La comunicación académica y la evaluación de los trabajos en ciencias sociales. La revista científica complutense: Teknokultura, de Cultura Digital y Movimientos Sociales

Este proyecto de innovación docente persigue la formación de los estudiantes, en el ámbito de las prácticas de grado, en las características de las publicaciones científicas, en especial a la tarea de evaluación, para que adquieran una mayor capacidad crítica y auto-crítica en sus producciones universitarias y profesionales. Asimismo, se pretende incidir en la importancia de un recurso de la Universidad como son las revistas científicas complutenses, desconocidas para la mayoría de alumnos de grado. Se colaborará con la revista revista científica complutense: Teknokultura, de Cultura Digital y Movimientos Sociales, de tal modo que su equipo editorial aportará el conocimiento y las experiencias en la publicación de trabajos científico académicos. La principal utilidad es el trabajo para la adquisición de sentido de la crítica y la evaluación de la calidad de los alumnos con respecto a sus producciones. Esto se pretende conseguir a partir del conocimiento más profundo de los procesos editoriales,con una revista científica complutense de referencia como Teknokultura. Se destaca el conocimiento de un recurso tan importante como las revistas científicas complutenses en los estudios de grado, así como una comprensión del funcionamiento de la publicación científica en revistas. Este proyecto aunque está diseñado para grados de ciencias sociales es extensible a otras ramas del conocimiento como las humanidades y ciencias naturales

Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis

In the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of NSCs have been hypothesized to be at the origin of glioma. Thus, unravelling the molecular underpinnings of the regulated activation that NSCs must undergo to proliferate and generate new progeny is of considerable relevance. Current research has identified cues promoting or restraining NSCs activation. Yet, whether NSCs depend on external signals to survive or if intrinsic factors establish a threshold for sustaining their viability remains elusive, even if this knowledge could involve potential for devising novel therapeutic strategies. Kidins220 (Kinase D-interacting substrate of 220 kDa) is an essential effector of crucial pathways for neuronal survival and differentiation. It is dramatically altered in cancer and in neurological and neurodegenerative disorders, emerging as a regulatory molecule with important functions in human disease. Herein, we discover severe neurogenic deficits and hippocampal-based spatial memory defects accompanied by increased neuroblast death and high loss of newly formed neurons in Kidins220 deficient mice. Mechanistically, we demonstrate that Kidins220-dependent activation of AKT in response to EGF restraints GSK3 activity preventing NSCs apoptosis. We also show that NSCs with Kidins220 can survive with lower concentrations of EGF than the ones lacking this molecule. Hence, Kidins220 levels set a molecular threshold for survival in response to mitogens, allowing adult NSCs growth and expansion. Our study identifies Kidins220 as a key player for sensing the availability of growth factors to sustain adult neurogenesis, uncovering a molecular link that may help paving the way towards neurorepair

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Regulación de la proteína Kidins220/ARMS en excitotoxicidad e isquemia cerebral: implicaciones en supervivencia neuronal

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 20-11-2009Families of neurotrophin (Trk) and ephrin (Eph) tyrosine kinase receptors, and NMDA type of glutamate receptors (NMDARs) play essential roles in the development and functioning of the central nervous system. Physical and functional associations among these proteins have been reported, and contribute to modulate the activity, efficiency and intensity of the cascades in which they are individually involved. A shared downstream effector for neurotrophin and ephrin signaling is the kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS). Kidins220/ARMS is an integral membrane protein originally identified as the first physiological substrate for protein kinase D, and whose expression is enriched in developing neuronal populations. Because this molecule is obligatory for neurotrophin and ephrin signaling, and given these two pathways are connected with those of NMDARs, we asked whether Kidins220/ARMS and this type of glutamate receptors were functionally related. In this study we report the identification of an association between Kidins220/ARMS and the NMDAR taking place at the plasma membrane of primary cultured cortical neurons and in adult rat brain. Importantly, we also discover that excitotoxicity, a specific form of neuronal death induced by synaptic and extrasynaptic NMDAR overstimulation, dramatically decreases Kidins220/ARMS levels in neuronal cultures and in an animal model of transient cerebral ischemia. Kidins220/ARMS downregulation is triggered by overactivation of NMDARs containing NR2B subunits and calcium influx, and involves a dual mechanism: rapid cleavage by the calcium-dependent protease calpain and calpainindependent silencing of Kidins/Arms gene transcription. Interestingly, in silico analysis and in vitro proteolysis by purified calpain have allowed us to predict the processing sites for this protease in Kidins220/ARMS sequence. Additionally, we have characterized the activation state of Rap1 GTPase and ERK-1/2, demonstrating for the first time that overstimulation of NMDARs induces a transient increase not only in ERK-1/2 but also in Rap1 activity after brief exposure to NMDAR coagonists. Furthermore, under excitotoxic conditions calpain also proteolyses S-SCAM and PDZGEF1, two PDZ proteins implicated, together with Kidins220/ARMS, in the sustained activation of Rap1 and ERK-1/2 induced by neurotrophins. Finally, we show that knocking-down Kidins220/ARMS reduces ERK-1/2 activity under both basal and excitotoxic conditions, and results in a decrease in neuronal survival as well as an enhanced neuronal death triggered by NMDARs overstimulation. Our results demonstrate Kidins220/ARMS participation in neuronal survival and death pathways, and constitute the first report of its regulation under pathological conditions

