Biomedical subjects

Xiangdong Xu

Publications and source records attributed to Xiangdong Xu.

8 recordsLinked to original sources

PubMed2006

Synthesis and structure-activity relationships of N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1- methylprop-2-ynyl}carboxy derivatives as selective acetyl-CoA carboxylase 2 inhibitors.

A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC50<20 nM and >1000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2 activity and lowered muscle malonyl-CoA dose-dependently in acute rodent studies, whereas (R)-enantiomer 9o was weak and had no effect on the malonyl-CoA level.

Acetyl-CoA Carboxylase↗

PubMed2005

Dephosphorylation-dependent sorting of SR splicing factors during mRNP maturation.

SR proteins are a family of sequence-specific RNA binding proteins originally discovered as essential factors for pre-mRNA splicing and recently implicated in mRNA transport, stability, and translation. Here, we used a genetic complementation system derived from conditional knockout mice to address the function and regulation of SR proteins in vivo. We demonstrate that ASF/SF2 and SC35 are each required for cell viability, but, surprisingly, the effector RS domain of ASF/SF2 is dispensable for cell survival in MEFs. Although shuttling SR proteins have been implicated in mRNA export, prevention of ASF/SF2 from shuttling had little impact on mRNA export. We found that shuttling and nonshuttling SR proteins are segregated in an orderly fashion during mRNP maturation, indicating distinct recycling pathways for different SR proteins. We further showed that this process is regulated by differential dephosphorylation of the RS domain, thus revealing a sorting mechanism for mRNP transition from splicing to export.

Animals↗

PubMed2005

ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle.

The transition from juvenile to adult life is accompanied by programmed remodeling in many tissues and organs, which is key for organisms to adapt to the demand of the environment. Here we report a novel regulated alternative splicing program that is crucial for postnatnal heart remodeling in the mouse. We identify the essential splicing factor ASF/SF2 as a key component of the program, regulating a restricted set of tissue-specific alternative splicing events during heart remodeling. Cardiomyocytes deficient in ASF/SF2 display an unexpected hypercontraction phenotype due to a defect in postnatal splicing switch of the Ca(2+)/calmodulin-dependent kinase IIdelta (CaMKIIdelta) transcript. This failure results in mistargeting of the kinase to sarcolemmal membranes, causing severe excitation-contraction coupling defects. Our results validate ASF/SF2 as a fundamental splicing regulator in the reprogramming pathway and reveal the central contribution of ASF/SF2-regulated CaMKIIdelta alternative splicing to functional remodeling in developing heart.

Alternative Splicing↗

PubMed2005

Conditional knockout mice to study alternative splicing in vivo.

Analysis of genomes has revealed that the total number of human genes is comparable to those of simpler organisms, and thus, the number of genes does not correlate with the complexity and functional diversity of different organisms. Multiple mechanisms, including alternative splicing, are believed to contribute to the molecular complexity in higher eukaryotes. Given the fact that more than half of human genes undergo alternative splicing, however, little is known about the biological relevance of most alternative splicing events and their regulatory mechanisms. Recent work has highlighted the power of reverse genetic approaches in addressing regulated splicing in animal models. Here, we focus on the conditional knockout approach adapted for splicing research with the intention to provide a general guide to the generation of mouse models to study regulated splicing in development and disease.

Alternative Splicing↗

PubMed2004

Ultrathin polymer film formation by collision-induced cross-linking of adsorbed organic molecules with hyperthermal protons.

A new synthetic approach for the formation of ultrathin polymer films with customizable properties was developed. In this approach, the kinematic nature of proton collisions with simple organic molecules condensed on a substrate is exploited to break C-H bonds preferentially. The subsequent recombination of carbon radicals gives a cross-linked polymer thin film, and the selectivity of C-H cleavage preserves the chemical functionalities of the precursor molecules. The nature and validity of the method are exemplified with theoretical results from ab initio molecular dynamics calculations and experimental evidence from a variety of characterization techniques. Its applicability is demonstrated by the synthesis of ultrathin polymer films with precursor molecules such as dotriacontane, docosanoic acid, poly(acrylic acid) oligomer, and polyisoprene. The approach is fundamentally different from conventional chemical synthesis as it involves an unusual mix of physical and chemical processes including charge exchange, projectile penetration, kinematics, collision-induced dissociation, inelastic energy transfer, chain transfer, and chain cross-linking.

