A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.

Thousands die each year from sudden infant death syndrome (SIDS). Neither the cause nor basis for varied prevalence in different populations is understood. While 2 cases have been associated with mutations in type Valpha, cardiac voltage-gated sodium channels (SCN5A), the "Back to Sleep" campaign has decreased SIDS prevalence, consistent with a role for environmental influences in disease pathogenesis. Here we studied SCN5A in African Americans. Three of 133 SIDS cases were homozygous for the variant S1103Y. Among controls, 120 of 1,056 were carriers of the heterozygous genotype, which was previously associated with increased risk for arrhythmia in adults. This suggests that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. As risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wild-type channels were subjected to lowered intracellular pH. Only Y1103 channels gained abnormal function, demonstrating late reopenings suppressible by the drug mexiletine. The variant appeared to confer susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. Overall, homozygous and rare heterozygous SCN5A missense variants were found in approximately 5% of cases. If our findings are replicated, prospective genetic testing of SIDS cases and screening with counseling for at-risk families warrant consideration

Arsenic transport by zebrafish aquaglyceroporins

<p>Abstract</p> <p>Background</p> <p>Arsenic is one of the most ubiquitous toxins and endangers the health of tens of millions of humans worldwide. It is a mainly a water-borne contaminant. Inorganic trivalent arsenic (As^III) is one of the major species that exists environmentally. The transport of As^IIIhas been studied in microbes, plants and mammals. Members of the aquaglyceroporin family have been shown to actively conduct As^IIIand its organic metabolite, monomethylarsenite (MAs^III). However, the transport of As^IIIand MAs^IIIin in any fish species has not been characterized.</p> <p>Results</p> <p>In this study, five members of the aquaglyceroporin family from zebrafish (<it>Danio rerio</it>) were cloned, and their ability to transport water, glycerol, and trivalent arsenicals (As^IIIand MAs^III) and antimonite (Sb^III) was investigated. Genes for at least seven aquaglyceroporins have been annotated in the zebrafish genome project. Here, five genes which are close homologues to human AQP3, AQP9 and AQP10 were cloned from a zebrafish cDNA preparation. These genes were named <it>aqp3, aqp3l, aqp9a, aqp9b </it>and <it>aqp10 </it>according to their similarities to the corresponding human AQPs. Expression of <it>aqp9a, aqp9b</it>, <it>aqp3, aqp3l </it>and <it>aqp10 </it>in multiple zebrafish organs were examined by RT-PCR. Our results demonstrated that these aquaglyceroporins exhibited different tissue expression. They are all detected in more than one tissue. The ability of these five aquaglyceroporins to transport water, glycerol and the metalloids arsenic and antimony was examined following expression in oocytes from <it>Xenopus leavis</it>. Each of these channels showed substantial glycerol transport at equivalent rates. These aquaglyceroporins also facilitate uptake of inorganic As^III, MAs^IIIand Sb^III. Arsenic accumulation in fish larvae and in different tissues from adult zebrafish was studied following short-term arsenic exposure. The results showed that liver is the major organ of arsenic accumulation; other tissues such as gill, eye, heart, intestine muscle and skin also exhibited significant ability to accumulate arsenic. The zebrafish larvae also accumulate considerable amounts of arsenic.</p> <p>Conclusion</p> <p>This is the first molecular identification of fish arsenite transport systems and we propose that the extensive expression of the fish aquaglyceroporins and their ability to transport metalloids suggests that aquaglyceroporins are the major pathways for arsenic accumulation in a variety of zebrafish tissues. Uptake is one important step of arsenic metabolism. Our results will contribute to a new understanding of aquatic arsenic metabolism and will support the use of zebrafish as a new model system to study arsenic associated human diseases.</p

Genomic selection analysis of morphological and adaptation traits in Chinese indigenous dog breeds

The significant morphological differences and abundant germplasm resources of Chinese indigenous dog breeds can be attributed to the diverse geographical environment, including plateaus, mountains, and a long history of raising dogs. The combination of both natural and artificial selection during the past several thousand years has led to hundreds of dog breeds with distinct morphological traits and environmental adaptations. China is one of the earliest countries to domesticate dogs and there are more than 50 ancient indigenous dog breeds. In this study, the run of homozygosity (ROH) and proportion of the autosomal genome covered by ROHs (FROH) were calculated for 10 dog breeds that are the most representative Chinese indigenous dogs based on 170K SNP microarray. The results of FROH showed that the Chuandong hound dogs (HCSSC) have the highest level of inbreeding among the tested breeds. The inbreeding in HCSSC occurred more recently than the Liangshan dogs (SCLSQ) dogs because of more numbers of long ROHs in HCSSC dogs, and the former also have higher inbreeding degree. In addition, there are significant differences in the inbreeding degree among different subpopulations of the same breed, such as the Thin dogs from Shaanxi and Shandong province. To explore genome-wide selection signatures among different breeds, including coat color, ear shape, and altitude adaptability, we performed genome selection analyses of FST and cross population extended haplotype homozygosity (XP-EHH). For the coat color, the FST analysis between Xiasi dogs (XSGZ) and HCSSC dogs was performed and identified multiple genes involved in coat color, hair follicle, and bone development, including MC1R, KITLG, SOX5, RSPO2, and TBX15. For the plateau adaptability, we performed FST and XP-EHH analyses between dogs from Tibet (Tibetan Mastiffs and Nyingchi dogs) and plain regions (Guangxi Biwei dogs GXBWQ and Guandong Sharpei dogs). The results showed the EPAS1 gene in dogs from Tibet undergo strong selection. Multiple genes identified for selection signals based on different usage of dogs. Furthermore, the results of ear shape analyses showed that MSRB3 was likely to be the main gene causing the drop ear of domestic dogs. Our study provides new insights into further understanding of Chinese indigenous dogs

Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Background/Aims: Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, and an increased accumulation of LDs in the liver is closely linked to hepatic steatosis. Our previous studies suggested that resveratrol (RSV) supplement could improve hepatic steatosis, but the underlying mechanism, particularly which related to LD accumulation, has not yet been elucidated. Methods: A high-fat diet (HFD) and palmitic acid were used to induce hepatic steatosis in mouse liver and hepatocytes, respectively. The effects of RSV on LD accumulation were analyzed in vivo and in vitro. The effects of RSV on the expression levels of LD-associated genes (ATF6, Fsp27β/CIDEC, CREBH, and PLIN1) were measured by qRT-PCR and western blot assays, followed by KD or overexpression of SIRT1 and ATF6 with small interfering RNAs or overexpressed plasmids, respectively. The dual luciferase reporter assay, chromatin immunoprecipitation assay, coimmunoprecipitation, and proximity ligation assay were utilized to clarify the mechanism of transcriptional regulation and possible interaction between SIRT1 and ATF6. Results: There was a significant increase in the accumulation of LDs in liver and hepatocytes during the process of HFD-induced steatosis, respectively, which was significantly inhibited by RSV supplementation. RSV notably activated SIRT1 expression and decreased the expression levels of ATF6, Fsp27β/CIDEC, CREBH, and PLIN1, which are associated with LD accumulation. Interestingly, the inhibitory effects of RSV on LD accumulation and the associated expression of genes in hepatocytes were abrogated or strengthened with SIRT1 silencing or overexpression, respectively. On the contrary, the benefits of RSV in hepatocytes were eliminated or aggravated when transfected with the overexpressed ATF6 or ATF6 siRNA, respectively. Furthermore, we found that RSV stimulated SIRT1 expression significantly, which was followed by increased deacetylation and inactivation of ATF6, resulting in a positive feedback loop for SIRT1 transcription associated with ATF6 binding to the SIRT1 promoter region. Conclusion: Taken together, these findings indicate that RSV supplementation improves hepatic steatosis by ameliorating the accumulation of LDs, and this might be partially mediated by a SIRT1/ATF6-dependent mechanism

Mechanistic Investigation for Solidification of Pb in Fly Ash by Alkali Mineral Slag—Calcium Chloroaluminate as an Example

With the increase in municipal solid waste incineration, fly ash, its heavy metal content, and its disposal methods have attracted wide attention. This work investigates if the alkali-activated mineral slag gel solidification of heavy metals in fly ash has positive significance in promoting the harmless treatment of fly ash. This study obtained the optimal solidification conditions of fly ash from a grate incinerator, which are mineral slag content of 40%, activator content of 4%, and water content of 27.5%. Furthermore, the stability of synthesized calcium chloroaluminate is systematically investigated. The solidification effect of calcium chloroaluminate on Pb at pH = 10–13 was conducted at ambient temperatures from 15 °C to 35 °C to simulate the solidification environment of fly ash. The results show that the adsorption capacity of calcium chloroaluminate to Pb in a strongly alkaline environment is 0.1–3.5 mg/g. Pb is mainly solidified as lead-acid calcium chloroaluminate. This work provides a novel treatment strategy for fly ash

Mutation of Basic Residues R283, R286, and K288 in the Matrix Protein of Newcastle Disease Virus Attenuates Viral Replication and Pathogenicity

