Glacial/Interglacial simulations with an Earth System model of intermediate complexity

This is a contribution to the project TIC-MOC (CTM2011-28867) funded by the 2008-2011 Spanish R+D Plan. C. Herrero acknowledges a CSIC JAE-Predoc scholarship co-financed by the European Social Fund (FSE) and wishes to thank all PalMA group members for their help and kindnessPeer Reviewe

Development of in vitro systems to study IFN signalling in gilthead seabream (Sparus aurata)

Type I interferon (IFN I) triggers specific signalling pathways leading to the activation of the innate immune defence of vertebrates against viral infections. In contrats, type II IFN (IFN II) is generally accepted to be part of the adaptive response. Among IFN I-stimulated genes, those coding the Mx proteins play a main role due to the direct antiviral activity of these proteins. The study of Mx genes in gilthead seabream, one of the most important species in the Mediterranean aquaculture, is especially interesting, as this species displays a high natural resistance to viral diseases, and behaves as asymptomatic carrier and/or reservoir of several viruses, such as viral nervous necrosis virus (VNNV), infectious pancreatic necrosis virus (IPNV), and viral haemorrhagic septicaemia virus (VHSV), which are pathogenic to other fish species. Three Mx genes (Mx1, Mx2, and Mx3) have been identified in S. aurata, showing the three proteins a wide spectrum of antiviral activity. The structure of the three promoters (pMx1, pMx2 and pMx3) has been disclosed, and their response to IFN I, IPNV and VHSV indicated a clear induction of the three promoters, with some differences in the kinetics and magnitude of the response. Several studies evidenced the important role of Mx transcription regulation on virus-host interaction: i) Mx promoters can respond to both IFN I and IFN II, thus Mx might be the link between innate and adaptive immunity; ii) Mx activation is blocked by several viruses, thus Mx transcription is the target of their IFN I antagonistic activity; and iii) A fish cell line modified with the promoter of a fish Mx gene was used to measure viraemia in serum with high sensitivity. Therefore, assessing the regulatory mechanisms controlling the transcription of fish Mx genes could significantly contribute to both, understanding virus-host interactions, and designing strategies to control viral infections. In our case, this approach can also give light to understand the successful antiviral strategies developed by gilthead seabream in nature. Thus, the purpose of the present work was to develop three stable transgenic cell lines expressing the firefly luciferase gene under the control of the gilthead seabream Mx promoters. These in vitro systems were established and their response to poly I:C, and to two viral infections was characterized. In the case of IPNV, a clear antagonistic activity was observed for pMx2, as the activity of the promoter was 78.53% lower, however, this effect was not observed for pMx1 and pMx3. When cells were infected with VHSV, no changes in the promoters’ activity were detected, thus indicating that seabream Mx promoters are not targeted by VHSV antagonistic activity. These results confirm the specificity of the interactions between each virus/promoter combination, and support the use of the three cell lines developed as useful tools to characterize virus-host interactions in this species. Further studies aimed at the identification of the molecular mechanisms behind our observations will allow us to get more insight into this complex system.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Hif-1α knockdown reduces glycolytic metabolism and induces cell death of human synovial fibroblasts under normoxic conditions

[Abstract] Increased glycolysis and HIF-1α activity are characteristics of cells under hypoxic or inflammatory conditions. Besides, in normal O2 environments, elevated rates of glycolysis support critical cellular mechanisms such as cell survival. The purpose of this study was to analyze the contribution of HIF-1α to the energy metabolism and survival of human synovial fibroblasts (SF) under normoxic conditions. HIF-1α was silenced using lentiviral vectors or small-interfering RNA (siRNA) duplexes. Expression analysis by qRT-PCR and western blot of known HIF-1α target genes in hypoxia demonstrated the presence of functional HIF-1α in normoxic SF and confirmed the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a HIF-1α target even in normoxia. HIF-1α silencing induced apoptotic cell death in cultured SF and, similarly, treatment with glycolytic, but not with OXPHOS inhibitors, induced SF death. Finally, in vivo HIF-1α targeting by siRNA showed a significant reduction in the viability of human SF engrafted into a murine air pouch. Our results demonstrate that SF are highly dependent on glycolytic metabolism and that HIF-1α plays a regulatory role in glycolysis even under aerobic conditions. Local targeting of HIF-1α provides a feasible strategy to reduce SF hyperplasia in chronic arthritic diseases.Instituto de Salud Carlos III; FIS 12/439Instituto de Salud Carlos III; RETICS RD12/009Instituto de Salud Carlos III; CP13/00014Comunidad de Madrid; RAPHYME-CM S2010/BMD235

