Igualdad de género en España, Castilla y León y Valladolid: anásis de sus políticas

Nuestra sociedad, siempre, ha visto y descrito a la mujer como delicada, dócil, tímida…entre otros adjetivos que denotan inferioridad y desigualdad en un mundo dominado por el patriarcado, donde el hombre ocupa una posición de superioridad jerárquica en todo los ámbitos de la sociedad, relegando así a la mujer, a un segundo plano, donde esta” jerarquía de género” ha sido estudiada y demostrada desde diferentes puntos de vista. Este trabajo pretende mostrar la evolución de la situación de la mujer desde la instauración de nuestra Constitución española en 1978 hasta nuestros días, realizando un análisis de las distintas políticas en dicha materia mostrando la distancia entre la igualdad formal y la real.Grado en Trabajo Socia

DNA metabolism's role in neuronal activity-dependent processes

Programa de Doctorado en NeurocienciasRecently some studies demonstrate that adult neuronal genome is a genetic mosaic but the role of this mosaicism and how is generated are not well known. The two main mechanisms that could result in the neuronal mosaic genome are somatic recombination and the LINE-1 (L1) retrotransposition. Some evidences, alterations in central nervous system development found in knock-out (KO) mice for proteins related with DNA repair processes and L1 activation in neuronal precursors, suggest that neuronal genome mosaicism may be related with the generation of neuronal diversity during central nervous system development. However, if genome reorganization processes happen in the adult nervous system during neuronal plasticity events are not established. Recently, it has been reported that neuronal activity transiently provokes increase of neuronal DNA breaks in cerebral areas where long-term neuronal plasticity events takes place, in some case related with cognition. DNA breaks have been related with the initial steps of gene expression activation, but also can be compatible with genomic reorganization. The main objective of this PhD project was determinate the potential role of processes that may result in genomic reorganization during neuronal activation. Firstly, we studied the importance of adult L1 retrotransposition in neuronal activation processes. Our results showed an activity-dependent increase in genome de novo L1 insertions in the hippocampus. Also using systemic pharmacologic and intrahippocampal genetic approaches, we demonstrate that L1 activation in the adult hippocampus is required for long-term memory formation. Secondly, we looked for evidences of potential genome reorganization events induced by exploration of an enriched environment, a protocol that provokes neuronal activity-dependent events. Exploratory session provoked an increase in the number of neurons containing DNA breaks, measured as the number of cells with 53BP1 foci, and in gene expression of genes related with DNA metabolism and DNA breaks. Both events happen in a sequential temporal-dependent manner in hippocampus and prefrontal cortex. Thirdly, to clear up the possible physiological role of DNA metabolism proteins in cognition, we made transient knock down of tyrosil-DNA phosphodiesterases 1 and 2, and h2ax, by intrahippocampal administration with specific antisense oligonucleotides (ASOs), and passive avoidance, an hippocampal-dependent cognition test. Hippocampal knock down of these three proteins provoked impairment in long-term memory formation in passive avoidance test. Finally, using the H2AX-/- mice we studied the role of H2AX in central nervous system function. H2AX-/- mice showed morphological alterations in the amygdala and hippocampus compared with the wt mice. Also, at behavioral level H2AX-/- mice presented deficits in depressive, cognition and social behaviors. In conclusion, all these data together suggest activity-dependent neural DNA reorganizations in the adult hippocampus. In addition, genetic and pharmacological manipulations of DNA reorganizations events in adult brain seem to affect cognition processes such as memory formation. Finally, depletion of H2AX in the germinal line provokes alteration in central nervous system function.Universidad Pablo de Olavide. Departamento de Fisiología, Anatomía y Biología CelularPostprin

HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study

The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tarnbaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity

The HERC proteins and the nervous system

The HERC protein family is one of three subfamilies of Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases. Six HERC genes have been described in humans, two of which encode Large HERC proteins -HERC1 and HERC2- with molecular weights above 520 kDa that are constitutively expressed in the brain. There is a large body of evidence that mutations in these Large HERC genes produce clinical syndromes in which key neurodevelopmental events are altered, resulting in intellectual disability and other neurological disorders like epileptic seizures, dementia and/or signs of autism. In line with these consequences in humans, two mice carrying mutations in the Large HERC genes have been studied quite intensely: the tambaleante mutant for Herc1 and the Herc2+/530 mutant for Herc2. In both these mutant mice there are clear signs that autophagy is dysregulated, eliciting cerebellar Purkinje cell death and impairing motor control. The tambaleante mouse was the first of these mice to appear and is the best studied, in which the Herc1 mutation elicits: (i) delayed neural transmission in the peripheral nervous system; (ii) impaired learning, memory and motor control; and (iii) altered presynaptic membrane dynamics. In this review, we discuss the information currently available on HERC proteins in the nervous system and their biological activity, the dysregulation of which could explain certain neurodevelopmental syndromes and/or neurodegenerative diseases.Ministerio de Economía y Competitividad SAF2015-64171-

The HERC proteins and the nervous system

The HERC protein family is one of three subfamilies of Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases. Six HERC genes have been described in humans, two of which encode Large HERC proteins -HERC1 and HERC2- with molecular weights above 520 kDa that are constitutively expressed in the brain. There is a large body of evidence that mutations in these Large HERC genes produce clinical syndromes in which key neurodevelopmental events are altered, resulting in intellectual disability and other neurological disorders like epileptic seizures, dementia and/or signs of autism. In line with these consequences in humans, two mice carrying mutations in the Large HERC genes have been studied quite intensely: the tambaleante mutant for Herc1 and the Herc2+/530 mutant for Herc2. In both these mutant mice there are clear signs that autophagy is dysregulated, eliciting cerebellar Purkinje cell death and impairing motor control. The tambaleante mouse was the first of these mice to appear and is the best studied, in which the Herc1 mutation elicits: (i) delayed neural transmission in the peripheral nervous system; (ii) impaired learning, memory and motor control; and (iii) altered presynaptic membrane dynamics. In this review, we discuss the information currently available on HERC proteins in the nervous system and their biological activity, the dysregulation of which could explain certain neurodevelopmental syndromes and/or neurodegenerative diseases

The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement

Neuromuscular disorders (NMDs) affect 1 in 3000 people worldwide. There are more than 150 different types of NMDs, where the common feature is the loss of muscle strength. These disorders are classified according to their neuroanatomical location, as motor neuron diseases, peripheral nerve diseases, neuromuscular junction diseases, and muscle diseases. Over the years, numerous studies have pointed to protein homeostasis as a crucial factor in the development of these fatal diseases. The ubiquitin-proteasome system (UPS) plays a fundamental role in maintaining protein homeostasis, being involved in protein degradation, among other cellular functions. Through a cascade of enzymatic reactions, proteins are ubiquitinated, tagged, and translocated to the proteasome to be degraded. Within the ubiquitin system, we can find three main groups of enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin-protein ligases). Only the ubiquitinated proteins with specific chain linkages (such as K48) will be degraded by the UPS. In this review, we describe the relevance of this system in NMDs, summarizing the UPS proteins that have been involved in pathological conditions and neuromuscular disorders, such as Spinal Muscular Atrophy (SMA), Charcot-Marie-Tooth disease (CMT), or Duchenne Muscular Dystrophy (DMD), among others. A better knowledge of the processes involved in the maintenance of proteostasis may pave the way for future progress in neuromuscular disorder studies and treatments.Ministerio de Economía y Competitividad RTI2018-098645-B-10

Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response

Microglia represent a specialized population of macrophages-like cells in the central nervous system (CNS) considered immune sentinels that are capable of orchestrating a potent inflammatory response. Microglia are also involved in synaptic organization, trophic neuronal support during development, phagocytosis of apoptotic cells in the developing brain, myelin turnover, control of neuronal excitability, phagocytic debris removal as well as brain protection and repair. Microglial response is pathology dependent and affects to immune, metabolic. In this review, we will shed light on microglial activation depending on the disease context and the influence of factors such as aging, environment or cell-to-cell interaction

Endoglin, a novel biomarker and therapeutical target to prevent malignant peripheral nerve sheath tumor growth and metastasis.

