week−1, for 5 weeks, ip). Gastric motor function was studied non-invasively throughout treatment (W1- W5) and 1 week after treatment finalization (W6). During W6, upper gastrointestinal motility was also invasively studied and small intestinal samples were collected for histopathological and molecular studies. Structural alterations in the small intestinal wall, mucosa, submucosa, muscle layers, and lymphocytic nodules were histologically studied. Periodic acid-Schiff staining and immunohistochemistry for Ki-67, chromogranin A, and neuronal-specific enolase were used to detect secretory, proliferating, endocrine and neural cells, respectively. The expression of different markers in the tunica muscularis was analyzed by RT/qPCR., [Key Results] Repeated cisplatin induced motility alterations during and after treatment. After treatment (W6), the small intestinal wall showed histopathological alterations in most parameters measured, including a reduction in the thickness of circular and longitudinal muscle layers. Expression of c-KIT (for interstitial cells of Cajal), nNOS (for inhibitory motor neurons), pChAT, and cChAT (for excitatory motor neurons) increased significantly (although both ChATs to a lesser extent)., [Conclusions and Inferences] Repeated cisplatin induces relatively long-lasting gut dysmotility in rat associated with important histopathological and molecular alterations in the small intestinal wall. In cancer survivors, the possible chemotherapy-induced histopathological, molecular, and functional intestinal sequelae should be evaluated., This work was supported by Ministerio de Educación y Ciencia (SAF2009-12422-C02-01, SAF2012-40075-C02-01), Instituto de Salud Carlos III (PI13/01150), Comunidad de Madrid (S2010/BMD-2308), and Fundación Mapfre (convocatoria 2011).

ResumenObjetivoRealizar una revisión bibliográfica para identificar las diferentes metodologías empleadas en el proceso de conciliación de los tratamientos farmacológicos que sean aplicables a pacientes pluripatológicos.DiseñoRevisión sistemática.Fuentes de datosSe realizó una revisión bibliográfica (febrero de 2012) en las bases de datos Pubmed, EMBASE, CINAHL, PsycINFO e Índice Médico Español de métodos de conciliación del tratamiento en pacientes pluripatológicos, o en su defecto, ancianos o polimedicados.Selección de estudiosSe recuperaron 273artículos, de los que se seleccionaron 25.Extracción de datosSe extrajo información relativa a la metodología empleada: nivel asistencial en el que se realiza, fuentes de información, uso de formulario, tiempo establecido, profesional responsable, información recogida y variables registradas como errores de conciliación.ResultadosLa mayoría de estudios fueron al ingreso y al alta hospitalarios Como principales fuentes de información destacan la entrevista y la historia clínica. En la mayoría de trabajos no se especifica un tiempo preestablecido, ni se usa formulario, y el principal responsable es el farmacéutico clínico. Además de la medicación domiciliaria, los hábitos de automedicación y la fitoterapia también son registrados. Se recogen como errores de conciliación desde omisiones de fármacos hasta interacciones medicamentosas.ConclusionesExiste gran heterogeneidad en la metodología empleada para la actividad de la conciliación. No existe ningún trabajo realizado específicamente en el paciente pluripatológico, que por su complejidad y susceptibilidad a errores de conciliación requiere una metodología estandarizada.AbstractObjectiveTo carry out a bibliographic review in order to identify the different methodologies used along the reconciliation process of drug therapy applicable to polypathological patients.DesignWe performed a literature review.Data sources The bibliographic review (February 2012) included the following databases: Pubmed, EMBASE, CINAHL, PsycINFO and Spanish Medical Index (IME). The different methodologies, identified on those databases, to measure the conciliation process in polypathological patients, or otherwise elderly patients or polypharmacy, were studied.Study selection Two hundred and seventy three articles were retrieved, of which 25 were selected.Data extraction Specifically: the level of care, the sources of information, the use of registration forms, the established time, the medical professional in charge and the registered variables such as errors of reconciliation.ResultsMost of studies selected when the patient was admitted into the hospital and after the hospital discharge of the patient. The main sources of information to be highlighted are: the interview and the medical history of the patient. An established time is not explicitly stated on most of them, nor the registration form is used. The main professional in charge is the clinical pharmacologist. Apart from the home medication, the habits of self-medication and phytotherapy are also identified. The common errors of reconciliation vary from the omission of drugs to different forms of interaction with other medicinal products (drugs interactions).ConclusionsThere is a large heterogeneity of methodologies used for reconciliation. There is not any work done on the specific figure of the polypathological patient, which precisely requires a standardized methodology due to its complexity and its susceptibility to errors of reconciliation.

