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Background: Genetic generalized epilepsies (GGE) including childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and GGE with tonic–clonic seizures alone (GGE-TCS), are common types of epilepsy mostly determined by a polygenic mode of inheritance. Recent studies showed that susceptibility genes for GGE are numerous, and their variants rare, challenging their identification. In this study, we aimed to assess GGE genetic etiology in a Sudanese population. Methods: We performed whole-exome sequencing (WES) on DNA of 40 patients from 20 Sudanese families with GGE searching for candidate susceptibility variants, which were prioritized by CADD software and functional features of the corresponding gene. We assessed their segregation in 138 individuals and performed genotype–phenotype correlations. Results: In a family including three sibs with GGE-TCS, we identified a rare missense variant in ADGRV1 encoding an adhesion G protein-coupled receptor V1, which was already involved in the autosomal recessive Usher type C syndrome. In addition, five other ADGRV1 rare missense variants were identified in four additional families and absent from 119 Sudanese controls. In one of these families, an ADGRV1 variant was found at a homozygous state, in a female more severely affected than her heterozygous brother, suggesting a gene dosage effect. In the five families, GGE phenotype was statistically associated with ADGRV1 variants (0R = 0.9 103). Conclusion: This study highly supports, for the first time, the involvement of ADGRV1 missense variants in familial GGE and that ADGRV1 is a susceptibility gene for CAE/JAE and GGE-TCS phenotypes.

Genetic generalized epilepsies (GGE) (childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME) and epilepsy with generalized tonic-clonic seizures (GTCS)) are mainly determined by genetic factors. Since few mutations were identified in rare families with autosomal dominant GGE, a polygenic inheritance was suspected in most patients. Recent studies on large American or European cohorts of sporadic cases showed that susceptibility genes were numerous although their variants were rare, making their identification difficult. Here, we reported clinical and genetic characteristics of 30 Tunisian GGE families, including 71 GGE patients. The phenotype was close to that in sporadic cases. Nineteen pedigrees had a homogeneous type of GGE (JME-CAE-CGTS), and 11 combined these epileptic syndromes. Rare non-synonymous variants were selected in probands using a targeted panel of 30 candidate genes and their segregation was determined in families. Molecular studies incriminated different genes, mainly CACNA1H and MAST4. The segregation of at least two variants in different genes in some pedigrees was compatible with the hypothesis of an oligogenic inheritance, which was in accordance with the relatively low frequency of consanguineous probands. Since at least 2 susceptibility genes were likely shared by different populations, genetic factors involved in the majority of Tunisian GGE families remain to be discovered. Their identification should be easier in families with a homogeneous type of GGE, in which an intra-familial genetic homogeneity could be suspected.

Human genetics studies have implicated GALNT2, encoding GalNAc-T2, as a novel regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, but the mechanisms relating GALNT2 to HDL-C remain unclear. We investigated the impact of homozygous GALNT2 deficiency on HDL-C in humans and mammalian models. We identified two humans homozygous for loss-of-function mutations in GALNT2 who demonstrated low HDL-C. We also found that GALNT2 loss-of-function in mice, rats, and nonhuman primates decreased HDL-C. O-glycoproteomics studies of a human GALNT2 deficient subject validated ANGPTL3 and ApoC-III as GalNAc-T2 targets. Additional glycoproteomics in rodents identified targets influencing HDL-C, including phospholipid transfer protein (PLTP). GALNT2 deficiency reduced plasma PLTP activity in humans and rodents, and in mice this was rescued by reconstitution of hepatic Galnt2. We also found that GALNT2 GWAS SNPs associated with reduced HDL-C also correlate with lower hepatic GALNT2 expression. These results posit GALNT2 as a direct modulator of HDL metabolism across mammals.

The development and testing of protective coatings against corrosion for magnesium is reported. The coatings were based on the MgOx–TiOx composite and for their fabrication the reactive RF-sputtering technique in the co-deposition mode was employed. MgOx–TiOx coatings with chemical composition ranging from pure Mg oxides to pure Ti oxides, including its mixture, were obtained through the variation of the rate of the sputtering powers applied to the Mg and Ti targets. Characterization (XRD and XPS) showed changes in the crystalline structure according to the rate of the sputtering powers and confirmed the presence of MgO2, MgO, Ti2O3 and TiO2 in different proportions. Electrochemical polarization measurements (Tafel) made by employing the Hank's solution showed that both Vcorr and Icorr depend on the chemical composition of the coatings, having better corrosion resistance when the content of Ti oxides is higher. Results showed that corrosion resistance of Mg could be modulated by changing the chemical composition of the MgOx–TiOx coatings.