PURPOSE Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGF-β coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. EXPERIMENTAL DESIGN ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. RESULTS ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis. CONCLUSIONS Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.We apologize to those authors whose work could not be cited due to size limitations. We thank Dr. Eduard Serra, Dr. Conxi Lázaro and Dr. David Lyden for their support in the project. We also thank Héctor Tejero for his help in analyzing RNA-seq data. Dr. Peinado laboratory is funded by US Department of Defense (W81XWH-16-1-0131), Agencia Estatal de Investigación/Ministerio de Ciencia e Innovación (AEI/MCIN) (PID2020-118558RB-I00/AEI/10.13039/501100011033), Fundación Proyecto Neurofibromatosis, European Union’s Horizon 2020 research and innovation programme “proEVLifeCycle” under the Marie Skłodowska-Curie grant agreement No 860303, and Fundación Científica AECC. We are also grateful for the support of the Ministerio de Universidades (Programa de Formación de Profesorado Universitario (FPU)) for the fellowship FPU016/05356 awarded to T. González-Muñoz and to the Translational NeTwork for the CLinical application of Extracellular VesicleS (TeNTaCLES) RED2018-102411-T(AEI/10.13039/501100011033). A. Di Giannatale was supported during this work by a research gran Nuovo-Soldati Foundation. The CNIO, certified as Severo Ochoa Excellence Centre, is supported by the Spanish Government through the Instituto de Salud Carlos III.N

Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas of the peripheral nervous system that develop either sporadically or in the context of neurofibromatosis type 1 (NF1). MPNST diagnosis can be challenging and treatment outcomes are poor. We present here a resource consisting of the genomic characterization of 9 widely used human MPNST cell lines for their use in translational research. NF1-related cell lines recapitulated primary MPNST copy number profiles, exhibited NF1 , CDKN2A , and SUZ12/EED tumor suppres-sor gene (TSG) inactivation, and presented no gain-of-function mutations. In contrast, sporadic cell lines collectively displayed different TSG inactivation patterns and presented kinase-activating mutations, fusion genes, altered muta-tional frequencies and COSMIC signatures, and different methylome-based clas-sifications. Cell lines re-classified as melanomas and other sarcomas exhibited a different drug-treatment response. Deep genomic analysis, methylome-based classification, and cell-identity marker expression, challenged the identity of common MPNST cell lines, opening an opportunity to revise MPNST differential diagnosis

Vedolizumab and ART in recent HIV-1 infection unveil the role of α4β7 in reservoir size

BACKGROUND. We evaluated the safety and viral rebound, after analytical treatment interruption (ATI), of vedolizumab and ART in recent HIV-1 infection. We used this model to analyze the effect of alpha 4 beta 7 on the HIV-1 reservoir size. METHODS. Participants started ART with monthly vedolizumab infusions, and ATI was performed at week 24. Biopsies were obtained from ileum and cecum at baseline and week 24. Vedolizumab levels, HIV-1 reservoir, flow cytometry, and cell-sorting and antibody competition experiments were assayed. RESULTS. Vedolizumab was safe and well tolerated. No participant achieved undetectable viremia off ART 24 weeks after ATI. Only a modest effect on the time to achieve more than 1,000 HIV-1 RNA copies/mL and the proportion of participants off ART was observed, being higher in the vedolizumab group compared with historical controls. Just before ATI, alpha 4 beta 7 expression was associated with HIV-1 DNA and RNA in peripheral blood and with PD1 and TIGIT levels. Importantly, a complete blocking of alpha 4 beta 7 was observed on peripheral CD4+ T cells but not in gut (ileum and cecum), where alpha 4 beta 7 blockade and vedolizumab levels were inversely associated with HIV-1 DNA. CONCLUSION. Our findings support alpha 4 beta 7 as an important determinant in HIV-1 reservoir size, suggesting the complete alpha 4 beta 7 blockade in tissue as a promising tool for HIV-cure combination strategies. TRIAL REGISTRATION. ClinicalTrials.gov NCT03577782. FUNDING. This work was supported by the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, a way to make Europe, research contracts FI17/00186 and FI19/00083 and research projects PI18/01532, PI19/01127, PI22/01796), Conserjer & iacute;a de Econom & iacute;a, Conocimiento, Empresas y Universidad, Junta de Andaluc & iacute;a (research projects P20/00906), the Red Tem & aacute;tica de Investigaci & oacute;n Cooperativa en SIDA (RD16/0025/0020), and the Spanish National Research Council