Methodological resources for the acquisition of competences and the students’ insertion with regard to the reality of homeless people

El proyecto de innovación docente presentado pretende concienciar y sensibilizar a los estudiantes de la realidad de las Personas Sin Hogar (PSH), para adquirir valores de respeto, solidaridad y empatía por este sector de la sociedad, a través de actividades académicamente dirigidas (ADD), empleando una metodología activa y participativa centrada en el trabajo grupal y cooperativo que facilite el logro de competencias propias de su titulación. Para ello, se planificaron una serie de actividades que favorecieron la coordinación horizontal y vertical de las materias participantes en las Titulaciones de Grado en Educación Infantil y de Grado en Educación Primaria del Centro de Magisterio “Sagrado Corazón”. De esta forma, los resultados implican la conexión y continuidad entre las materias participantes. Por último, las conclusiones muestran que los estudiantes universitarios interiorizan los valores necesarios para la transferencia de aprendizajes adquiridos, a través de la experiencia vivencial con la realidad de las PSH, la cual permite una mirada conjunta de la inclusión y la invisibilidad social, empleando un enfoque participativo donde las opiniones e inquietudes de ambos colectivos se tengan en cuenta. Para ello, es preciso no poner barreras excluyentes a la educación del estudiante como futuro docente.The present innovative teaching proyect aims at raising awareness and moving students about the reality of homeless people, in order to acquire values of respect, solidarity and empathy for this society sector, through curricular activities, implementing an active and participatory methodology based on group and cooperative work which promotes the attainment of competences of their own degree. For this purpose, a set of activities that favoured horizontal and vertical coordination of the subjects involved in the Degrees in Early Childhood Education and Primary Education of the “Sagrado Corazón” Teacher Training School were planned. Thus, the outcomes involve the connection and the continuity between the subjects concerned. Finally, the findings show that university students internalize the values necessary for the transfer of learning acquired, through the lived experience with the reality of homelessness, which allows for an overall perspective of inclusion and social invisibility, by applying a participatory approach where views and concerns of both sides are given due consideration. This requires the removal of exclusive barriers to the education of the student as a future teacher

Perfiles de inteligencia emocional y conducta social en adolescentes españoles

Este trabajo tuvo dos objetivos, por una parte, identificar diferentes perfiles de inteligencia emocional (IE) y, por otra parte, comprobar si entre los perfiles identificados existen diferencias estadísticamente significativas respecto a la conducta social. Participaron 1.071 adolescentes españoles (50,2% chicas) españoles con edades de 14 a 17 años, a los que se les administró la “Escala de inteligencia emocional percibida” (Trait Meta-Mood Scale-24, TMMS-24) y la “Batería de socialización BAS-3”. El análisis de conglomerados identificó cuatro perfiles de IE: un grupo de adolescentes con un perfil de baja IE, un grupo con puntuaciones altas en percepción, un grupo con predominio de elevada regulación emocional y un último grupo de adolescentes con alta IE. Los resultados también indicaron diferencias estadísticamente significativas entre los perfiles en los patrones de comportamiento social, destacando los estudiantes de los grupos con alta IE generalizada y alta puntuación en regulación emocional, los cuales muestran mayores puntuaciones en conductas sociales positivas. Los descubrimientos se discuten en términos de sus implicaciones prácticas con adolescentes españoles.This work had two objectives. First, to identify different profiles of emotional intelligence (EI), and second, to verify the existence of significant statistical differences between the profiles identified in relation to social behavior. The participants were 1071 Spanish adolescents (50.2% girls), ranging in age from 14 to 17 years, who completed the Trait Meta-Mood Scale-24 (TMMS-24) and the Socialization Battery BAS-3. Cluster analysis identified four EI profiles: a group of adolescents with a low EI profile, a group with high scores in perception, a group with predominantly high emotional regulation, and a group of adolescents with high EI. The results also indicated statistically significant differences in the profiles in most of social behaviors. The students from the groups with high general EI scores and high scores in emotional regulation also show higher scores in several positive social behaviors. Findings are discussed in terms of their practical implications for Spanish adolescents.Este trabajo ha sido realizado a través del Proyecto con Ref: EDU2009-10316 perteneciente al Plan Nacional de Investigación Científica, Desarrollo de Innovación Tecnológica del Ministerio de Innovación y Ciencia, y fondos FEDER, concedido al primer autor