La División de Ingenierías del Campus Irapuato-Salamanca (DICIS) de la Universidad de Guanajuato está comprometida a servir a la sociedad por medio de la formación de recursos humanos de alta calidad y de actividades de extensión e investigación de alto nivel. La investigación en el área de nanociencia y nanotecnología (NyN) abarca varios cuerpos académicos, y líneas de aplicación y generación de conocimientos mediante la impartición de cursos de maestría y doctorado en la DICIS.Recientemente la DICIS se equipó con un cuarto limpio de clase 1000 ubicado en la sede del Departamento de Estudios Multidisciplinarios (DEM) en Yuriria, Gto., con un evaporador térmico para la deposición de materiales en forma de película delgada, y cuenta con un sistema de medida I-V en campo magnético de hasta 1T.La DICIS fomenta la colaboración entre investigadores de la misma universidad pertenecientes a diferentes departamentos y cuerpos académicos, así como la colaboración interuniversitaria a nivel nacional e internacional. La DICIS está comprometida con el desarrollo de la NyN para la mejora de materiales funcionales y sensores.

Objective: The aim of this study was to identify the causal gene in a consanguineous Moroccan family with temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy, previously mapped to the 6q16–q22 region. Methods: We used exome sequencing and analyzed candidate variants in the 6q16–q22 locus, as well as a rescue assay in Fig4 -null mouse fibroblasts and immunohistochemistry of Fig4 -null mouse brains. Results: A homozygous missense mutation (p.Asp783Val) in the phosphoinositide phosphatase gene FIG4 was identified. Pathogenicity of the variant was supported by impaired rescue of the enlarged vacuoles in transfected fibroblasts from Fig4 -deficient mice. Histologic examination of Fig4- null mouse brain revealed neurodevelopmental impairment in the hippocampus, cortex, and cerebellum as well as impaired cerebellar gyration/foliation reminiscent of human cortical malformations. Conclusions: This study extends the spectrum of phenotypes associated with FIG4 mutations to include cortical malformation associated with seizures and psychiatric manifestations, in addition to the previously described Charcot-Marie-Tooth disease type 4J and Yunis-Varon syndrome.

Alcohols 4a,bderived from ketone 3 were transformed, in acidic medium, to the rearranged compounds 6 (or 6′) and to the pentacyclic derivative 8. This procedure provides easy access to the 16-deethylapovincamine skeleton.

International audience; The main familial focal epilepsies are autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy and familial focal epilepsy with variable foci. A frameshift mutation in the DEPDC5 gene (encoding DEP domain-containing protein 5) was identified in a family with focal epilepsy with variable foci by linkage analysis and exome sequencing. Subsequent pyrosequencing of DEPDC5 in a cohort of 15 additional families with focal epilepsies identified 4 nonsense mutations and 1 missense mutation. Our findings provided evidence of frequent (37%) loss-of-function mutations in DEPDC5 associated with a broad spectrum of focal epilepsies. The implication of a DEP (Dishevelled, Egl-10 and Pleckstrin) domain-containing protein that may be involved in membrane trafficking and/or G protein signaling opens new avenues for research.

ResumenPelículas delgadas Ferroeléctricas de BaTiO3 (BTO) se depositaron a partir de un blanco de BaTiO3 mediante la técnica de RF-Sputtering (erosión catódica por radio frecuencia) sobre substratos de nicromel y cuarzo. Se estudió el efecto de la temperatura de sustrato in-situ en la cristalinidad del material durante su depósito. Estas muestras fueron comparadas con películas depositadas a temperatura ambiente y tratadas térmicamente posterior al depósito fuera de la cámara de crecimiento. El estudio de la cristalinidad fue realizado mediante la técnica de difracción de rayos-X. Adicionalmente, se llevaron a cabo caracterizaciones ópticas mediante un espectrofotómetro UV-Vis. El crecimiento de películas delgadas con temperatura de sustrato permite la obtención de materiales cristalinos a temperaturas por debajo de las reportadas por otros autores.AbstractFerroelectric thin films of BaTiO3 (BTO) were grown on quartz, and nichrome substrates using a BaTiO3 target by RF-Sputtering technique. It was studied the effect of the substrate temperature in the crystallization of the material. These samples were compared with films deposited at room temperature and heat treated out of the growth Chamber. Their crystallinity were studied by X-ray diffraction. Additionally, the optical characterizations were carried out by UV-Vis spectrophotometer. The growth of thin films with substrate temperature allows the obtaining of crystalline materials at temperatures below those reported by other authors.

The 2-oxo functionalized title compound 1 was synthesised in 7 steps from tryptamine via rearrangement of the bromoiminium ion 13 in alkaline medium to azepinone 14 with concomitant formation of ketone 15. The ratio 14:15 was shown to depend on the nature of the hydroxide counterion.

International audience; Deeply incised drainage networks are thought to be robust and not easily modified, and are commonly used as passive markers of horizontal strain. Yet, reorganizations (rearrangements) appear in the geologic record. We provide field evidence of the reorganization of a Miocene drainage network in response to strike-slip and vertical displacements in Guatemala. The drainage was deeply incised into a 50-km-wide orogen located along the North America-Caribbean plate boundary. It rearranged twice, first during the Late Miocene in response to transpressional uplift along the Polochic fault, and again in the Quaternary in response to transtensional uplift along secondary faults. The pattern of reorganization resembles that produced by the tectonic defeat of rivers that cross growing tectonic structures. Compilation of remote sensing data, field mapping, sediment provenance study, grain-size analysis and Ar40/Ar39 dating from paleovalleys and their fill reveals that the classic mechanisms of river diversion, such as river avulsion over bedrock, or capture driven by surface runoff, are not sufficient to produce the observed diversions. The sites of diversion coincide spatially with limestone belts and reactivated fault zones, suggesting that solution-triggered or deformation-triggered permeability have helped breaching of interfluves. The diversions are also related temporally and spatially to the accumulation of sediment fills in the valleys, upstream of the rising structures. We infer that the breaching of the interfluves was achieved by headward erosion along tributaries fed by groundwater flow tracking from the valleys soon to be captured. Fault zones and limestone belts provided the pathways, and the aquifers occupying the valley fills provided the head pressure that enhanced groundwater circulation. The defeat of rivers crossing the rising structures results essentially from the tectonically enhanced activation of groundwater flow between catchments.

The 2-oxo functionalized title compound 1 was synthesised in 7 steps from tryptamine via rearrangement of the bromoiminium ion 13 in alkaline medium to azepinone 14 with concomitant formation of ketone 15. The ratio 14:15 was shown to depend on the nature of the hydroxide counterion.

Alcohols 4a,bderived from ketone 3 were transformed, in acidic medium, to the rearranged compounds 6 (or 6′) and to the pentacyclic derivative 8. This procedure provides easy access to the 16-deethylapovincamine skeleton.

"En este trabajo se presenta el diseño y construcción de un calentador de sustratos de bajo costo, el cual es capaz de operar en sistemas de alto vacío. Su utilización se centra en proporcionar tratamiento térmico in-situ durante el crecimiento de películas delgadas bajo condiciones de presión controlada y atmósfera corrosiva. El calentador fue construido principalmente de acero inoxidable, cerámica y una resistencia comercial de khantal-A1. El cuerpo del horno es enfriado usando un sistema de aletas y líquido refrigerante, el cual se encuentra completamente aislado de la cámara de depósito. El diseño del calentador también incorpora un sistema de rotación que permite que el sustrato gire durante el proceso de crecimiento proporcionando uniformidad a la película. La temperatura del sustrato es monitoreada mediante un termopar tipo "K" que retroalimenta a un controlador de temperatura, el cual modula una fuente de poder variable que suministra el voltaje a la resistencia. Con el propósito de evaluar la funcionalidad del sistema de calentamiento, éste se montó en un equipo de rf-sputtering y se crecieron películas delgadas de BaTiO3 con distintas temperaturas de sustrato en una geometría off-axis. El sistema de tratamientos térmicos in-situ es capaz de proveer una temperatura uniforme al sustrato así como de operar por largos periodos de tiempos."