Background: Scientific evidence suggests that diet plays a role in obesity and its comorbidities, partly via its interactions with the individual's gut microbiota. Likewise, the individual's microbiota influences the efficacy of dietary interventions to reduce body weight. However, we require a better understanding of the key components of the gut microbiota that are responsive to specific diets and of their effects on energy balance in order to use this information in practice. Scope and approach: This review provides an up-to-date description of the influence of dietary fibers and fat on gut microbiota and the mechanisms presumably mediating their effects on metabolic health. We also discuss the main knowledge gaps and the need to gain greater understanding of the role of diet-microbe interactions in obesity and the associated comorbidities. Key findings and conclusions: Dietary fibers are major drivers of gut microbiota composition and function, stimulating the dominance of bacteria able to utilize these substrates as energy source, although effects vary depending on both the type of fiber and the individual's microbiota. However, the key bacteria and the primary and secondary metabolic pathways mediating specific fiber-induced effects on the metabolic phenotype remain unclear, and this information is necessary to personalize fiber-based interventions. The literature also shows that gut microbiota contributes to the adverse consequences of high-fat diets on the metabolic phenotype; however, little is known about the effects of dietary fat type. Further progress is expected from translational approaches integrating controlled dietary intervention human trials, combining functional omics technologies and physiological/clinical endpoints, and mechanistic studies in experimental models. This will ultimately help us to progress towards establishing informed microbiome-based dietary recommendations and interventions, which can contribute to tackling the obesity epidemic and its comorbidities., This works was supported by the European Union's Seventh Framework Program under the grant agreement no 613979 (MyNewGut) and by FUNDACION MAPFRE under grant ″Hernando de Larramendi″ call 2014.

Clinical interest on human mesenchymal progenitor cells (hMPC) relies on their potential applicability in cell-based therapies. An in vitro characterization is usually performed in order to define MPC potency. However, in vitro predictions not always correlate with in vivo results and thus there is no consensus in how to really assess cell potency. Our goal was to provide an in vivo testing method to define cell behavior before therapeutic usage, especially for bone tissue engineering applications. In this context, we wondered whether bone marrow stromal cells (hBMSC) would proceed in an osteogenic microenvironment. Based on previous approaches, we developed a fibrin/ceramic/BMP-2/hBMSCs compound. We implanted the compound during only 2 weeks in NOD-SCID mice, either orthotopically to assess its osteoinductive property or subcutaneously to analyze its adequacy as a cell potency testing method. Using fluorescent cell labeling and immunohistochemistry techniques, we could ascertain cell differentiation to bone, bone marrow, cartilage, adipocyte and fibrous tissue. We observed differences in cell potential among different batches of hBMSCs, which did not strictly correlate with in vitro analyses. Our data indicate that the method we have developed is reliable, rapid and reproducible to define cell potency, and may be useful for testing cells destined to bone tissue engineering purposes. Additionally, results obtained with hMPCs from other sources indicate that our method is suitable for testing any potentially implantable mesenchymal cell. Finally, we propose that this model could successfully be employed for bone marrow niche and bone tumor studies. This work was supported by Seventh Framework Programme of the European Commission (EuroNanomed ERA-NET initiative, REBONE project; PI10/02985FIS to J.G-C), Madrid regional government (CellCAM; P2010/BMD-2420 to J.G-C), Ministerio de Ciencia e Innovación (PI11/00377FIS to J.G-C, CSD2009-00088 to J.L.L-L.) and Mapfre foundation (SA/12/AYU/197 to Ar.A). We are grateful to Elena Andrés, David Castejón and María Encarnación Fernandez-Valle for their support in image techniques, to Daniel Baizan for his technical support in animal care, to Isabel Mirones for her technical support in immunohistochemistry and to Isabel Colmenero, pathologist, for her support in sample characterizations. Sí