A novel neuroprotection target with distinct regulation in stroke and Alzheimer’s disease

Stroke and Alzheimer’s disease (AD) share a common mechanism of neuronal death known as excitotoxicity. Therapeutic approaches blocking excitotoxic responses, with agents, such as the NMDA receptor antagonist memantine, inhibitors of the protease calpain or GSK3 have been tested in poststroke and AD treatments. Novel therapies for neuroprotection are based on the use of cell-penetrating peptides (CPPs) targeting molecules and signaling pathways involved in neurodegeneration. The study of the molecular mechanisms that regulate the levels of the prosurvival protein Kidins220/ARMS in acute versus chronic AD-related neurodegeneration has established a clear parallelism with those controlling tau proteostasis that involve changes in GSK3 phosphorylation and calpain processing. The development of a neuroprotective CPP derived from this molecule, effective against acute excitotoxicity provide new evidence to support the use of GSK3 inhibitors in combination with specific CPPs as a novel strategy to reduce neuronal damage in AD.Peer reviewe

Development of a neuroprotective peptide that preserves survival pathways by preventing Kidins220/ARMS calpain processing induced by excitotoxicity

Kinase D-interacting substrate of 220kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), has a central role in the coordination of receptor crosstalk and the integration of signaling pathways essential for neuronal differentiation, survival and function. This protein is a shared downstream effector for neurotrophin- and ephrin-receptors signaling that also interacts with the N-methyl-d-aspartate type of glutamate receptors (NMDARs). Failures in neurotrophic support and glutamate signaling are involved in pathologies related to excitotoxicity and/or neurodegeneration, where different components of these dynamic protein complexes result altered by a combination of mechanisms. In the case of Kidins220/ARMS, overactivation of NMDARs in excitotoxicity and cerebral ischemia triggers its downregulation, which contributes to neuronal death. This key role in neuronal life/death decisions encouraged us to investigate Kidins220/ARMS as a novel therapeutic target for neuroprotection. As the main mechanism of Kidins220/ARMS downregulation in excitotoxicity is proteolysis by calpain, we decided to develop cell-penetrating peptides (CPPs) that could result in neuroprotection by interference of this processing. To this aim, we first analyzed in detail Kidins220/ARMS cleavage produced in vitro and in vivo, identifying a major calpain processing site in its C-terminal region (between amino acids 1669 and 1670) within a sequence motif highly conserved in vertebrates. Then, we designed a 25-amino acids CPP (Tat-K) containing a short Kidins220/ARMS sequence enclosing the identified calpain site (amino acids 1668-1681) fused to the HIV-1 Tat protein basic domain, able to confer membrane permeability to attached cargoes. Transduction of cortical neurons with Tat-K reduced Kidins220/ARMS calpain processing in a dose- and time-dependent manner upon excitotoxic damage and allowed preservation of the activity of pERK1/2 and pCREB, signaling molecules central to neuronal survival and functioning. Importantly, these effects were associated to a significant increase in neuronal viability. This Kidins220/ARMS-derived peptide merits further research to develop novel neuroprotective therapies for excitotoxicity-associated pathologies.This work was supported by the Ministerio de Economía y Competitividad (SAF2011-26233 and SAF2014-52737- P to TI, BFU2010-18380/BFI and BFU2013-43808- R to MD-G.); Comunidad de Madrid (P2010/BMD-2331-Neurodegmodels to TI) and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Instituto de Salud Carlos III, to TI). CL-M was a recipient of a contract from SAF2011-26233; AG-M has been funded by contracts from P2010/BMD-2331, SAF2011-26233 and CIBERNED; SAD is a recipient of a FPI pre-doctoral fellowship associated to BFU2010-18380/BFI and GST has been funded by contracts from Consejo Superior de Investigaciones Cientıficas associated to projects BFU2010-18380/BFI and BFU2013-43808- R.Peer Reviewe

