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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract (CdTe) 1-x (In 2 Te 3 ) x films, with 0.1 ≤ x ≤ 1, were deposited by radio frequency sputtering on glass substrates employing different targets, prepared for each composition. The x-ray ...diffractograms were consistent with substitutional In incorporation into the CdTe lattice up to a value of x = 0.2. For higher In contents, the films presented structural disorder without reaching full amorphous characteristics. For x = 1, corresponding to In 2 Te 3 , preferential growth was observed. The bandgap of the solid solution varied between 1.46 and 1.2 eV, reaching a maximum of 1.58 eV for x = 0.3. For both end binary compounds the random incorporation of a third chemical element produced a significant broadening of the Raman modes consistent with a reduction of the lifetime of the optical phonons. The electrical resistivity was dependent on the Cd concentration reaching a minimum for x = 0.8.
ABSTRACT
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.
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 10
3
).
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.
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-Varón syndrome.
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.
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.
Human genetics studies have implicated GALNT2, encoding GalNAc-T2, as a 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.
Display omitted
•Genetic loss of function of GALNT2 lowers HDL-C in man, rodents, and nonhuman primates•ANGPTL3 and ApoC-III are non-redundant targets of GalNAc-T2 in humans•PLTP O-glycosylation by GalNAc-T2 potentiates its activity and raises HDL-C•GALNT2 GWAS SNP alleles associated with lower HDL-C reduce hepatic GALNT2 expression
SNPs in GALNT2 are associated with HDL-C metabolism, but whether GALNT2 causes HDL-C to go up or down has been debated. Khetarpal et al. show that loss of function of GALNT2 reduces HDL-C in humans, rodents, and nonhuman primates. They also show species-specific glycosylation targets for GalNAc-T2.
Boride coating on the surface of WC–Co-based cemented carbide Márquez-Herrera, Alfredo; Bermúdez-Rodríguez, Gabriel; Hernández-Rodríguez, Eric Noé ...
International journal of materials research,
07/2016, Letnik:
107, Številka:
7
Journal Article
Recenzirano
Odprti dostop
In this study, the structural properties and enhancement in the hardness of commercial WC–Co-based cemented carbide inserts are reported after the formation of a boronised layer on the surface. A ...boronising thermochemical treatment was given at 900 °C for 4 h. X-ray diffraction analysis verified the treatment in the presence of peaks associated with the Co
B and W
CoB
phases. The hardness of the samples used in the boronising process increased from 1492 HV up to 2000 HV. The typical values of the thickness of the boronised layer were measured to be around 28 μm. The results of a tool-life test suggest that boride coating effectively enhances the cutting performance of the samples.
Películas 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.
Ferroelectric 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.
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