5-Fluorouracil (5-FU) is the most used chemotherapeutic agent in colorectal cancer. However, resistance to this drug is relatively frequent, and new strategies to overcome it are urgently needed. The aim of this work was to determine the antitumor properties of a supercritical fluid rosemary extract (SFRE), alone and in combination with 5-FU, as a potential adjuvant therapy useful for colon cancer patients. This extract has been recognized as a healthy component by the European Food Safety Authority (EFSA). The effects of SFRE both alone and in combination with 5-FU were evaluated in different human colon cancer cells in terms of cell viability, cytotoxicity, and cell transformation. Additionally, colon cancer cells resistant to 5-FU were used to assay the effects of SFRE on drug resistance. Finally, qRT-PCR was performed to ascertain the mechanism by which SFRE potentiates the effect of 5-FU. Our results show that SFRE displays dose-dependent antitumor activities and exerts a synergistic effect in combination with 5-FU on colon cancer cells. Furthermore, SFRE sensitizes 5-FU-resistant cells to the therapeutic activity of this drug, constituting a beneficial agent against both 5-FU sensitive and resistant tumor cells. Gene expression analysis indicates that the enhancement of the effect of 5-FU by SFRE might be explained by the downregulation of TYMS and TK1, enzymes related to 5-FU resistance. © 2013 Elsevier Ltd. All rights reserved., This work has been supported by Spanish Ministry of Science and Innovation (Plan Nacional I+D+i AGL2010-21565, RyC 2008-03734), Comunidad de Madrid (ALIBIRD, S2009/AGR-1469), Fundación Mapfre, and European Union Structural Funds.

ResumenObjetivoAnalizar la adecuación del tratamiento farmacológico y realizar, si es necesario, intervenciones para su mejora en una cohorte de pacientes pluripatológicos.DiseñoEstudio descriptivo, prospectivo, de 21 meses de duración.EmplazamientoÁrea Hospitalaria Virgen del Rocío.ParticipantesPacientes pluripatológicos incluidos para un proyecto de atención integrada.MétodosLa variable principal consistió en el número de inadecuaciones detectadas. Para evaluar la adecuación del tratamiento farmacológico el farmacéutico especialista siguió un procedimiento normalizado que consistía en la aplicación del cuestionario Medication Aproppriateness Index (MAI) modificado como método implícito y de la lista de criterios Screening Tool of Older Person's potentially inappropriate Prescription/Screening Tool to Alert doctors to the Right (STOPP-START) como método explícito.ResultadosSe incluyeron un total de 244 pacientes, con una edad media de 76 ± 8 (± DE) años siendo el 50% hombres. El número medio de diagnósticos por paciente fue de 8 ± 3 (± DE) y de fármacos de 12 ± 4 (± DE). Se detectaron un total de 840 inadecuaciones, siendo la mayoritaria la presencia de interacciones. Respecto a los criterios STOPP los más frecuentemente incumplidos fueron: clase de medicamento duplicada y uso prolongado de benzodiacepinas de vida media larga o con metabolitos de acción larga, y para los START los IECA en la insuficiencia cardiaca crónica y estatinas y antiagregantes en la diabetes mellitus si coexisten uno o más factores de riesgo.ConclusionesEl gran número de inadecuaciones detectadas pone de manifiesto la importancia de evaluar la adecuación del tratamiento farmacológico en el paciente pluripatológico. Para ello es recomendable utilizar una estrategia de intervención farmacéutica combinada que incluya tanto un método implícito como un método explícito.AbstractObjetiveTo analyze the appropriateness of pharmacotherapy and, if necessary, carry out interventions for its improvement in a cohort of patients with multiple chronic conditions.DesignDescriptive, prospective study of 21 months duration.LocationHospital Universitario Virgen del Rocío.ParticipantsPatients with multiple chronic conditions included in a project for integrated healthcare.MethodsThe primary endpoint was the number of inappropriate treatments. To evaluate the appropriateness of pharmacotherapy, the specialist in hospital pharmacy followed a standardized procedure consisting of the Medication Appropriateness Index (MAI) questionnaire, modified as an implicit method, and the list of criteria of the Screening Tool of Older Person's Potentially Inappropriate Prescription/Screening Tool to Alert doctors to the Right (STOPP-START) as an explicit method.ResultsA total of 244 patients were included, with a mean age of 76 ± 8 (± SD) years. Half (50%) of the patients were men. The mean number of diagnoses per patient was 8 ± 3 (± SD) and 12 ± 4 drugs (± SD). A total of 840 inappropriate treatments were detected, most of them being due to the presence of interactions. The STOPP criteria most not complied with, were duplicate drug class, and prolonged use of benzodiazepines with long half-life or long-acting metabolites, and START for ACE inhibitors in chronic heart failure and statins and antiplatelets in diabetes mellitus, if one or more coexisting risk factors.ConclusionsWe detected a large number of inappropriate treatments. This highlights the importance of evaluating the appropriateness of drug treatment in patients with multiple conditions. It is advisable to use a combined pharmacist intervention strategy that includes both an implicit method and an explicit method.

The impact of a wildfire on some selected physicochemical, chemical (water retention, pH, electrical conductivity, free Fe and Al oxides, total C, extractable C), biochemical (microbial C, soil respiration, bacterial activity, β-glucosidase, urease and phosphatase activities) and microbiological properties (analysis of phospholipid fatty acids, PLFA pattern) was evaluated in Fragas do Eume Natural Park (NW Spain). Soil samples were collected three months after the wildfire from the A horizon (0–2.5 and 2.55 cm) of the unburnt and burnt soil under climax vegetation (Quercus) and non-autochthonous vegetation (Eucalyptus). The results indicated that, independent of the vegetation considered, the wildfire induced short-term modifications of most soil properties analysed, more accentuated changes being those related to labile fractions of the soil organic matter (extractable C and microbial biomass C, negative effects) as well as those in pH and bacterial growth values (positive effects). The fire effect was often more noticeable in the 0–2.5 cm layer than in the 2.5–5 cm layer. The results of a principal component analysis performed with the matrix of the physicochemical and biochemical data showed that vegetation was the most important factor controlling the overall quality of these soils and that wildfire is also an important source of variation in soil quality. This is in agreement with the PLFA pattern, differentiating clearly the Quercus soil samples from the Eucalyptus ones and, to a lesser extent, the burnt soil samples from the corresponding unburnt ones. Medium- and long-term consequences of these microbial changes in the functioning of the plant–soil system should be investigated in order to preserve the biodiversity of the Natural Park., This study was supported by the Ministerio Español de Economía y Competitividad (AGL2012-39686-C02-01) and by Fundación MAPFRE (MA-12-AYU-374). A. Barreiro and A. Lombao are recipients of FPU grants from Spanish Ministry of Education (AP2010-2284, AP2010-1900).

BACKGROUND: Observational cohort studies and a secondary prevention trial have shown inverse associations between adherence to the Mediterranean diet and cardiovascular risk. METHODS: In a multicenter trial in Spain, we assigned 7447 participants (55 to 80 years of age, 57% women) who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). After a median follow-up of 4.8 years, the trial was stopped on the basis of a prespecified interim analysis. In 2013, we reported the results for the primary end point in the Journal. We subsequently identified protocol deviations, including enrollment of household members without randomization, assignment to a study group without randomization of some participants at 1 of 11 study sites, and apparent inconsistent use of randomization tables at another site. We have withdrawn our previously published report and now report revised effect estimates based on analyses that do not rely exclusively on the assumption that all the participants were randomly assigned. RESULTS: A primary end-point event occurred in 288 participants; there were 96 events in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). In the intention-to-treat analysis including all the participants and adjusting for baseline characteristics and propensity scores, the hazard ratio was 0.69 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.72 (95% CI, 0.54 to 0.95) for a Mediterranean diet with nuts, as compared with the control diet. Results were similar after the omission of 1588 participants whose study-group assignments were known or suspected to have departed from the protocol. CONCLUSIONS: In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet., Supported by Instituto de Salud Carlos III, Spanish Ministry of Health, through grants provided to research networks specifically developed for the study (RTIC G03/140, to Dr. Estruch, and RTIC RD 06/0045, to Dr. Martínez-González); Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición; and grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and P11/02505), Ministerio de Ciencia e Innovación (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010-181, GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011). Dr. Hernán was supported by a grant (ME-1503-28119) from the Patient-Centered Outcomes Research Institute.

[EN]: Diabetes mellitus (DM) is a group of diseases highly prevalent nowadays. Its different types produce very similar symptoms with acute and chronic complications. Amongst these, gastrointestinal (GI) dysmotility, associated with the development of neuropathy in the enteric nervous system (ENS) is recognized. The objective is to review the current knowledge on GI dysmotility and enteric neuropathy associated to diabetes mellitus. The different functional and structural alterations within the digestive tract in diabetic patients and animal models are described. Finally, the therapeutic and preventive strategies tested so far in the context of enteric diabetic neuropathy are briefly summarized. In conclusion, amongst the alterations described in DM, the loss of inhibitory intrinsic innervation of the gut is most remarkable. Different therapeutic and/or preventive strategies, including the use of insulin, nerve growth factor or antioxidants, as well as myenteric neuron transplantation, are proposed., [ES]: La diabetes mellitus (DM) es un conjunto de enfermedades de gran prevalencia en la actualidad. Sus diferentes variantes se caracterizan por producir síntomas muy semejantes con complicaciones agudas y crónicas. Entre estas se encuentra la dismotilidad gastrointestinal (GI) asociada al desarrollo de neuropatía en el sistema nervioso entérico (SNE). El objetivo de este artículo es revisar los conocimientos sobre la dismotilidad GI y la neuropatía entérica asociada a diabetes mellitus. Para ello se describen las diversas alteraciones funcionales y estructurales encontradas en el sistema digestivo tanto en el hombre como en diversos modelos animales de diabetes. Para finalizar, se hace un breve resumen de las estrategias de tratamiento y prevención de la neuropatía diabética entérica que se han considerado hasta la fecha. En conclusión, entre las alteraciones descritas en la DM destaca especialmente la pérdida de inervación intrínseca inhibidora. Como posibles estrategias terapéuticas y/o preventivas se propone desde el uso de insulina, el factor de crecimiento nervioso y antioxidantes hasta el trasplante de neuronas mientéricas., The authors thank the financial support from: Ministerio de Educación y Ciencia (SAF2009-12422-C02-01; SAF2012-40075-C02-01), Comunidad de Madrid (S2010/ BMD-2308) and Fundación Mapfre (Ayudas a la Investigación-Promoción de la Salud 2009: Alimentación y Ejercicio Físico).

[EN] Mulching treatment is often recommended in order to reduce post-!re erosion and sediment yields, but information concerning their e"ects on soil properties and hence on soil quality is scarce. In the present investigation, the in#uence of straw application on soil quality was evaluated on hillslope shrubland in Saviñao (Lugo, NW Spain) that is susceptible to post-!re erosion (38% slope). In this area, which was a"ected by a medium-high severity wild!re in September 2012, di"erent treatments with wheat straw were applied to the burnt soil in mulch strips (0.8 and 1 Mg ha-1) using quadruplicate 10 m x 40 m plots and compared with the corresponding burnt untreated control. Soil samples were collected from the A horizon (0-2.5 cm depth) at di"erent sampling times for 12 months after the wild!re, and a wide range of physicochemical, chemical and biochemical soil properties (water retention, pH, electric conductivity, total C, 13C, extractable C, water soluble C, soluble carbohydrates, total N, 15N, microbial biomass C, soil respiration, bacterial activity, !-glucosidase, urease and phosphatase activities) were analyzed. $e results showed that the application of straw mulch had a minor in#uence on the post- !re soil quality but, in contrast, the sampling time showed a signi!cant in#uence attributed to shortand medium term changes in soil properties induced by both !re and climatic conditions., [ES] Entre las técnicas para reducir la erosión post-incendio se recomienda la aplicación de un acolchado de paja al suelo quemado; sin embargo, es escasa la información disponible acerca de sus efectos sobre la calidad del suelo. En esta investigación se evaluó la in!uencia de la aplicación de paja sobre la calidad del suelo en un matorral afectado por un incendio no controlado de media-alta severidad en el año 2012, localizado en Saviñao (Lugo, NO España) y situado en una ladera susceptible de sufrir erosión post-incendio (pendiente 38%). En esta área quemada se instalaron parcelas grandes (10 m de ancho x 40 m de largo) con diferentes tratamientos de paja de trigo aplicado en franjas (0, 0,8 y 1 Mg ha-1, 4 repeticiones por tratamiento). Se recogieron muestras de suelo del horizonte super"cial (0-2,5 cm) de los diferentes tratamientos y a diferentes períodos de tiempo durante 1 año y se analizaron diversas propiedades físico-químicas, químicas y bioquímicas del suelo (retención de agua, pH, conductividad eléctrica, C total, 13C, C extraíble, C soluble, hidratos de C solubles, N total, 15N, biomasa microbiana, respiración, actividad bacteriana y las actividades enzimáticas glucosidasa, ureasa y fosfatasa). Los resultados demostraron que la adición de paja no produjo ningún efecto sobre la calidad del suelo quemado mientras que, por el contrario, la época de muestreo ejerció una marcada in!uencia sobre la misma que se atribuye a cambios en las propiedades del suelo inducidos por el fuego y a las condiciones climáticas a corto y medio plazo., [PT] Uma das técnicas para reduzir a erosão após incêndios !orestais é a aplicação ao solo queimado de um "mulch" de palha; contudo, a informação disponível relativamente aos efeitos desta técnica na qualidade do solo é muito escassa. O objetivo desta pesquisa foi avaliar a in!uência da aplicação de palha na qualidade do solo de um matagal localizado no Saviñao (Lugo, NO da Espanha) e sito numa encosta sob in!uência da erosão pós incêndio (declive 38%). Nesta área, afectada em setembro do 2012 por um fogo não controlado de média-alta intensidade, aplicou-se ao solo queimado diferentes tratamentos em faixas de palha de trigo (0.8 e 1 Mg ha-1) , em quatro parcelas de 10 m de largura x 40 m de comprimento, e compararam-se com o correspondente solo controlo sem nenhum tratamento. Retiraram-se amostras da camada super"cial do solo (0-2.5 cm) dos diferentes tratamentos em distintos tempos ao longo de um ano e após incêndio. Determinaram-se as propriedades físico-químicas, químicas e bioquímicas do solo (retenção de água, pH, condutividade elétrica, carbono (C) total, 13C, C extraível, C solúvel, hidratos de C solúveis, nitrogênio (N) total, 15N, biomassa microbiana, respiração basal, actividade bacteriana e as actividades enzimáticas da glucosidase, ureasea e fosfatase. Os resultados mostraram que a adição da palha teve um efeito reduzido na qualidade do solo queimado, enquanto pelo contrário se observou um forte efeito da época da amostragem atribuído à mudança nas propriedades do solo sob in!uencia do fogo e das condições climáticas a curto e médio prazo., This study was supported by the Ministerio Español de Economía y Competitividad (AGL2012-39686-C02-01) and by Fundación MAPFRE. A. Barreiro and A. Lombao are recipients of FPU grants from the Spanish Ministry of Education.

International audience; Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients.

[ES]: Objetivo: Identificar los hábitos y experiencias actuales de los investigadores españoles en ciencias de la salud en relación con la gestión y el intercambio de los datos brutos de investigación. Material y métodos: Se diseñó un cuestionario compuesto por 40 preguntas distribuidas en tres bloques: A) Datos personales; B) Creación y reutilización de los datos; C) Preservación de los datos. El cuestionario se envió por correo electrónico a investigadores de varias instituciones sanitarias españolas. Resultados: La mayor parte de los investigadores españoles de las ciencias de la salud carecen de políticas o planes de gestión de los datos. Los principales motivos por los que no existen estas políticas son la ausencia de una obligación institucional, la falta de tiempo, el esfuerzo que se requiere para llevarlas a cabo y la falta de apoyo y de orientación. Desconocen la existencia de repositorios, instituciones y otros sistemas de gestión y preservación de los datos. A una amplia mayoría les gustaría utilizar los datos de investigación recogidos por otros investigadores. Conclusión: Es necesario adquirir una conciencia colectiva de la importancia de compartir datos como práctica que mejora la transmisión del conocimiento y, en definitiva, la eficiencia de las inversiones en investigación. También es necesario que las agencias e instituciones que financian la investigación proporcionen el apoyo necesario para llevarla a cabo., [EN]: Objective: To identify the habits and current experiences of Spanish researchers in health sciences in relation to the management and sharing of raw research data. Material and method: A questionnaire composed of 40 questions divided into three blocks was designed: A) Personal information; B) Creation and reuse of data; C) Preservation of Data. The questionnaire was sent by email to researchers from several Spanish healthcare institutions. Results: Most of the Spanish health science researchers lack policies or plans of management data. The main reasons why there are no such policies is the absence of an institutional duty, lack of time, the effort required to carry it out and lack of support and guidance. They are unaware of repositories, institutions and other systems of management and data preservation. A vast majority would like to use the research data collected by other researchers. Conclusion: It is necessary to acquire a collective awareness of the importance of data sharing as a practice that improves the transmission of knowledge and, ultimately, the efficiency of research investments. It is also required that the agencies and institutions that fund research provide the necessary support to carry it out., Esta investigación ha sido financiada por FUNDACIÓN MAPFRE.

© 2015 Pereira, Medina, Baena, Planas and Pozas. The adult subventricular zone (SVZ) is the main neurogenic niche in normal adult brains of mice and rats. Interferon gamma (IFNγ) has somewhat controversially been associated with SVZ progenitor proliferation and neurogenesis. The in vivo involvement of IFNγ in the physiology of the adult SVZ niche is not fully understood and its intracellular mediators are unknown. Here we show that IFNγ, through activation of its canonical signal transducer and activator of transcription 1 (STAT1) pathway, acts specifically on Nestin+ progenitors by decreasing both progenitor proliferation and the number of cycling cells. In addition, IFNγ increases the number of neuroblasts generated without shifting glial fate determination. The final result is deficient recruitment of newborn neurons to the olfactory bulb (OB), indicating that IFNγ-induced stimulation of neuronal differentiation does not compensate for its antiproliferative effect. We conclude that IFNγ signaling via STAT1 in the SVZ acts dually as an antiproliferative and proneurogenic factor, and thereby regulates neurogenesis in normal adult brains., This work was supported by the Marató TV3, and a Mapfre foundation award to EP, and Spanish Ministry of Economy MINECO (SAF2014-56279-R) to AMP. Also EP was a researcher in the Spanish government’s Ramón y Cajal program (MICINN-Spain)

The impact of a wildfire on some selected physicochemical, biochemical and microbiological properties was assessed in an ecosystem located in the Fragas do Eume Natural Park (NW Spain). Soil samples were collected from the topsoil (0-2.5 and 2.5-5 cm) of the unburnt and burnt soil under the autochthonous (Quercus) and non autochthonous (Eucalyptus) vegetation. The results indicated that, independently of the vegetation considered, a short-term impact of the wildfire on most soil properties analyzed was detected; the effect being more pronounced for the biochemical properties than for the physical and chemical ones. As expected soil properties varied with soil depth, and the fire effect was more noticeable in the 0-2.5 cm layer than in the 2.5-5 cm layer., This study was supported by the Ministerio Español de Economía y Competitividad (AGL2012-39686-C02-01) and by Fundación MAFRE. A. Barreiro and A. Lombao are recipients of FPU grants from Spanish Ministry of Education.

Editorial. Plan Nacional de I + D + i, 2012, del Ministerio de Economía y Competitividad. Fundación Mapfre, convocatoria 2012.

[EN]: Introduction: The open Access to publications and the raw data allows its re-use and enhances the advancement of science. The aim of this paper is to identify these practices in Spanish pediatrics journals. Method: We reviewed the author's instructions in 13 Spanish pediatrics journals, identifyingtheir open access and deposit policy. Results: Eight journals allow open access without restriction, and 5 provide information on theability to re-use and depositing data in repositories or websites. Conclusions: Most of the journals have open access, but do not promote the deposit of additionalmaterial or articles in repositories or websites., [ES]: Introducción: La publicación en abierto de los artículos y de los datos brutos que han servido de soporte a la investigación permite su reutilización y mejoran el avance de la ciencia. El objetivo de este trabajo es identificar estas prácticas en las revistas pediátricas españolas. Método: Se han revisado las instrucciones de 13 revistas pediátricas españolas, identificando su política sobre acceso abierto y depósito. Resultados: Ocho revistas permiten el acceso abierto sin restricciones y 5 ofrecen indicaciones sobre la reutilización de los datos y el depósito en repositorios o páginas webs personales o institucionales. Conclusiones: La mayor parte de las revistas son accesibles en abierto pero no promocionan el depósito de material suplementario ni de los artículos en repositorios institucionales o en páginas webs., Este trabajo se ha beneficiado de una ayuda del Plan Nacional de I + D + I del Ministerio de Economía y Competitividad (CSO2012-39632-C02-01) y de la Fundación MAPFRE (Convocatoria 2012).