3D bioprinted functional skeletal muscle models have potential applications for studies of muscle wasting in cancer cachexia

Acquired muscle diseases such as cancer cachexia are responsible for the poor prognosis of many patients suffering from cancer. In vitro models are needed to study the underlying mechanisms of those pathologies. Extrusion bioprinting is an emerging tool to emulate the aligned architecture of fibers while implementing ad- ditive manufacturing techniques in tissue engineering. However, designing bioinks that reconcile the rheological needs of bioprinting and the biological requirements of muscle tissue is a challenging matter. Here we formulate a biomaterial with dual crosslinking to modulate the physical properties of bioprinted models. We design 3D bioprinted muscle models that resemble the mechanical properties of native tissue and show improved prolif- eration and high maturation of differentiated myotubes suggesting that the GelMA-AlgMA-Fibrin biomaterial possesses myogenic properties. The electrical stimulation of the 3D model confirmed the contractile capability of the tissue and enhanced the formation of sarcomeres. Regarding the functionality of the models, they served as platforms to recapitulate skeletal muscle diseases such as muscle wasting produced by cancer cachexia. The genetic expression of 3D models demonstrated a better resemblance to the muscular biopsies of cachectic mouse models. Altogether, this biomaterial is aimed to fabricate manipulable skeletal muscle in vitro models in a non- costly, fast and feasible manne

Analyzing the Impact of COVID-19 Trauma on Developing Post-Traumatic Stress Disorder among Emergency Medical Workers in Spain

Producción CientíficaThe early stages of the COVID-19 pandemic presented the characteristics of a traumatic event that could trigger post-traumatic stress disorder. Emergency Medical Services workers are already a high-risk group due to their professional development. The research project aimed to analyse the impact of the COVID-19 pandemic on EMS professionals in terms of their mental health. For this purpose, we present a descriptive crosssectional study with survey methodology. A total of 317 EMS workers (doctors, nurses, and emergency medical technicians) were recruited voluntarily. Psychological distress, post-traumatic stress disorder, and insomnia were assessed. The instruments were the General Health Questionnaire-12 (GHQ-12), the Davidson Trauma Scale (DTS-8), and the Athens Insomnia Scale (AIS-8). We found that 36% of respondents had psychological distress, 30.9% potentially had PTSD, and 60.9% experienced insomnia. Years of work experience were found to be positively correlated, albeit with low effect, with the PTSD score (r = 0.133). Finally, it can be stated that the COVID-19 pandemic has been a traumatic event for EMS workers. The number of professionals presenting psychological distress, possible PTSD, or insomnia increased dramatically during the early phases of the pandemic. This study highlights the need for mental health disorder prevention programmes for EMS workers in the face of a pandemic.Departamento de Enfermería de la Universidad de Valladoli

The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.Enrique de Álava’s lab is supported by the AECC (Asociación Española Contra el Cáncer), the Ministry of Economy and Competitiveness of Spain-FEDER (PI081828, RD06/0020/0059 RD12/0036/0017, PT13/0010/0056, PI110018, ISCIII Sara Borrell postdoc grant CD06/00001), the European Project EuroSARC (FP7-HEALTH-2011- two-stage, Project ID 278742 EUROSARC), Fundación Memoria de D. Manuel Solorzano Barruso, Fundación Cris contra el cancer, and Fundación María García Estrada. JLO was sponsored by the CSIC and the European Social Fund (post-doctoral grant JAE DOC) and is at present funded by the AECC. ATA is sponsored by the Fundaçao para a Ciência e Tecnologia, Portugal (fellowship SFRH/BD/69318/2010). OMT is funded by Fondo de Investigaciones Sanitarias-ISCIII (CES12/021) and the AECC. DHM is funded by the AECC. Work supported by the Xarxa de Bancs de Tumors de Catalunya (XBTC) sponsored by Pla Director d’Oncologia de Catalunya. AMC acknowledges funding from the European Union Seventh Framework Programme (FP7/2007-2013) under a Marie Curie International Reintegration Grant (PIRG-08- GA-2010-276998) and ISCIII-FEDER (CP13/00189).Peer Reviewe

TGF-β antagonist attenuates fibrosis but not luminal narrowing in experimental tracheal stenosis.