The matrix (M) protein of Newcastle disease virus (NDV) contains large numbers of unevenly distributed basic residues, but the precise function of most basic residues in the M protein remains enigmatic. We previously demonstrated that the C-terminus (aa 264–313) of M protein interacted with the extra-terminal (ET) domain of chicken bromodomain-containing protein 2 (chBRD2), which promoted NDV replication by downregulating chBRD2 expression and facilitating viral RNA synthesis and transcription. However, the key amino acid sites determining M’s interaction with chBRD2/ET and their roles in the replication and pathogenicity of NDV are not known. In this study, three basic residues—R283, R286, and K288—in the NDV M protein were verified to be responsible for its interaction with chBRD2/ET. In addition, mutation of these basic residues (R283A/R286A/K288A) in the M protein changed its electrostatic pattern and abrogated the decreased expression of endogenic chBRD2. Moreover, a recombinant virus harboring these mutations resulted in a pathotype change of NDV and attenuated viral replication and pathogenicity in chickens due to the decreased viral RNA synthesis and transcription. Our findings therefore provide a better understanding of the crucial biological functions of M’s basic residues and also aid in understanding the poorly understood pathogenesis of NDV

Mechanistic Investigation for Solidification of Pb in Fly Ash by Alkali Mineral Slag&mdash;Calcium Chloroaluminate as an Example

With the increase in municipal solid waste incineration, fly ash, its heavy metal content, and its disposal methods have attracted wide attention. This work investigates if the alkali-activated mineral slag gel solidification of heavy metals in fly ash has positive significance in promoting the harmless treatment of fly ash. This study obtained the optimal solidification conditions of fly ash from a grate incinerator, which are mineral slag content of 40%, activator content of 4%, and water content of 27.5%. Furthermore, the stability of synthesized calcium chloroaluminate is systematically investigated. The solidification effect of calcium chloroaluminate on Pb at pH = 10&ndash;13 was conducted at ambient temperatures from 15 &deg;C to 35 &deg;C to simulate the solidification environment of fly ash. The results show that the adsorption capacity of calcium chloroaluminate to Pb in a strongly alkaline environment is 0.1&ndash;3.5 mg/g. Pb is mainly solidified as lead-acid calcium chloroaluminate. This work provides a novel treatment strategy for fly ash

Submarine Landslides and their Distribution in the Gas Hydrate Area on the North Slope of the South China Sea

Integrated investigations have revealed abundant resources of gas hydrates on the northern slope of the South China Sea (SCS). Regarding the gas hydrate research of northern SCS, the gas hydrate related environment problem such as seabed landslides were also concentrated on in those areas. Based on 2D seismic data and sub-bottom profiles of the gas hydrate areas, submarine landslides in the areas of Qiongdongnan, Xisha, Shenhu, and Dongsha have been identified, characterized, and interpreted, and the geophysical characteristics of the northern SCS region investigated comprehensively. The results show 6 major landslides in the gas hydrate zone of the northern SCS and 24 landslides in the Shenhu and Dongsha slope areas of the northern SCS. The landslide zones are located mainly at water depths of 200&#8315;3000 m, and they occur on the sides of valleys on the slope, on the flanks of volcanoes, and on the uplifted steep slopes above magmatic intrusions. All landslides extend laterally towards the NE or NEE and show a close relationship to the ancient coastline and the steep terrain of the seabed. We speculate that the distribution and development of submarine landslides in this area has a close relationship with the tectonic setting and sedimentary filling characteristics of the slopes where they are located. Seismic activity is the important factor controlling the submarine landslide in Dongsha area, but the important factor controlling the submarine landslides in Shenhu area is the decomposition of natural gas hydrates

A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.

Thousands die each year from sudden infant death syndrome (SIDS). Neither the cause nor basis for varied prevalence in different populations is understood. While 2 cases have been associated with mutations in type Valpha, cardiac voltage-gated sodium channels (SCN5A), the "Back to Sleep" campaign has decreased SIDS prevalence, consistent with a role for environmental influences in disease pathogenesis. Here we studied SCN5A in African Americans. Three of 133 SIDS cases were homozygous for the variant S1103Y. Among controls, 120 of 1,056 were carriers of the heterozygous genotype, which was previously associated with increased risk for arrhythmia in adults. This suggests that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. As risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wild-type channels were subjected to lowered intracellular pH. Only Y1103 channels gained abnormal function, demonstrating late reopenings suppressible by the drug mexiletine. The variant appeared to confer susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. Overall, homozygous and rare heterozygous SCN5A missense variants were found in approximately 5% of cases. If our findings are replicated, prospective genetic testing of SIDS cases and screening with counseling for at-risk families warrant consideration