The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior

In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.Ministerio de Economía y Competitividad RTI2018-098645-B-I00, PID2019-109569GB-I00, RTI2018-099778-B-I00Junta de Andalucía P18-RT-1372, US-1264806, PI-0080-2017, PI-0009-2017, PI-0134-2018, PEMP-0008-2020, P20_00958, CTS-510Instituto de Salud Carlos III PI18/01691Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz-INiBICA LI19/06IN-CO22, IN-C09European Union 95568

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

The titin gene (TTN) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine

Ética Profesional y Responsabilidad Social Universitaria

este libro compila reflexiones y experiencias en responsabilidad social y ética profesional desde instituciones de Educación Superior. La responsabilidad social universitaria, como ámbito de investigación y de desarrollo conceptual y metodológico es transversal a las universidades, tanto desde el punto de vista organizacional, como desde el misional e investigativo. Quienes impulsen la responsabilidad social, requieren de ética profesional, que debe ser la clave para la construcción de principios que guíen a empresarios, políticos, gestores sociales, investigadores, entre otros, para lograr consensuar el a veces difícil equilibrio entre el bien común y el desarrollo personal

Gestión del conocimiento: perspectiva multidisciplinaria. Volumen 12

El libro “Gestión del Conocimiento. Perspectiva Multidisciplinaria”, Volumen 12, de la Colección Unión Global, es resultado de investigaciones. Los capítulos del libro, son resultados de investigaciones desarrolladas por sus autores. El libro cuenta con el apoyo de los grupos de investigación: Universidad Sur del Lago “Jesús María Semprúm” (UNESUR), Zulia – Venezuela; Universidad Politécnica Territorial de Falcón Alonso Gamero (UPTAG), Falcón – Venezuela; Universidad Politécnica Territorial de Mérida Kleber Ramírez (UPTM), Mérida – Venezuela; Universidad Guanajuato (UG) - Campus Celaya - Salvatierra - Cuerpo Académico de Biodesarrollo y Bioeconomía en las Organizaciones y Políticas Públicas (C.A.B.B.O.P.P), Guanajuato – México; Centro de Altos Estudios de Venezuela (CEALEVE), Zulia – Venezuela, Centro Integral de Formación Educativa Especializada del Sur (CIFE - SUR) - Zulia - Venezuela, Centro de Investigaciones Internacionales SAS (CIN), Antioquia - Colombia.y diferentes grupos de investigación del ámbito nacional e internacional que hoy se unen para estrechar vínculos investigativos, para que sus aportes científicos formen parte de los libros que se publiquen en formatos digital e impreso

Environmental evolution in the Picos de Europa (Cantabrian Mountains, SW Europe) since the Last Glaciation

The Western Massif of the Picos de Europa (latitude 43 N, longitude 4e5 W) includes some of the highest peaks in the Cantabrian Mountains. This massif was heavily glaciated during the Last Glaciation, though the post-glacial environmental evolution is still poorly understood. Using a complementary geomorphological and sedimentological approach, we have reconstructed the environmental events occurred in this massif since the last Pleistocene glaciation. The geomorphological distribution of glacial landforms suggests the occurrence of four main glacial stages: maximum glacial advance, glacial expansion after the maximum advance, Late Glacial and Little Ice Age. Moreover, a 5.4-m long sedimentary sequence was retrieved from the karstic depression of Belbín providing a continuous record of the paleoenvironmental conditions in this area since the Last Glaciation until nowadays. This section suggests that the maximum glacial expansion occurred at a minimum age of 37.2 ka cal BP, significantly prior to the global Last Glacial Maximum. Subsequently, periglacial processes prevailed in the mid lands of the massif until glaciers expanded between 22.5 and 18.7 ka cal BP. Following the melting of the glaciers, a shallow lake appeared in the Belbín depression. Lake sediments do not show evidence of a cold stage during the Late Glacial, when moraine systems formed at higher locations. The terrestrification of this lake started at 8 ka cal BP and the area turned into grassland. At 4.9 ka cal BP the existence of charcoal particles in the sediments of Belbín sequence reveals the onset of human occupation in the massif through the use of fire activity for grazing purposes. Finally, the presence of moraines inside the highest northern cirques shows evidence of the last glacial phase that occurred during the Little Ice Age cold event. Since then, the warming climate has led to the melting of these glaciers and periglacial processes prevail in the high lands of the massif.info:eu-repo/semantics/publishedVersio

Comunidades emocionales y cambio social

This image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Ranch houses | Dwelling | Miami Heights Addition (Toledo, Ohio) | South Toledo Area (Toledo, Ohio

Hydrogen peroxide derived from NADPH oxidase 4- and 2 contributes to the endothelium-dependent vasodilatation of intrarenal arteries

The role of NADPH oxidase (Nox)-derived reactive oxygen species in kidney vascular function has extensively been investigated in the harmful context of oxidative stress in diabetes and obesity-associated kidney disease. Since hydrogen peroxide (H2O2) has recently been involved in the non-nitric oxide (NO) non-prostanoid relaxations of intrarenal arteries, the present study was sought to investigate whether NADPH oxidases may be functional sources of vasodilator H2O2 in the kidney and to assess their role in the endothelium-dependent relaxations of human and rat intrarenal arteries. Renal interlobar arteries isolated from the kidney of renal tumor patients who underwent nephrectomy, and from the kidney of Wistar rats, were mounted in microvascular myographs to assess function. Superoxide (O2.-) and H2O2 production was measured by chemiluminescence and Amplex Red fluorescence, and Nox2 and Nox4 enzymes were detected by Western blotting and by double inmunolabeling along with eNOS. Nox2 and Nox4 proteins were expressed in the endothelium of renal arterioles and glomeruli co-localized with eNOS, levels of expression of both enzymes being higher in the cortex than in isolated arteries. Pharmacological inhibition of Nox with apocynin and of CYP 2C epoxygenases with sulfaphenazol, but not of the NO synthase (NOS), reduced renal NADPH-stimulated O2.- and H2O2 production. Under conditions of cyclooxygenase and NOS blockade, acetylcholine induced endothelium-dependent relaxations that were blunted by the non-selective Nox inhibitor apocynin and by the Nox2 or the Nox1/4 inhibitors gp91ds-tat and GKT136901, respectively. Acetylcholine stimulated H2O2 production that was reduced by gp91ds-tat and by GKT136901. These results suggest the specific involvement of Nox4 and Nox2 subunits as physiologically relevant endothelial sources of H2O2 generation that contribute to the endothelium-dependent vasodilatation of renal arteries and therefore have a protective role in kidney vasculature. Keywords: Endothelium-mediated vasodilatation, Hydrogen peroxide, Nox4, Nox2, Human intrarenal arterie

Exilio y presencia : Costa Rica y México en el siglo XX

Exilio Iberoamericano es parte de los estudios sobre este tema en los siglos XIX y XX. Los ensayos que componen la obra, realizados por investigadores de diversas nacionalidades y disciplinas, muestran la movilidad forzada de ciertos sectores de la población de desplazamientos a través de las coyunturas políticas que han afectado a distintas naciones en los ámbitos regional y mundial, y que motivaron el exilio de grupos de activistas políticos, intelectuales y científicos, así como la salida masiva de ciudadanos en busca de salvaguardar su vida. Un texto imprescindible para comprender las causas y efectos de este fenómeno, así como para evitar su repetición en el siglo XXI.Libro