Introduction/Objective: Acquired tracheal stenosis (ATS) is an unusual disease often secondary to prolonged mechanical trauma. ATS pathogenesis involves inflammation and subsequent fibrosis with narrowing of the tracheal lumen. TGF-β represents a pivotal factor in most fibrotic processes and therefore, a potential target in this context. The aim of this study is to analyze the role of TGF-β as a target for anti-fibrotic interventions in tracheal stenosis. Methods: Human stenotic tracheobronchial tissues from patients with benign airway stenosis and normal controls from pneumonectomy specimens were analyzed. Tracheal stenosis was induced in adult NZ rabbits by a circumferential thermal injury to the mucosa during open surgery and re-anastomosis. Rabbits were treated postoperatively with a peritracheal collagen sponge containing a TGF-β peptide antagonist (p17) or vehicle. Fibrosis was determined by Masson’s trichrome staining, and α-SMA+ Results: Human and rabbit stenotic tissues showed extensive submucosal fibrosis, characterized by significantly increased α-SMA myofibroblasts, CTGF and p-Smad2/3 expression by immunohistochemistry. + myofibroblasts and CTGF expression. In human stenotic lesions, increased p-Smad2/3+ nuclei were also observed. p17 treatment significantly reduced the fibrotic thickness as well as the density of α-SMA+ myofibroblasts and CTGF+ Conclusion: ATS is characterized by a TGF-β dependent fibrotic process but reduction of the fibrotic component by TGF-β1 antagonist therapy was not sufficient to improve tracheal narrowing, suggesting that fibrosis may not be the main contributor to luminal stenosis. cells in rabbit stenotic lesions but failed to improve the luminal area.pre-print1304 K

Gilthead seabream (Sparus aurata) Mx proteins show positive and negative synergy in their antiviral activity

Due to their direct antiviral activity, Mx proteins play a main role in the response mediated by the type I interferon against viral infections. The study of the farmed fish gilthead seabream Mx genes is specially interesting, since this species displays an unusually high natural resistance to viral diseases, becoming a potential asymptomatic carrier and/or reservoir for several viruses pathogenic to other fish species. Gilthead seabream has three Mx proteins (Mx1, Mx2 and Mx3) that, separately, display antiviral activity against a wide range of viruses, showing interesting differences in their antiviral specificities. In this work, the possible synergy between the three Mx isoforms has been studied using in vitro systems, consisting of permanently transfected CHSE-214 cells expressing two or the three gilthead seabream Mx proteins. The antiviral activity of these Mx combinations has been tested against the infection by the Infectious Pancreatic Necrosis Virus (IPNV), the Viral Haemorrhagic Septicaemia Virus (VHSV) and the European Sheatfish Virus (ESV) in cells inoculated at 0.1 and 0.01 multiplicity of infection (MOI). The antiviral effect was evaluated by viral titration (TCID50 method). Interestingly, a positive synergistic effect in the antiviral activity against ESV was observed when Mx2 and Mx3 were combined, and this effect was intensified when the three isoforms were present in these cells. In contrast, the presence of more than one Mx isoform interfered with the antiviral activity against IPNV and VHSV showed by the Mx proteins expressed separately. Furthermore, Mx2 combined with Mx3, and the combination of the three Mx proteins exerted a negative synergistic effect against IPNV infection. Specifically, the viral titres were significantly higher in Mx expressing cells than in control cells. In the same way, in Mx1 and Mx2 expressing cells infected with VHSV the viral replication was alsoincreased. These results suggest the interaction between Mx isoforms, in which the expression level of each isoform might be an important factor, and support the idea of finely tuned mechanisms controlling the antiviral activity of Mx proteins. The authors want to thank Dr. C. P. Dopazo (University of Santiago de Compostela, Spain) and Dr. K. Way (CEFAS, Weymouth lab, UK) for supplying the viruses VHSV and ESV, respectively, used in this work.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech