Development and Maintenance of the Brain’s Immune Toolkit: Microglia and Non-Parenchymal Brain Macrophages

Microglia and non-parenchymal macrophages located in the perivascular space, the meninges and the choroid plexus are independent immune populations that play vital roles in brain development, homeostasis, and tissue healing. Resident macrophages account for a significant proportion of cells in the brain and their density remains stable throughout the lifespan thanks to constant turnover. Microglia develop from yolk sac progenitors, later evolving through intermediate progenitors in a fine-tuned process in which intrinsic factors and external stimuli combine to progressively sculpt their cell type-specific transcriptional profiles. Recent evidence demonstrates that non-parenchymal macrophages are also generated during early embryonic development. In recent years, the development of powerful fate mapping approaches combined with novel genomic and transcriptomic methodologies have greatly expanded our understanding of how brain macrophages develop and acquire specialized functions, and how cell population dynamics are regulated. Here, we review the transcription factors, epigenetic remodeling, and signaling pathways orchestrating the embryonic development of microglia and non-parenchymal macrophages. Next, we describe the dynamics of the macrophage populations of the brain and discuss the role of progenitor cells, to gain a better understanding of their functions in the healthy and diseased brain. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 561-579, 2018Spanish Ministry of Economy and Competitiveness (MINECO) with European Regional Development Fund (ERDF) funds; contract grant numbers: BFU201566689, RYC-2013-12817. BBVA Foundation and a Basque Government; contract grant number: PI_2016_1_0011. "Ramon y Cajal" and European Social Fund (ESF) and national resources (MINEICO-AEI); contract grant number: RYC-2015-18056. MINECO co-financed by the European Regional Development Fund (ERDF); contract grant number: SAF2014-60233-JIN. Instituto de Neurociencias is a "Centre of Excellence Severo Ochoa"; contract grant number: SEV-2013-0317. Medical Research Council, Alzheimer's Research UK and The Leverhulme Trust

La formalización laboral del régimen de construcción civil en la Inmobiliaria y Constructora San Fernando S. A. C.; Trujillo, 2019

El presente trabajo tiene como finalidad describir los aspectos que abarca la formalización laboral del régimen de construcción civil en la empresa inmobiliaria y constructora San Fernando S.A.C. De este modo la investigación es no experimental descriptiva, con un estudio cuantitativo siendo necesario hacer un análisis mediante una ficha de observación y documental de los principales aspectos y documentos relacionados la formalización laboral. Las empresas que pertenecen al régimen de construcción civil juegan un papel muy importante por su incidencia en la generación de empleo. Sin embargo, existen dificultades en el cumplimiento de este régimen laboral. Es por ello, que la formalización laboral se convierte en una herramienta para el desarrollo productivo en el crecimiento inclusivo con más y mejores condiciones laborales. De este modo, en el presente trabajo de investigación primero se describen las diferentes obligaciones administrativas, tales como el registro de los trabajadores en planilla y el cumplimiento de los diferentes aspectos que conlleva el ingreso de un trabajador; después, se exponen los cálculos de las remuneraciones y beneficios sociales. Luego, se muestra los aportes y contribuciones; para que finalmente, se identifique las condiciones de trabajo que se debe tener en cuenta en el régimen de construcción civil. Todo esto para llegar a determinar que la formalización laboral del régimen de construcción civil es relevante para los empresarios dispuesto a tener mayor conocimiento de la ley e incorporar dentro de su gestión administrativa laboral y de este modo tener un ambiente laboral óptimo para sus trabajadores

Loss of neuronal 3d chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction

The interior of the neuronal cell nucleus is a highly organized three-dimensional (3D) structure where regions of the genome that are linearly millions of bases apart establish sub-structures with specialized functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice expressing GFP-tagged histone H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons caused chromocenter declustering and disrupted the association of heterochromatin with the nuclear lamina. The loss of these structures did not affect neuronal viability but was associated with specific transcriptional and behavioural deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D organization of chromatin within neuronal cells provides an additional level of epigenetic regulation of gene expression that critically impacts neuronal function. This in turn suggests that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture

Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis

Altres ajuts: Fundación Tatiana Pérez de Guzman el Bueno; SynCogDis Network (SAF2014-52624-REDT, SAF2017-90664-REDT); Human Frontiers Science Program (HFSP RGP0022/2013); Fondo Europeo de Desarrollo Regional (FEDER).Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type-specific vulnerability and their progression and histopathological classification remain controversial. Using single-cell electrophysiology in vivo and immediate-early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rodents. Bulk tissue and single-nucleus expression profiling disclose sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage channels, synaptic signaling, and cell adhesion are deregulated differently by epilepsy across sublayers, whereas neurodegenerative signatures primarily involve superficial cells. Pseudotime analysis of gene expression in single nuclei and in situ validation reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis

Methodology to optimize fluid-dynamic design in a redox cell

[EN] The present work is aimed at the optimization of a redox cell design. The studied redox cell consists on a device designed to convert the energy of reactants into electrical energy when a liquid electrolyte reacts at the electrode in a conventional manner. In this particular sort of cells, the two electrolytes are present and separated by a proton exchange membrane. Therefore, the flow of the electrolyte and the interaction with the membrane takes a paramount importance for the general performance of the cell. A methodology for designing the inlet part of the cell based on optimizing the uniformity of the flow and the initial position of the membrane is presented in this study. This methodology, based on the definition and optimization of several parameters related to the electrolyte flow in different regions of the geometry, is depicted. The CFD (Computational Fluid Dynamics) model coupled with the statistical study pointed to several practical conclusions on how to improve the final geometry construction of the redox cell. A particular case study of redox cell is implemented in order to validate the proposed methodology[ES] El presente trabajo tiene como objetivo la optimización de un diseño de la batería redox. La pila redox estudiada consiste en un dispositivo diseñado para convertir la energía de los reactivos en energía eléctrica cuando un electrolito líquido reacciona en el electrodo de una manera convencional . En este tipo particular de células , los dos electrolitos están presentes y separados por una membrana de intercambio de protones . Por lo tanto , el flujo del electrolito y la interacción con la membrana tiene una importancia primordial para el rendimiento general de la célula . La metodología propuesta para el diseño de la parte de entrada de la celda en base a la optimización de la uniformidad del flujo y la inicial posición de la membrana se presenta en este estudio . Esta metodología, basada en la definición y optimización de varios parámetros relacionados con el flujo de electrolito en las diferentes regiones de la geometría , es representado . El modelo de CFD (Computational Fluid Dynamics ), junto con el estudio estadístico se refirió a varias conclusiones prácticas sobre la manera de mejorar la construcción geometría final de la pila redox . El estudio de caso particular de célula redox que se describe, se implementa con el fin de validar la metodología propuestaEscudero González, J.; López Jiménez, PA. (2014). Methodology to optimize fluid-dynamic design in a redox cell. Journal of Power Sources. 251(1):243-253. doi:10.1016/j.jpowsour.2013.11.058S243253251

Modelling of redox flow battery electrode processes at a range of length scales : a review

In this article, the different approaches reported in the literature for modelling electrode processes in redox flow batteries (RFBs) are reviewed. RFB models vary widely in terms of computational complexity, research scalability and accuracy of predictions. Development of RFB models have been quite slow in the past, but in recent years researchers have reported on a range of modelling approaches for RFB system optimisation. Flow and transport processes, and their influence on electron transfer kinetics, play an important role in the performance of RFBs. Macro-scale modelling, typically based on a continuum approach for porous electrode modelling, have been used to investigate current distribution, to optimise cell design and to support techno-economic analyses. Microscale models have also been developed to investigate the transport properties within porous electrode materials. These microscale models exploit experimental tomographic techniques to characterise three-dimensional structures of different electrode materials. New insights into the effect of the electrode structure on transport processes are being provided from these new approaches. Modelling flow, transport, electrical and electrochemical processes within the electrode structure is a developing area of research, and there are significant variations in the model requirements for different redox systems, in particular for multiphase chemistries (gas–liquid, solid–liquid, etc.) and for aqueous and non-aqueous solvents. Further development is essential to better understand the kinetic and mass transport phenomena in the porous electrodes, and multiscale approaches are also needed to enable optimisation across the relevent length scales

Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry

The Rubinstein-Taybi Syndrome (RSTS) is a congenital disease that affects brain development causing severe cognitive deficits. In most cases the disease is associated with dominant mutations in the gene encoding the CREB binding protein (CBP). In this work, we present the first quantitative analysis of brain abnormalities in a mouse model of RSTS using magnetic resonance imaging (MRI) and two novel self-developed automated algorithms for image volumetric analysis. Our results quantitatively confirm key syndromic features observed in RSTS patients, such as reductions in brain size (-16.31%, p < 0.05), white matter volume (-16.00%, p < 0.05), and corpus callosum (-12.40%, p < 0.05). Furthermore, they provide new insight into the developmental origin of the disease. By comparing brain tissues in a region by region basis between cbp(+/-) and cbp(+/+) littermates, we found that cbp haploinsufficiency is specifically associated with significant reductions in prosencephalic tissue, such us in the olfactory bulb and neocortex, whereas regions evolved from the embryonic rhombencephalon were spared. Despite the large volume reductions, the proportion between gray-, white-matter and cerebrospinal fluid were conserved, suggesting a role of CBP in brain size regulation. The commonalities with holoprosencephaly and arhinencephaly conditions suggest the inclusion of RSTS in the family of neuronal migration disorders.We are grateful to Begona Fernandez for her excellent technical assistance. We would like to thank S. Sawiak (Wolfson Imaging Centre, University of Cambridge, Cambridge, United Kingdom) for the mouse brain tissue probability maps and the SPMmouse plug-in, and to N. Kovacevic (Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada) for the atlas of the mouse brain. Supported by grants from the Spanish MINECO to S.C. (BFU 2012-39958) and MINECO and FEDER to D.M. (TEC 2012-33778) and from MINECO (SAF2011-22855) and Generalitat Valenciana (Prometeo/2012/005) to A.B. The Instituto de Neurociencias is "Centre of Excellence Severo Ochoa".Ateca Cabarga, JC.; Cosa, A.; Pallares, V.; Lopez-Atalaya, JP.; Barco, A.; Canals, S.; Moratal Pérez, D. (2015). Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry. Scientific Reports. 5. https://doi.org/10.1038/srep16256S5Rubinstein, J. H. & Taybi, H. Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. Am J Dis Child 105, 588–608 (1963).Van Belzen, M., Bartsch, O., Lacombe, D., Peters, D. J. & Hennekam, R. C. Rubinstein-Taybi syndrome (CREBBP, EP300). Eur J Hum Genet. 19, preceeding 118–120 (2011).Hennekam, R. C. 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Phenotypic expansion of the interstitial 16p13.3 duplication: a case report and review of the literature. Gene. 531, 502–505 (2013).Demeer, B. et al. Duplication 16p13.3 and the CREBBP gene: confirmation of the phenotype. Eur J Med Genet. 56, 26–31 (2013).Kumar, S., Suthar, R., Panigrahi, I. & Marwaha, R. K. Rubinstein-Taybi syndrome: Clinical profile of 11 patients and review of literature. Indian J Hum Genet. 18, 161–166 (2012).Giussani, C. et al. The association of neural axis and craniovertebral junction anomalies with scoliosis in Rubinstein-Taybi syndrome. Childs Nerv Syst. 28, 2163–2168 (2012).Parsley, L., Bellus, G., Handler, M. & Tsai, A. C. Identical twin sisters with Rubinstein-Taybi syndrome associated with Chiari malformations and syrinx. Am J Med Genet A. 155A, 2766–2770 (2011).Thienpont, B. et al. Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. J Med Genet. 47, 155–161 (2010).Kim, S. H., Lim, B. C., Chae, J. H., Kim, K. J. & Hwang, Y. S. A case of Rubinstein-Taybi Syndrome with a CREB-binding protein gene mutation. Korean J Pediatr. 53, 718–721 (2010).Wójcik, C. et al. Rubinstein-Taybi syndrome associated with Chiari type I malformation caused by a large 16p13.3 microdeletion: a contiguous gene syndrome? Am J Med Genet A. 152A, 479–483 (2010).Wachter-Giner, T., Bieber, I., Warmuth-Metz, M., Bröcker, E. B. & Hamm, H. Multiple pilomatricomas and gliomatosis cerebri--a new association? Pediatr Dermatol. 26, 75–78 (2009).Verstegen, M. J., van den Munckhof, P., Troost, D. & Bouma, G. J. Multiple meningiomas in a patient with Rubinstein-Taybi syndrome. Case report. J Neurosurg. 102, 167–168 (2005).Agarwal, R., Aggarwal, R., Kabra, M. & Deorari, A. K. Dandy-Walker malformation in Rubinstein-Taybi syndrome: a rare association. Clin Dysmorphol. 11, 223–224 (2002).Ihara, K., Kuromaru, R., Takemoto, M. & Hara, T. Rubinstein-Taybi syndrome: a girl with a history of neuroblastoma and premature thelarche. Am J Med Genet. 83, 365–366 (1999).Sener, R. N. Rubinstein-Taybi syndrome: cranial MR imaging findings. Comput Med Imaging Graph 19, 417–418 (1995).Robinson, T. W., Stewart, D. L. & Hersh, J. H. Monozygotic twins concordant for Rubinstein-Taybi syndrome and implications for genetic counseling. Am J Med Genet. 45, 671–673 (1993).Guion-Almeida, M. L. & Richieri-Costa, A. Callosal agenesis, iris coloboma and megacolon in a Brazilian boy with Rubinstein-Taybi syndrome. Am J Med Genet. 43, 929–931 (1992).Albanese, A. et al. [Role of diagnostic imaging in Rubinstein-Taybi syndrome. personal experience with 8 cases]. Radiol Med. 81, 253–261 (1991).Rubinstein, J. H. Broad thumb-hallux (Rubinstein-Taybi) syndrome 1957-1988. Am J Med Genet Suppl. 6, 3–16 (1990).Hennekam, R. C., Stevens, C. A. & Van de Kamp, J. J. Etiology and recurrence risk in Rubinstein-Taybi syndrome. 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From genetics to epigenetics: new perpectives in Tourette Syndrome research

Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder marked by the appearance of multiple involuntary motor and vocal tics. TS presents high comorbidity rates with other disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). TS is highly heritable and has a complex polygenic background. However, environmental factors also play a role in the manifestation of symptoms. Different epigenetic mechanisms may represent the link between these two causalities. Epigenetic regulation has been shown to have an impact in the development of many neuropsychiatric disorders, however very little is known about its effects on Tourette Syndrome.This review provides a summary of the recent findings in the genetic background of TS, followed by an overview on different epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs in the regulation of gene expression. Epigenetic studies in other neurological and psychiatric disorders are discussed along with the TS-related epigenetic findings available in the literature to date. Moreover, we are proposing that some general epigenetic mechanisms seen in other neuropsychiatric disorders may also play a role in the pathogenesis of TS