Purpose:After spinal cord injury (SCI) a glial scar is generated in the area affected that forms a barrier for axon growth and myelination, preventing functional recovery. Recently, we have described a synthetic glycolipid (IG20) that inhibited proliferation of human glioma cells. We show now that IG20 inhibited the proliferation of astrocytes and microglial cells, the principal cellular components of the glial scar, and promoting axonal outgrowth and myelin production in vitro. Methods:Glial cells were inhibited with IG20 (IC50≈10 μM) and studied by RT-PCR, Western Blotting, immunoprecipitation and fluorescence microscopy. Axonal outgrowth in dorsal root ganglia (DRG) and myelin production by oligodendrocytes were analyzed by immunocytochemistry. Adult rats were assayed in spinal cord contusion model and the recovery of treated animals (n = 6) and controls (n = 6) was followed. Results:The IG20 was localized in the cytosol of glial cells, forming a complex with RhoGDIα, a regulator of RhoGTPases. Treatment of astroglial cultures with IG20 increase the expression of BDNF receptor genes (TrkBT1, TrkB Full). IG20 reduced the astroglial marker GFAP, while increasing production of myelin basic protein in oligodendrocytes and promoted axonal outgrowth from DRG neurons. Local injection of IG20, near a spinal cord contusion, promoted the recovery of lesioned animals analyzed by BBB test (P < 0.05). Conclusions:We propose that inhibition of astrocytes and microglia by IG20 could be diminished the glial scar formation, inducing the re-growth and myelination of axons, these elements constitute a new approach for SCI therapy., This work was supported by Grants: PI11/00592, PI11/01436 from the Instituto de Salud Carlos III (ISCIII); 201280E091 from the CSIC and co-financed by European Regional Development Funds. The financial support from Mapfre Foundation is also acknowledged. We thank to Drs. J. A. Rodriguez - Alfaro, J. Mazario and Mrs A. Fernandez-Rodríguez for their help with microscopical techniques, and Mrs G. Barroso-García and V. Moral-Darde for their assistance in mass spectrometry

Trabajo presentado en la European Geosciences Union General Assembly, celebrada en Viena (Austria), del 12 al 17 de abril de 2015, It is well known that soil properties determining the thermal transmissivity (moisture, texture, organic matter, etc.) and the duration and temperatures reached during soil heating are key factors driving the fire-induced changes in soil microbial communities. However, despite its interest, the information about this topic is scarce. The aim of the present study is to analyze, under laboratory conditions, the impact of the thermal shock (infrared lamps reaching temperatures of 100 ºC, 200 ºC and 400 ºC) on microbial communities of three acid soils under different moisture level (0 %, 25 % and 50 % per soil volume). Soil temperature was measured with thermocouples and the impact of soil heating was evaluated by means of the analysis of the temperature-time curves calculating the maximum temperature reached (Tmax) and the degree-hours (GH) as an estimation of the amount of heat supplied to the samples (fire severity). The bacterial growth (leucine incorporation) and the total microbial biomass (PLFA) were measured immediately after the heating and one month after the incubation of reinoculated soils. The results showed clearly the importance of moisture level in the transmission of heat through the soil and hence in the further direct impact of high temperatures on microorganisms living in soil. In general, the values of microbial parameters analyzed were low, particularly immediately after soil heating at higher temperatures; the bacterial activity measurements (leucine incorporation technique) being more sensitive to detect the thermal shock showed than total biomass measurements (PLFA). After 1 month incubation, soil microbial communities tend to recover due to the proliferation of surviving population using as substrate the dead microorganisms (soil sterilization). Thus, time elapsed after the heating was found to be decisive when examining the relationships between the microbial properties and the soil heating parameters (GH, Tmax). Analysis of results also showed that the measurement of the heat supplied to the soil (GH) rather than Tmax is a useful parameter to interpret microbial changes induced by soil heating., This work was supported by Spanish Ministry of Economy and Competitiveness (AGL2012-39686-C02-01) and for the for the MAPFRE foundation. A. Barreiro and A. Lombao are recipients of FPU grant from Spanish Ministry of Education

The BIOLOG and Phospholipid Fatty Acid (PLFA) techniques were used to evaluate the short- and medium- term effects produced by an experimental fire and different stabilisation treatments (seeding, mulching) on soil microbial community. The study was performed in a shrubland ecosystem from Galicia (NW Spain) affected by an experimental fire of low-severity and two different post-fire treatments (seeding and mulching). Soil samples were collected from the top layer (0-5 cm) of the A horizon immediately and 90, 180 and 365 days after the fire and the microbial community was determined using both the BIOLOG and the PLFA methods. The results indicated that, independently of the method used, the experimental fire induced marked changes on the soil microbial community, which persisted even after 1 year and that there was no evidence of noticeable microbial changes between the two different post-fire treatments and the corresponding burnt treatment. In addition, a clear significant effect of the sampling time on the soil microbial community structure was observed, the impact being even most important than that observed for the experimental fire., This study was supported by the Ministerio Español de Economía y Competitividad (AGL2012-39686-C02-01) and by Fundación MAFRE. A. Barreiro and A. Lombao are recipients of FPU grants from Spanish Ministry of Education