Journal Article↗

PubMed2004

Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart.

Many genetic diseases are caused by mutations in cis-acting splicing signals, but few are triggered by defective trans-acting splicing factors. Here we report that tissue-specific ablation of the splicing factor SC35 in the heart causes dilated cardiomyopathy (DCM). Although SC35 was deleted early in cardiogenesis by using the MLC-2v-Cre transgenic mouse, heart development appeared largely unaffected, with the DCM phenotype developing 3-5 weeks after birth and the mutant animals having a normal life span. This nonlethal phenotype allowed the identification of downregulated genes by microarray, one of which was the cardiac-specific ryanodine receptor 2. We showed that downregulation of this critical Ca2+ release channel preceded disease symptoms and that the mutant cardiomyocytes exhibited frequency-dependent excitation-contraction coupling defects. The implication of SC35 in heart disease agrees with a recently documented link of SC35 expression to heart failure and interference of splicing regulation during infection by myocarditis-causing viruses. These studies raise a new paradigm for the etiology of certain human heart diseases of genetic or environmental origin that may be triggered by dysfunction in RNA processing.

Animals↗

PubMed2003

[Effect of long-term fertilization practices on mobility of phosphorus in a Huangnitu paddy soil receiving low P input in the Taihu Lake region, Jiangsu Province].

Analysis of mobile forms of phosphorus of a Huangnitu, a typical paddy soil in the Taihu Lake region, Jiangsu was conducted. The soil has been put into a scheme of longterm fertilization treatments for 13 years. Total P content varied in arrange of 0.3-0.5 g.kg-1 under a range of total P fertilizer input of 0-53 kg/(hm2.a). As estimated from the total P pool values by mass balance principle, the soil had been subjected to water loss of P 2-8 kg/(hm2.a), with that under chemical fertilizers only being the biggest. The ratio of soluble P to the total was in a range of 0.2%-0.4%, without significant influence by the different fertilization schemes. While chemical fertilizer plus pig slurry manure applications had remarkably enhanced the resin-P pool by 20-40 mg.kg-1, P mobilization was not observed due to combined application of chemical fertilizers and straw amendments despite of the increase of the SOM. Therefore, P water loss in paddy soils might have active under continuous chemical fertilization alone in agriculture of this region and could not be accounted for by dissolution in water and subsequent runoff migration. For reducing the present prominent non point source pollution of N and P in the region, it is suggested that chemical fertilizers are applied in combination with an appropriate amount of manure or straw return for reducing soil P loss and, in turn, the non-point source pollution loading.

Crops, Agricultural↗

PubMed2003

[Change of available pool of heavy metals in paddy soils under human land use impacts from the Taihu Lake region, Jiangsu Province, China].

A number of representative farms under various human land uses were selected through a general survey in the Taihu Lake region, Jiangsu Province, China. The land uses covered vicinity of smelt industry and township industry, long history of high-yielding performance, long term fertilization treatments. Top layers of the paddy soils were sampled for analysis of available pool of heavy metals. A prevalent trend of increasing availability was observed of heavy metals by a degree of 30% up to 200% in the soils under these human impacts as compared with that under relative conserved conditions. This increasing trend was most remarkably exhibited in the top sub-layer of the paddy soils. The highest rise of the available pool largest was found in those under smelt industry impact and under long term chemical fertilization alone. The result showed that available pool of surface soil Cu and Pb under these impacts were 7.96-2.15 mg.kg-1, 24.7-3.47 mg.kg-1 and 8.34-4.42 mg.kg-1, 9.01-4.95 mg.kg-1 respectively. The dramatic rise of the availability with the increasing trend of the total (as previously reported) might stand for contemporary soil environmental quality and, thus, require severe concerns for agriculture and food security in this rapidly developing region.

Crops, Agricultural↗