High frequency of Machado-Joseph disease identified in Southeastern Chinese kindreds with spinocerebellar ataxia

<p>Abstract</p> <p>Background</p> <p>Machado-Joseph disease (MJD), caused by a CAG repeat expansion located in exon10 of the <it>ATXN3 </it>gene, is now regarded as one of the most common spinocerebellar ataxia (SCA) in the world. The relative frequency of MJD among SCA has previously been estimated at about 50% in the Chinese population and has been reported to be related to the frequency of large normal alleles in some populations. Taq polymerase has been used for PCR in nearly all studies reported previously.</p> <p>Methods</p> <p>Normal and expanded alleles of <it>ATXN3 </it>were detected via PCR using LA Taq DNA polymerase (better for GC-rich sequences) and denaturing polyacrylamide gel electrophoresis in 150 normal individuals and 138 unrelated probands from autosomal dominant SCA families. To compare reaction efficiency, 12 MJD patients' expanded alleles were amplified with La Taq and Taq polymerase respectively in the same amplifying systems and reaction conditions.</p> <p>Results</p> <p>Normal alleles ranged from 12 to 42 CAG repeats. The most common allele contained 14 repeats with a frequency of 23.3%, which corroborates previous reports. The frequency of large normal alleles (>27 repeats) was 0.28, which was very high relative to previous reports. The frequency of MJD in SCA patients was 72.5%, which was significantly higher than those in previous reports about the Chinese and other Asian populations. This frequency was one of the highest reported worldwide, with only Portuguese and Brazilian populations exhibiting higher proportions. All 12 expanded alleles were amplified in PCR with La Taq polymerase, whereas only 2 expanded alleles were amplified with Taq polymerase.</p> <p>Conclusion</p> <p>We have first reported the highest relative frequency of MJD in Asia, and we attribute this high frequency to a more efficient PCR using LA Taq polymerase and hypothesized that large ANs may act as a reservoir for expanded alleles in the Southeastern Chinese population.</p

B-vitamin consumption and the prevalence of diabetes and obesity among the US adults: population based ecological study

<p>Abstract</p> <p>Background</p> <p>The global increased prevalence of obesity and diabetes occurred after the worldwide spread of B-vitamins fortification, in which whether long-term exposure to high level of B vitamins plays a role is unknown. Our aim was to examine the relationships between B-vitamins consumption and the obesity and diabetes prevalence.</p> <p>Methods</p> <p>This population based ecological study was conducted to examine possible associations between the consumption of the B vitamins and macronutrients and the obesity and diabetes prevalence in the US population using the per capita consumption data from the US Economic Research Service and the prevalence data from the US Centers for Disease Control and Prevention.</p> <p>Results</p> <p>The prevalences of diabetes and adult obesity were highly correlated with per capita consumption of niacin, thiamin and riboflavin with a 26-and 10-year lag, respectively (<it>R</it>²= 0.952, 0.917 and 0.83 for diabetes, respectively, and <it>R</it>²= 0.964, 0.975 and 0.935 for obesity, respectively). The diabetes prevalence increased with the obesity prevalence with a 16-year lag (<it>R</it>²= 0.975). The relationships between the diabetes or obesity prevalence and per capita niacin consumption were similar both in different age groups and in male and female populations. The prevalence of adult obesity and diabetes was highly correlated with the grain contribution to niacin (<it>R</it>²= 0.925 and 0.901, respectively), with a 10-and 26-year lag, respectively. The prevalence of obesity in US adults during 1971-2004 increased in parallel with the increase in carbohydrate consumption with a 10-year lag. The per capita energy and protein consumptions positively correlated with the obesity prevalence with a one-year lag. Moreover, there was an 11-year lag relationship between per capita energy and protein consumption and the consumption of niacin, thiamin and riboflavin (<it>R</it>²= 0.932, 0.923 and 0.849 for energy, respectively, and <it>R</it>²= 0.922, 0.878 and 0.787 for protein, respectively).</p> <p>Conclusions</p> <p>Long-term exposure to high level of the B vitamins may be involved in the increased prevalence of obesity and diabetes in the US in the past 50 years. The possible roles of B-vitamins fortification and excess niacin consumption in the increased prevalence of obesity and diabetes were discussed.</p

Multi-Locus Analysis Reveals A Different Pattern of Genetic Diversity for Mitochondrial and Nuclear DNA between Wild and Domestic Pigs in East Asia

BACKGROUND: A major reduction of genetic diversity in mtDNA occurred during the domestication of East Asian pigs. However, the extent to which genetic diversity has been lost in the nuclear genome is uncertain. To reveal levels and patterns of nucleotide diversity and to elucidate the genetic relationships and demographic history of domestic pigs and their ancestors, wild boars, we investigated 14 nuclear markers (including 8 functional genes, 2 pseudogenes and 4 intergenic regions) from 11 different chromosomes in East Asia-wide samples and pooled them with previously obtained mtDNA data for a combined analysis. PRINCIPAL FINDINGS: The results indicated that domestic pigs and wild boars possess comparable levels of nucleotide diversity across the nuclear genome, which is inconsistent with patterns that have been found in mitochondrial genome. CONCLUSIONS: This incongruence between the mtDNA and nuclear genomes is suggestive of a large-scale backcross between male wild boars and female domestic pigs in East Asia. Our data reveal the impacts of founder effects and backcross on the pig genome and help us better understand the complex demographic histories of East Asian pigs, which will be useful for future work on artificial selection