Magnetoimpedancia en composites granate de itrio y hierro/grafeno

Trabajo presentado al XIV Congreso Nacional de Materiales, celebrado en Gijón del 8 al 10 de junio de 2016.Es bien sabido que los materiales magnéticos pueden diferenciarse entre los metálicos, con una alta conductividad, y los aislantes, de tipo oxídico con una baja conductividad. En determinados casos, y mediante un tratamiento térmico en atmósferas reductoras, la conductividad de los aislantes magnéticos puede incrementarse hasta cierto punto. Sin embargo para algunas aplicaciones, como filtros de radiofrecuencia o microondas, el poder modificar substancialmente el valor de dicha conductividad puede dar lugar a interesantes aplicaciones.Peer Reviewe

Spark plasma sintered BaTiO3/graphene composites for thermoelectric applications

The viability of spark plasma sintered graphene/barium titanate ceramic matrix composites as thermoelectric materials is investigated. The temperature dependence of electrical conductivity, thermal conductivity and Seebeck coefficient was analyzed. The addition of low amounts of graphene oxide combined with the spark plasma sintering process increases electrical conductivity of pure BaTiO several orders of magnitude, whereas the thermal conductivity shows only a moderate enhancement. The composites display a semiconducting behaviour, with the resistivity decreasing with increasing temperature and following a thermally activated temperature dependence at high T. A strong dependence of ZT figure of merit with the graphene concentration and the measurement temperature was found. Optimal values are found for 1.7 wt% graphene oxide at the maximum experimental temperature (600 K).The authors acknowledge funding from Ministerio de Economía y Competitividad through the Project TEC2014-53088-C3-2-R, Principado de Asturias through the project GRUPIN14-109 and Junta de Castilla-La Mancha through the project N PPII-2014-019-P.Peer Reviewe

Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways

12 pages, 7 figures.Functional and protein interactions between the N-methyl-D-aspartate type of glutamate receptor (NMDAR) and neurotrophin or ephrin receptors play essential roles in neuronal survival and differentiation. A shared downstream effector for neurotrophin- and ephrin-receptor signaling is kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS). Because this molecule is obligatory for neurotrophin-induced differentiation, we investigated whether Kidins220/ARMS and NMDAR functions were related. Here, we identify an association between these proteins and discover that excitotoxicity, a specific form of neuronal death induced by NMDAR overstimulation, dramatically decreases Kidins220/ARMS levels in cortical neurons and in a model of cerebral ischemia. Kidins220/ARMS downregulation is triggered by overactivation of NMDARs containing NR2B subunits and subsequent Ca2+ influx, and involves a dual mechanism: rapid cleavage by the Ca2+-dependent protease calpain and calpain-independent silencing of Kidins220/Arms gene transcription. Additionally, Kidins220/ARMS knockdown decreases ERK activation and basal neuronal viability, and enhances neuronal death under excitotoxic conditions. Our results demonstrate Kidins220/ARMS participation in neuronal life and death pathways, and constitute the first report of its regulation under pathological conditions.This work was supported by grants BFU2007-67695 from `Ministerio de Ciencia e Innovación and `Fundación Mutua Madrileña' to M.D.-G.; and SAF2008-01951 from `Ministerio de Ciencia e Innovación', CAM S-SAL-0202-2006-01 from `Comunidad de Madrid' and CIBERNED from `Instituto de Salud Carlos III' to T.I. C.L.-M. and S.G. were recipients of a research contract and a predoctoral fellowship, respectively, funded by `Comunidad de Madrid'.Peer reviewe

Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization

Epithelial-mesenchymal transition (EMT) has been associated with increased aggressiveness and acquisition of migratory properties providing tumor cells with the ability to invade into adjacent tissues. Downregulation of E-cadherin, a hallmark of EMT, is mediated by several transcription factors (EMT-TFs) that act also as EMT inducers, among them, Snail1 and the bHLH transcription factor E47. We previously described lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family, as a Snail1 regulator and EMT inducer. Here we show that LOXL2 is also an E47-interacting partner and functionally collaborates in the repression of E-cadherin promoter. Loss and gain of function analyses combined with in vivo studies in syngeneic breast cancer models demonstrate the participation of LOXL2 and E47 in tumor growth and their requirement for lung metastasis. Furthermore, LOXL2 and E47 contribute to early steps of metastatic colonization by cell and noncell autonomous functions regulating the recruitment of bone marrow progenitor cells to the lungs and by direct transcriptional regulation of fibronectin and cytokines TNFα, ANG-1 and GM-CSF. Moreover, fibronectin and GM-CSF proved to be necessary for LOXL2/E47-mediated modulation of tumor growth and lung metastasis.The work was supported by the Spanish Ministry of Science and Innovation (SAF2010–21143; Consolider 2007-CS00017); AICR (12–1057) and ISCIII (RETIC- RD12/0036/0007) to AC, and Comunidad de Madrid (S2010/BMD-2302) to AC and GMB. EPC and VS are founded from the AICR grant.Peer Reviewe