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

Is the High Frequency of Machado-Joseph Disease in China Due to New Mutational Origins?

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia 3 or SCA3) is the most common dominant ataxia worldwide, with an overall average prevalence of 1–5/100,000. To this date, two major ancestral lineages have been found throughout the world. In China, the relative frequency of MJD among the SCAs reaches as high as 63%, however, little is known about its mutational origin in this country. We analyzed 50 families with MJD patients in two or more generations to study the hypothesis that new mutational events have occurred in this population. Haplotypes based on 20 SNPs have shown new genetic backgrounds segregating with MJD mutations in our cohort from China. We found the “Joseph-derived” lineage (Joseph lineage with a G variant in rs56268847) to be very common among Chinese MJD patients. Moreover, we estimated the time for the origin of this MJD SNP background based on STR diversity flanking the (CAG)n of ATXN3. It was surprising to find that the Chinese MJD population originated from 8,000 to 17,000 years ago, far earlier than the previous literature reports, which will be an important evidence to explain the origin, spread and founder effects of MJD

Identifying SYNE1 Ataxia With Novel Mutations in a Chinese Population

Objective: Variants in SYNE1 have been widely reported in ataxia patients in Europe, with highly variable clinical phenotype. Until now, no mutation of SYNE1 ataxia has been reported among the Chinese population. Our aim was to screen for SYNE1 ataxia patients in China and extend the clinicogenetic spectrum.Methods: Variants in SYNE1 were detected by high-throughput sequencing on a cohort of 126 unrelated index patients with unexplained autosomal recessive or sporadic ataxia. Pathogenicity assessments of SYNE1 variants were interpreted according to the ACMG guidelines. Potential pathogenic variants were confirmed by Sanger sequencing. Clinical assessments were conducted by two experienced neurologists.Results: Two Chinese families with variable ataxia syndrome were identified (accounting for 1.6%; 2/126), separately caused by the novel homozygous SYNE1 mutation (NM_033071.3: c.21568C&gt;T, p.Arg7190Ter), and compound heterozygous SYNE1 mutation (NM_033071.3: c.18684G&gt;A, p.Trp6228Ter; c.17944C&gt;T, p.Arg5982Ter), characterized by motor neuron impairment, mental retardation and arthrogryposis.Conclusions:SYNE1 ataxia exists in the Chinese population, as a rare form of autosomal recessive ataxia, with a complex phenotype. Our findings expanded the ethnic, phenotypic and genetic diversity of SYNE1 ataxia

A Quantitative Representation of Damage and Failure Response of Three-Dimensional Textile SiC/SiC Ceramics Matrix Composites Subjected to Flexural Loading

In the present work, the microstructure deformation and synergetic damage evolution of a three-dimensional textile SiC/SiC ceramic-matrix composite under flexural loading are investigated by in situ digital image correlation at ambient temperatures. The correlations between microstructure evolution and macro-mechanical degradation of 3D textile composites under flexural loading are established based on the experimental results. In addition, by establishing continuum damage mechanics and a thermodynamic framework with synergetic effects of microstructures, a flexural loading-induced damage evolution model is developed to reveal the relationship between the energy release rate and elastic modulus degradation. The proposed model can be used to predict the flexural stress-strain curves of 3D textile SiC/SiC composites to further improve the design and assessment of new textile architectures with specific mechanical properties

Transcriptome-wide analysis of differentially expressed chemokine receptors, SNPs, and SSRs in the age-related macular degeneration

Abstract Background Age-related macular degeneration (AMD) is the most common, progressive, and polygenic cause of irreversible visual impairment in the world. The molecular pathogenesis of the primary events of AMD is poorly understood. We have investigated a transcriptome-wide analysis of differential gene expression, single-nucleotide polymorphisms (SNPs), indels, and simple sequence repeats (SSRs) in datasets of the human peripheral retina and RPE-choroid-sclera control and AMD. Methods and results Adaptors and unbiased components were removed and checked to ensure the quality of the data sets. Molecular function, biological process, cellular component, and pathway analyses were performed on differentially expressed genes. Analysis of the gene expression datasets identified 5011 upregulated genes, 11,800 downregulated genes, 42,016 SNPs, 1141 indels, and 6668 SRRs between healthy controls and AMD donor material. Enrichment categories for gene ontology included chemokine activity, cytokine activity, cytokine receptor binding, immune system process, and signal transduction respectively. A functional pathways analysis identified that chemokine receptors bind chemokines, complement cascade genes, and create cytokine signaling in immune system pathway genes (p value < 0.001). Finally, allele-specific expression was found to be significant for Chemokine (C-C motif) ligand (CCL) 2, 3, 4, 13, 19, 21; C-C chemokine receptor (CCR) 1, 5; chemokine (C-X-C motif) ligand (CXCL) 9, 10, 16; C-X-C chemokine receptor type (CXCR) 6; as well as atypical chemokine receptor (ACKR) 3,4 and pro-platelet basic protein (PPBP). Conclusions Our results improve our overall understanding of the chemokine receptors’ signaling pathway in AMD conditions, which may lead to potential new diagnostic and therapeutic targets

Study on Nanofibrous Catalysts Prepared by Electrospinning for Methane Partial Oxidation

Electrospinning is a simple and efficient technique for fabricating fibrous catalysts. The effects of preparation parameters on catalyst performance were investigated on fibrous Ni/Al2O3 catalysts. The catalyst prepared with H2O/C2H5OH solvent showed higher catalytic activity than that with DMF/C2H5OH solvent because of the presence of NiO in the catalyst prepared with DMF/C2H5OH solvent. The metal ion content of the precursor also influences catalyst properties. In this work, the Ni/Al2O3 catalyst prepared with a solution containing the metal ion content of 30 wt % demonstrated the highest Ni dispersion and therefore the highest catalytic performance. Additionally, the Ni dispersion decreased as calcination temperature was enhanced from 700 to 900 &deg;C due to the increased Ni particle sizes, which also caused a high reduction temperature and low catalytic activity in methane partial oxidation. Finally, the fibrous Ni/Al2O3 catalysts can achieve high syngas yields at high reaction temperatures and high gas flow rates

Power-induced lasing state switching and bistability in a two-state quantum dot laser subject to optical injection

We theoretically investigate power-induced lasing state switching and bistability in a two-state quantum dot laser subject to optical injection. The simulated results show that, for a free-running two-state quantum dot laser operating at the ground state under low current, a power-induced lasing state switching between the ground state and the excited state can be achieved through introducing optical injection with a frequency (winj) close to the lasing frequency of excited state (wES). The injection power required for the state switching depends on the scanning route of injection power, i.e. there may exist state bistability for the injection power within a certain region. For forward scanning injection power, with the increase of frequency detuning (ΔΩ = winj – wES), the injection power required for the state switching shows a decreasing trend accompanied by slight fluctuations. However, for backward scanning injection power, the injection power required for the state switching exhibits obvious fluctuations with the increase of ΔΩ. The width of the hysteresis loop fluctuates with ΔΩ, and the fluctuation amplitude is increased with the increase of the injection current. Additionally, the influences of the inhomogeneous broadening factor and the electron escape rate on the bistability performances are analyzed