N6-methyl-adenosine (m6A) in RNA: An Old Modification with A Novel Epigenetic Function

AbstractN6-methyl-adenosine (m6A) is one of the most common and abundant modifications on RNA molecules present in eukaryotes. However, the biological significance of m6A methylation remains largely unknown. Several independent lines of evidence suggest that the dynamic regulation of m6A may have a profound impact on gene expression regulation. The m6A modification is catalyzed by an unidentified methyltransferase complex containing at least one subunit methyltransferase like 3 (METTL3). m6A modification on messenger RNAs (mRNAs) mainly occurs in the exonic regions and 3′-untranslated region (3′-UTR) as revealed by high-throughput m6A-seq. One significant advance in m6A research is the recent discovery of the first two m6A RNA demethylases fat mass and obesity-associated (FTO) gene and ALKBH5, which catalyze m6A demethylation in an α-ketoglutarate (α-KG)- and Fe2+-dependent manner. Recent studies in model organisms demonstrate that METTL3, FTO and ALKBH5 play important roles in many biological processes, ranging from development and metabolism to fertility. Moreover, perturbation of activities of these enzymes leads to the disturbed expression of thousands of genes at the cellular level, implicating a regulatory role of m6A in RNA metabolism. Given the vital roles of DNA and histone methylations in epigenetic regulation of basic life processes in mammals, the dynamic and reversible chemical m6A modification on RNA may also serve as a novel epigenetic marker of profound biological significances

Association of PDE11A global haplotype with major depression and antidepressant drug response

Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the intracellular second messengers cAMP and cGMP to their corresponding monophosphates. PDEs play an important role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. We have previously shown that the individual haplotype GAACC in the PDE11A gene was associated with major depressive disorder (MDD) based on block-by-block analysis. There are two PDE genes, PDE11A and PDE1A, located in chromosome 2q31–q32. In this study, we have further explored whether the whole region 2q31–q32 contribute to MDD or antidepressant response 278 depressed Mexican-American participants and 321 matched healthy controls. Although there is no significant interaction between the two genes, the remission rate of individual carrying the combination genotype at rs1880916 (AG/AA) and rs1549870 (GG) is significantly increased. We analyzed the global haplotype by examining 16 single-nucleotide polymorphisms (SNPs) in PDE11A and six SNPs in PDE1A. None of the haplotypes consisting of six SNPs in the PDE1A have a significant difference between depressed and control groups. Among haplotypes consisting of 16 SNPs across 440 kb in the PDE11A gene, 18 common haplotypes (with frequency higher than 0.8%) have been found in the studied population. Six haplotypes showed significantly different frequencies between the MDD group and the control group. The phylogenetic network result for the 16 SNPs showed that several historic recombination events have happened in the PDE11A gene. The frequency of one haplotype is significantly lower in the remitter group than in the nonremitter group for the depressed participants treated with either desipramine or fluoxetine. Thus, our data suggest that the PDE11A global haplotype is associated with both MDD and antidepressant drug response

Population phylogenomic analysis of mitochondrial DNA in wild boars and domestic pigs revealed multiple domestication events in East Asia

A fine-grained mitochondrial DNA phylogenomic analysis was conducted in domestic pigs and wild boars, revealing that pig domestication in East Asia occurred in the Mekong and the middle and downstream regions of the Yangtze river

AVE0991, a Nonpeptide Compound, Attenuates Angiotensin II-Induced Vascular Smooth Muscle Cell Proliferation via Induction of Heme Oxygenase-1 and Downregulation of p-38 MAPK Phosphorylation

The nonpeptide AVE0991 is an agonist of the angiotensin-(1–7) (Ang-(1–7)) Mas receptor and is expected to be a putative new drug for treatment of cardiovascular disease. However, the mechanisms involved in the antiproliferative effects of AVE0991 are not fully understood. We saw that the compound attenuated proliferation in an angiotensin II-induced rat vascular smooth muscle cells (VSMC) proliferation model. Moreover, treatment with AVE0991 (10−5 mol/L or 10−7 mol/L) significantly attenuated reactive oxygen species (ROS) production, phosphorylation of p38 MAPK, and dose-dependently (10−8 to 10−5 mol/L) inhibited Ang II-induced VSMC proliferation. Meanwhile, heme oxygenase-1 (HO-1) expression increased in the AVE0991 + Ang II group (10−5 mol/L or 10−6 mol/L). However, the beneficial effects of AVE0991 were completely abolished when the VSMC were pretreated with A-779 (10−6 mol/L). Furthermore, treatment with the HO-1 inhibitor ZnPPIX attenuated the inhibitory effect of AVE0991 on Ang II-induced p38MAPK phosphorylation. These results suggest that AVE0991 attenuates Ang II-induced VSMC proliferation in a dose-dependent fashion and that this effect is associated with the Mas/HO-1/p38 MAPK signaling pathway