SUMMARY The CACNA1A gene, encoding the voltage-gated calcium channel subunit α1A, is involved in pre- and postsynaptic Ca2+ signaling, gene expression, and several genetic neurological disorders. We found that CACNA1A employs a novel strategy to directly coordinate a gene expression program, using a bicistronic mRNA bearing a cryptic internal ribosomal entry site (IRES). The first cistron encodes the well-characterized α1A subunit. The second expresses a newly-recognized transcription factor, α1ACT, that coordinates expression of a program of genes involved in neural and Purkinje cell development. α1ACT also contains the polyglutamine (polyQ) tract that, when expanded, causes spinocerebellar ataxia type 6 (SCA6). When expressed as an independent polypeptide, α1ACT, bearing an expanded polyQ tract, lacks transcription factor function and neurite outgrowth properties, causes cell death in culture, and leads to ataxia and cerebellar atrophy in transgenic mice. Suppression of CACNA1A IRES function in SCA6 may be a potential therapeutic strategy.
BackgroundThe predictive potentials of neck circumference (NC) for cardio-metabolic risks remain uncertain. The aim of this study was to investigate whether NC independently contributes to the prediction of cardio-metabolic risks beyond body mass index (BMI), waist circumference (WC) and waist to hip ratio (WHpR) in a large Chinese population.MethodsA total of 4201 participants (2508 men and 1693 women) aged 20-85 were recruited from the Health Examination Centre between May 2009 and April 2010, anthropometric indices, biochemical and clinical parameters were measured. Receiver operating characteristic, partial correlation and logistic regression analyses were employed to evaluate the association of the anthropometric indices to cardio-metabolic risks separately by gender.ResultsNeck circumference was positively correlated with SBP and DBP (r=0.250 and 0.261), fasting blood glucose (FBP) (r=0.177), TG (r=0.240), TC (r=0.143) and LDL-C (r=0.088) and negatively correlated with HDL-C (r=-0.202) in males (all P<0.01). Similar results were found in females with the exception of TC. The AUCs of NC for metabolic abnormalities ranged from 0.558 (Increased LDL-C) to 0.683 (MS-rf) in men and 0.596 (Increased LDL-C) to 0.703 (MS-rf) in women (P<0.01). The NC of ≥37 cm for men and ≥33 cm for women were the best cut-off points for metabolic syndrome. The adjusted ORs (95% CIs) of NC in men and women respectively were 1.29 (1.12-1.48) and 1.44 (1.20-1.72) for metabolic syndrome risk factors (MS-rf), 1.15 (1.01-1.32) and 1.22 (1.03-1.46) for high BP, 1.16 (1.02-1.33) and 1.42 (1.18-1.71) for increased TG, and 1.26 (1.06-1.50) and 1.32 (1.06-1.65) for increased FBP; the adjusted OR of NC in women for decreased HDL-C was 1.29 (1.10-1.51).ConclusionsNeck circumference was significantly associated with cardio-metabolic risk factors and independently contributed to the prediction of cardio-metabolic risks beyond the classical anthropometric indices in adults of China.
Ca2+ release from internal stores is critical for mediating both normal and pathological intracellular Ca2+ signaling. Recent studies suggest that the inositol 1, 4, 5-triphosphate (IP3) receptor mediates Ca2+ release from internal stores upon cholinergic activation of the neuromuscular junction (NMJ) in both physiological and pathological conditions. Here we report that the type I IP3 receptor (IP3R1) -mediated Ca2+ release plays a crucial role in synaptic gene expression, development and neuromuscular transmission, as well as mediating degeneration during excessive cholinergic activation. We found that IP3R1-mediated Ca2+ release plays a key role in early development of the NMJ, in homeostatic regulation of neuromuscular transmission, and in synaptic gene expression. Reducing IP3R1-mediated Ca2+ release via siRNA knockdown or IP3R blockers in C2C12 cells decreased calpain activity, and prevented agonist-induced AChR cluster dispersal. In fully developed NMJ in adult muscle, IP3R1 knockdown or blockade effectively increased synaptic strength at pre- and postsynaptic sites, by increasing both quantal release and expression of AChR subunits and other NMJ-specific genes, in a pattern resembling muscle denervation. Moreover, in two mouse models of cholinergic overactivity and NMJ Ca2+ overload, anti-cholinesterase toxicity and the slow-channel myasthenic syndrome (SCS), IP3R1 knockdown eliminated NMJ Ca2+ overload, pathological activation of calpain and caspase proteases, and markers of DNA damage at subsynaptic nuclei, and improved both neuromuscular transmission and clinical measures of motor function. Thus, blockade or genetic silencing of muscle IP3R1 may be an effective and well-tolerated therapeutic strategy in SCS and other conditions of excitotoxicity or Ca2+ overload.
Sewage sludge based granular activated carbon (SSGAC) was prepared using calcium sulfate as binder. The porous structure and surface chemical properties of SSGAC were characterized by N2 adsorption isotherm, FTIR, PZC, and Boehm titration. The results showed that the SSGAC was a typical mesoporous adsorbent of which the percentages of mesoporous surface area and volume are 72.81 % and 88.89 %, and the acid groups were dominant on its surface. The adsorption mechanism of MB adsorption onto SSGAC was also investigated by different adsorption models. The results showed that the maximum MB adsorption amount could be 131.8 mg g–1, and the MB adsorption onto SSGAC was a heterogeneous, spontaneous, and endothermic process while physisorption was dominant. The MB adsorption process was well described by the pseudosecond-order kinetic mode, and the MB diffusion in micropores was the potential rate-controlling step.
The autosomal dominant spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders exhibiting cerebellar atrophy and Purkinje cell degeneration whose subtypes arise from 31 distinct genetic loci. Our group previously published the locus for SCA26 on chromosome 19p13.3. In this study, we performed targeted deep sequencing of the critical interval in order to identify candidate causative variants in individuals from the SCA26 family. We identified a single variant that co-segregates with the disease phenotype that produces a single amino acid substitution in eukaryotic elongation factor 2. This substitution, P596H, sits in a domain critical for maintaining reading frame during translation. The yeast equivalent, P580H EF2, demonstrated impaired translocation, detected as an increased rate of -1 programmed ribosomal frameshift read-through in a dual-luciferase assay for observing translational recoding. This substitution also results in a greater susceptibility to proteostatic disruption, as evidenced by a more robust activation of a reporter gene driven by unfolded protein response activation upon challenge with dithiothreitol or heat shock in our yeast model system. Our results present a compelling candidate mutation and mechanism for the pathogenesis of SCA26 and further support the role of proteostatic disruption in neurodegenerative diseases.
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