The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP

The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration of the cerebellum that results in movement disorder. Recently, a new heritable form of SCA, spinocerebellar ataxia type 48 (SCA48), was attributed to dominant mutations in STIP1 homology and U box-containing 1 (STUB1); however, little is known about how these mutations cause SCA48. STUB1 encodes for the protein C terminus of Hsc70 interacting protein (CHIP), an E3 ubiquitin ligase. CHIP is known to regulate proteostasis by recruiting chaperones via a N-terminal tetratricopeptide repeat domain and recruiting E2 ubiquitin-conjugating enzymes via a C-terminal U-box domain. These interactions allow CHIP to mediate the ubiquitination of chaperone-bound, misfolded proteins to promote their degradation via the proteasome. Here we have identified a novel, de novo mutation in STUB1 in a patient with SCA48 encoding for an A52G point mutation in the tetratricopeptide repeat domain of CHIP. Utilizing an array of biophysical, biochemical, and cellular assays, we demonstrate that the CHIP^A52G point mutant retains E3-ligase activity but has decreased affinity for chaperones. We further show that this mutant decreases cellular fitness in response to certain cellular stressors and induces neurodegeneration in a transgenic Caenorhabditis elegans model of SCA48. Together, our data identify the A52G mutant as a cause of SCA48 and provide molecular insight into how mutations in STUB1 cause SCA48.     

Targeting UPR branches,a potential strategy for enhancing efficacy of cancer chemotherapy

Cancer cells are often exposed to cell intrinsic stresses and environmental perturbations that may lead to accumulation of unfolded and/or misfolded proteins in...     

铅锌矿渣场植被自然演替与基质的交互效应

矿业废弃地生态系统自然恢复的植被演替过程与机理是生态恢复研究的重要内容之一.以空间代替时间的方法,选择立地条件基本一致的4个不同自然恢复年限铅锌矿区为对象,研究黔西北土法炼锌渣场废弃地植被自然演替与矿渣基质理化性质的交互效应.结果表明： 随着堆置时间的增加,矿渣基质的营养条件明显得到改善,全氮、全磷和全钾含量极显著增加, pH上升,电导率下降,容重降低,有效铅和镉显著降低. 同时,随着恢复时间的增长,植物群落的物种丰富度、多样性指数和均匀度也相应提高.植物群落组成以多年生草本植物为主,植物群落演替在前20年较为缓慢,30年后植被群落盖度可达到53%,超过40年盖度可达87%.矿渣理化性质与物种多样性显著相关,典型变量分别是全氮、全磷和全钾;物种多样性指数与有效铅和镉呈显著负相关.土法炼锌渣场废弃地植被自然演替过程在30年后速度加快,植被生长的限制因子是营养供给不足和重金属的有效性高.     

A highly selective and colorimetric assay of lysine by molecular-driven gold nanorods assembly

In this contribution, a simple, rapid, colorimeteric and selective assay for lysine was achieved by a controllable end-to-end assembly of gold nanorods (AuNRs) in the presence of Eu(3+) and lysine. This one-pot end-to-end assembly of 11-mercaptoundecanoic acid (MUA) modified AuNRs was occurred in Britton-Robinson buffer of pH 6.0, which involves the coordination binding between Eu(3+) and COO(-) groups as well as the electrostatic interaction of the COO(-) groups of MUA with the -NH(3)(+) group of lysine. As monitored by absorption spectra, scanning electron microscopic (SEM) images and dynamic light scattering (DLS) measurement, the end-to-end chain assembly results in large red-shift in the longitudinal plasmon resonance absorption (LPRA), giving red-to-blue color change of AuNRs. Importantly, it was found that the red-shift of LPRA is linearly proportional to the concentrations of lysine in the range of 5.0×10(-6)-1.0×10(-3)M with the limit of detection (LOD) being 1.6×10(-6)M (3σ/k). This red-shift of LPRA is highly selective, making it possible to develop a rapid, selective and visual assay for lysine in food samples.     

Metarhizium robertsii Produces an Extracellular Invertase (MrINV) That Plays a Pivotal Role in Rhizospheric Interactions and Root Colonization

As well as killing pest insects, the rhizosphere competent insect-pathogenic fungus Metarhizium robertsii also boosts plant growth by providing nitrogenous nutrients and increasing resistance to plant pathogens. Plant roots secrete abundant nutrients but little is known about their utilization by Metarhizium spp. and the mechanistic basis of Metarhizium-plant associations. We report here that M. robertsii produces an extracellular invertase (MrInv) on plant roots. Deletion of MrInv (⊿MrInv) reduced M. robertsii growth on sucrose and rhizospheric exudates but increased colonization of Panicum virgatum and Arabidopsis thaliana roots. This could be accounted for by a reduction in carbon catabolite repression in ⊿MrInv increasing production of plant cell wall-degrading depolymerases. A non-rhizosphere competent scarab beetle specialist Metarhizium majus lacks invertase which suggests that rhizospheric competence may be related to the sugar metabolism of different Metarhizium species.     

RNA sequencing reveals two major classes of gene expression levels in metazoan cells

The expression level of a gene is often used as a proxy for determining whether the protein or RNA product is functional in a cell or tissue. Therefore, it is of fundamental importance to understand the global distribution of gene expression levels, and to be able to interpret it mechanistically and functionally. Here we use RNA sequencing (RNA‐seq) of mouse Th2 cells, coupled with a range of other techniques, to show that all genes can be separated, based on their expression abundance, into two distinct groups: one group comprised of lowly expressed and putatively non‐functional mRNAs, and the other of highly expressed mRNAs with active chromatin marks at their promoters. These observations are confirmed in many other microarray and RNA‐seq data sets of metazoan cell types.     

Biogeographic Ancestry Is Associated with Higher Total Body Adiposity among African-American Females: The Boston Area Community Health Survey

Objectives

The prevalence of obesity is disproportionately higher among African-Americans and Hispanics as compared to whites. We investigated the role of biogeographic ancestry (BGA) on adiposity and changes in adiposity in the Boston Area Community Health Survey.

Methods

We evaluated associations between BGA, assessed via Ancestry Informative Markers, and adiposity (body mass index (BMI), percent body fat (PBF), and waist-to-hip ratio (WHR)) and changes in adiposity over 7 years for BMI and WHR and 2.5 years for PBF, per 10% greater proportion of BGA using multivariable linear regression. We also examined effect-modification by demographic and socio-behavioral variables.

Results

We observed positive associations between West-African ancestry and cross-sectional BMI (percent difference=0.62%; 95% CI: 0.04%, 1.20%), and PBF (β=0.35; 95% CI: 0.11, 0.58). We also observed significant effect-modification of the association between West-African ancestry and BMI by gender (p-interaction: <0.002) with a substantially greater association in women. We observed no main associations between Native-American ancestry and adiposity but observed significant effect-modification of the association with BMI by diet (p-interaction: <0.003) with inverse associations among participants with higher Healthy Eating Scores. No associations were observed between BGA and changes in adiposity over time.

Conclusion

Findings support that West-African ancestry may contribute to high prevalence of total body adiposity among African-Americans, particularly African-American women.