Identification of <em>CHIP</em> as a novel causative gene for autosomal recessive cerebellar ataxia

Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia

Investigation of interference phenomena of vector field in shallow water

info:eu-repo/semantics/publishe

L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-X_L

<p>Abstract</p> <p>Background</p> <p>Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinson’s disease (PD). Wild-type DJ-1 has cytoprotective roles against cell death through multiple pathways. The most commonly studied mutant DJ-1(L166P) shifts its subcellular distribution to mitochondria and renders cells more susceptible to cell death under stress stimuli. We previously reported that wild-type DJ-1 binds to Bcl-X_L and stabilizes it against ultraviolet B (UVB) irradiation-induced rapid degradation. However, the mechanisms by which mitochondrial DJ-1(L166P) promotes cell death under death stimuli are largely unknown.</p> <p>Results</p> <p>We show that DJ-1(L166P) is more prone to localize in mitochondria and it binds to Bcl-X_L more strongly than wild-type DJ-1. In addition, UVB irradiation significantly promotes DJ-1(L166P) translocation to mitochondria and binding to Bcl-X_L. DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-X_L, thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation.</p> <p>Conclusion</p> <p>Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating mitochondrial Bax/Bcl-X_L functions.</p

Stress&ndash;Strain&ndash;Time Description and Analysis of Frozen&ndash;Thawed Silty Clay under Low Stress Level

The construction of high-speed railways in cold regions needs to consider the effects of freeze&ndash;thaw cycles (FTHs) on the long-term deformation of subgrades. However, at present, research on the creep characteristics of frozen&ndash;thawed rocks and soils is not extensive. In the limited studies on frozen&ndash;thawed soil creep properties, current research focuses more on high stress&ndash;strain&ndash;time responses, but for the subgrades, the inner stress is usually low. This paper presents the results of triaxial compression creep tests on remolded, frozen&ndash;thawed silty clay sampled in the Yichun-Tieli area and describes its stress&ndash;strain&ndash;time relationship in an arctan function-based mathematical model. Each creep test condition is studied using three specimens. Frozen&ndash;thawed silty clay exhibits attenuation creep under low-level stress. In general, from 4 FTHs to 11 FTHs, the mean elasticity modulus decreases first, and then, increases. The exerted stress is higher than the yield stress; the more FTHs the specimens experience, the more time they need to be deformed stably under the same axial deviatoric stress (ADS). Under the same mean ADS, the mean stable strain of 7 FTHs exceeds the other two FTH conditions and, in general, the mean stable strain of 4 FTHs exceeds 11 FTHs. By dissecting the phenomena, it can be concluded that with FTHs increasing, moisture and voids reconstitute in the process; the elastic strain accounts for most of the total strain and significantly decides the extent of creep deformation; the arctan function-based model is basically able to describe, but not perfectly predict, the stress&ndash;strain&ndash;time relationship of frozen&ndash;thawed silty clay

Stress–Strain–Time Description and Analysis of Frozen–Thawed Silty Clay under Low Stress Level

The construction of high-speed railways in cold regions needs to consider the effects of freeze–thaw cycles (FTHs) on the long-term deformation of subgrades. However, at present, research on the creep characteristics of frozen–thawed rocks and soils is not extensive. In the limited studies on frozen–thawed soil creep properties, current research focuses more on high stress–strain–time responses, but for the subgrades, the inner stress is usually low. This paper presents the results of triaxial compression creep tests on remolded, frozen–thawed silty clay sampled in the Yichun-Tieli area and describes its stress–strain–time relationship in an arctan function-based mathematical model. Each creep test condition is studied using three specimens. Frozen–thawed silty clay exhibits attenuation creep under low-level stress. In general, from 4 FTHs to 11 FTHs, the mean elasticity modulus decreases first, and then, increases. The exerted stress is higher than the yield stress; the more FTHs the specimens experience, the more time they need to be deformed stably under the same axial deviatoric stress (ADS). Under the same mean ADS, the mean stable strain of 7 FTHs exceeds the other two FTH conditions and, in general, the mean stable strain of 4 FTHs exceeds 11 FTHs. By dissecting the phenomena, it can be concluded that with FTHs increasing, moisture and voids reconstitute in the process; the elastic strain accounts for most of the total strain and significantly decides the extent of creep deformation; the arctan function-based model is basically able to describe, but not perfectly predict, the stress–strain–time relationship of frozen–thawed silty clay

Identification of Loci Controlling the Dwarfism Trait in the White Sailfin Molly (<i>Poecilia latipinna</i>) Using Genome-Wide Association Studies Based on Genotyping-By-Sequencing

Dwarfism is a condition defined by low harvest weight in fish, but also results in strange body figures which may have potential for the selective breeding of new ornamental fish strains. The objectives of this study are to reveal the physiological causes of dwarfism and identify the genetic loci controlling this trait in the white sailfin molly. Skeletons of dwarf and normal sailfin mollies were observed by X-ray radioscopy and skeletal staining. Genome-wide association studies based on genotyping-by-sequencing (n = 184) were used to map candidate genomic regions associated with the dwarfism trait. Quantitative real-time PCR was performed to determine the expression level of candidate genes in normal (n = 8) and dwarf (n = 8) sailfin mollies. We found that the dwarf sailfin molly has a short and dysplastic spine in comparison to the normal fish. Two regions, located at NW_015112742.1 and NW_015113621.1, were significantly associated with the dwarfism trait. The expression level of three candidate genes, ADAMTS like 1, Larp7 and PPP3CA, were significantly different between the dwarf and normal sailfin mollies in the hepatopancreas, with PPP3CA also showing significant differences in the vertebrae and Larp7 showing significant differences in the muscle. This study identified genomic regions and candidate genes associated with the dwarfism trait in the white sailfin molly and would provide a reference to determine dwarf-causing variations