Abstract-Mitochondria have long been known to play a critical role in maintaining the bioenergetic status of cells under physiological conditions. It was also recognized early in mitochondrial research that the reduction of oxygen to generate the free radical superoxide occurs at various sites in the respiratory chain and was postulated that this could lead to mitochondrial dysfunction in a variety of disease states. Over recent years, this view has broadened substantially with the discovery that reactive oxygen, nitrogen, and lipid species can also modulate physiological cell function through a process known as redox cell signaling. These redox active second messengers are formed through regulated enzymatic pathways, including those in the mitochondrion, and result in the posttranslational modification of mitochondrial proteins and DNA. In some cases, the signaling pathways lead to cytotoxicity. Under physiological conditions, the same mediators at low concentrations activate the cytoprotective signaling pathways that increase cellular antioxidants. Thus, it is critical to understand the mechanisms by which these pathways are distinguished to develop strategies that will lead to the prevention of cardiovascular disease. In this review, we describe recent evidence that supports the hypothesis that mitochondria have an important role in cell signaling, and so contribute to both the adaptation to oxidative stress and the development of vascular diseases. (Circ Res. 2006;99:924-932.)Key Words: apoptosis Ⅲ atherosclerosis Ⅲ hypertension Ⅲ diabetes Ⅲ environmental tobacco smoke Ⅲ endothelial cells Ⅲ electrophilic lipids Ⅲ mitochondria Ⅲ prostaglandins Ⅲ redox signaling Ⅲ thiols T he "free radical hypothesis" for vascular dysfunction originally postulated that reactive oxygen and nitrogen species (ROS/RNS) led to nonspecific modification of lipids, proteins, and nucleic acids, which then contributed to the etiology of the disease. 1,2 However, this view has changed in recent years with the recognition that these molecules can play a role in signal transduction through specific modification of cell signaling proteins. 3,4 Overall this field has come to be known as "redox cell signaling" and describes how ROS/RNS can lead to the activation of pathways that control cell differentiation and apoptosis. 5,6 These mechanisms are of particular relevance to cardiovascular diseases (CVD), such as atherosclerosis and hypertension, and have been studied intensively in vascular cells. 4,7,8 During atherosclerosis, activation of the enzymes in both infiltrating macrophages and vascular cells generate high levels of ROS/RNS, thereby changing the oxidation status of thiols on signaling proteins: the redox tone. 8 -11 The redox cell signaling pathways that are activated are balanced between those that protect endothelial and vascular smooth muscle cells with those that initiate cell [12][13][14][15] A major challenge at the present time is to understand how the localized production of ROS/ RNS in the environment of the atherosclerot...

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E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.

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Esta obra reúne un trabajo de investigación inédito con énfasis cualitativo sobre la migración venezolana en el más reciente contexto de crisis humanitaria, privilegiando el examen de los contextos de acogida intrarregionales y extrarregionales. El producto final es el resultado de un diseño de investigación único aplicado en trece ciudades latinoamericanas durante el segundo semestre de 2018, por más de una treintena de investigadoras e investigadores latinoamericanos. Asimismo, incluye una descripción detallada de las condiciones de vida en Venezuela y del contexto de salida de esta migración. El problema de investigación que se aborda permite conocer cómo, al amparo de los marcos jurídicos vigentes, se producen los procesos de inclusión social de un flujo masivo, con poca experiencia de migración internacional, que huye de una crisis humanitaria dirigiéndose a países, alguno de los cuales también tienen poca o nula experiencia como contextos de acogida de la migración de este origen. La evidencia cualitativa recogida a través de más de 200 entrevistas semiestructuradas, combinada con la revisión exhaustiva de fuentes secundarias de información sobre la magnitud y perfil del flujo de venezolanos y el análisis de los instrumentos de protección jurídica vigentes a nivel nacional y regional, evidencian de qué manera los distintos contextos de acogida se han estructurado en torno a un gradiente de desprotección-seguridad jurídica. Este gradiente abarca desde el diseño y aplicación de instrumentos y acciones coyunturales, dentro de los que se encuentran las respuestas de Colombia, Chile, Perú o Brasil, hasta la implementación de marcos normativos más amplios, que como en el caso uruguayo o mexicano entienden a la migración desde el enfoque de derechos. La multiplicidad de respuestas nacionales y regionales para un flujo que superaba hacia 2017 los tres millones de personas, da lugar a distintas trayectorias individuales y familiares hacia la inclusión social que aquí analizamos atendiendo al acceso al trabajo, a la vivienda, salud, educación y seguridad social. Esta obra constituye a la literatura académica sobre migración internacional con hallazgos que interpelan las clasificaciones binarias de países de inmigración/emigración, al dar cuenta de las transformaciones más recientes de las migraciones sur-sur donde priman la heterogeneidad de motivaciones de la migración y la coexistencia de flujos de tránsito, emigración e inmigración.