This study investigated the characteristics of atrial natriunetic peptide (ANP) release from superfused sliced atria and ventricles of rats. Right atria spontaneously released more immunoreactive ANP (Ir-ANP: pg/min per mg tissue) (32 ± 3) than did left atria (11 ± 2) or right ventricles (1.5 ± 0.5). Addition of 10 −9 to 10 −5 M of arginine vasopressin (AVP) to the superfusing fluid or increasing its osmolarity (290 to 490 mOsM) resulted in a significant increase of the Ir-ANP outflow from right atria. The effect of AVP was prevented by a specific V 1 receptor antagonist, ([d(dh 2 ) 5 Tyr(Me)]AVP). Superfusion with indomethacin (10 −5 M) did not alter spontaneous release but inhibited the peak levels of Ir-ANP induced by AVP (10 −5 M). Moreover, DDAVP, a specific V 2 receptor agonist, did not induce Ir-ANP release. Ca 2+ -free medium alone or plus 1 mM EGTA induced a significant increase in basal Ir-ANP outflow. The Ir-ANP released chromatographed similarly to the standard α-rANP. These results suggest a specific stimulatory effect of AVP and osmolarity and a negative influence of extracellular Ca 2+ on atrial spontaneous Ir-ANP release. It appears that the effect of AVP could be mediated by prostaglandin synthesis.

Alexander disease (AxD) is a rare neurodegenerative disorder characterized by large cytoplasmic aggregates in astrocytes and myelin abnormalities and caused by dominant mutations in the gene encoding glial fibrillary acidic protein (GFAP), the main intermediate filament protein in astrocytes. We tested the effects of three mutations (R236H, R76H and L232P) associated with AxD in cells transiently expressing mutated GFAP fused to green fluorescent protein (GFP). Mutated GFAP-GFP expressed in astrocytes formed networks or aggregates similar to those found in the brains of patients with the disease. Time-lapse recordings of living astrocytes showed that aggregates of mutated GFAP-GFP may either disappear, associated with cell survival, or coalesce in a huge juxtanuclear structure associated with cell death. Immunolabeling of fixed cells suggested that this gathering of aggregates forms an aggresome-like structure. Proteasome inhibition and immunoprecipitation assays revealed mutated GFAP-GFP ubiquitination, suggesting a role of the ubiquitin-proteasome system in the disaggregation process. In astrocytes from wild-type-, GFAP-, and vimentin-deficient mice, mutated GFAP-GFP aggregated or formed a network, depending on qualitative and quantitative interactions with normal intermediate filament partners. Particularly, vimentin displayed an anti-aggregation effect on mutated GFAP. Our data indicate a dynamic and reversible aggregation of mutated GFAP, suggesting that therapeutic approaches may be possible.

This study investigates the release of Neuropeptide Y from eight human pheochromocytomas. Profil immunoreactive Neuropeptide Y (Ir-NPY) levels during the management of surgery were compared with these of norepinephrine (NE) while hemodynamics were monitored. Plasma IrNPY and NE levels increased during tumor manipulation and returned to near normal one hour after operation. However, Ir-NPY levels remained high just after tumor resection while NE levels were significantly decreased. At tumor manipulation and just after tumor resection, plasma Ir-NPY levels were correlated with the systemic vascular resistances (SVR) (r = 0.74; P

Background: Pulmonary hypertension (PH) is characterized by an increase in vascular tone and an abnormal proliferation of muscle cells in the walls of pulmonary arteries. Recent studies have found high plasma endothelin-1 (ET-1) concentrations in patients with PH. This study was conducted to assess whether elevated circulating ET-1 levels in PH really reflect excessive local pulmonary production. Methods: We prospectively studied ET-1 concentration in lung specimens from 6 control subjects and 13 patients with severe PH referred for lung or heart-lung transplantation (6 patients had primary PH and 7 PH secondary to congenital heart defect). Endothelin-like immunoreactivity (ET-LI) was measured in plasma and lung tissue, using a radioimmunoassay, after ET-1 extraction. Reverse-phase high-performance liquid chromatography was also performed. Results: Peripheral venous plasma ET-LI concentrations in patients with PH, whatever the cause, were greater than those in controls (10.7 ± 0.8 vs 5.3 ± 0.7 pg/ml; P < 0.0005). Pulmonary ET-LI was significantly higher in patients with PH, irrespective of its cause, than in controls (25.2 ± 5.1 vs 8.1 ± 1.1 pg/mg, P < 0.03). ET-LI pulmonary concentrations were slightly higher in Eisenmenger than in primary PH, but this was not significant (27.1 ± 8.6 vs 22.8 ± 5.4 pg/mg). Linear regression analysis indicated a small but significant correlation between ET-LI pulmonary concentrations and pulmonary vascular resistance in the patients with PH ( r = 0.38; P = 0.047). In each case, HPLC separation of ET indicated that most of the immuno-reactivity was detected in the same fraction as ET-1. Conclusions: The striking increase in ET-1 pulmonary concentration provides new evidence that excessive local pulmonary ET-1 production may contribute to the vascular abnormalities of pulmonary hypertension.