Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension

To identify renally expressed genes that influence risk for hypertension, we integrated expression quantitative trait locus (QTL) analysis of the kidney with genome-wide correlation analysis of renal expression profiles and blood pressure in recombinant inbred strains derived from the spontaneously hypertensive rat (SHR). This strategy, together with renal transplantation studies in SHR progenitor, transgenic and congenic strains, identified deficient renal expression of Cd36 encoding fatty acid translocase as a genetically determined risk factor for spontaneous hypertension.     

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.     

Design, function and structure of a monomeric ClC transporter

Channels and transporters of the ClC family cause the transmembrane movement of inorganic anions in service of a variety of biological tasks, from the unusual-the generation of the kilowatt pulses with which electric fish stun their prey-to the quotidian-the acidification of endosomes, vacuoles and lysosomes. The homodimeric architecture of ClC proteins, initially inferred from single-molecule studies of an elasmobranch Cl(-) channel and later confirmed by crystal structures of bacterial Cl(-)/H(+) antiporters, is apparently universal. Moreover, the basic machinery that enables ion movement through these proteins-the aqueous pores for anion diffusion in the channels and the ion-coupling chambers that coordinate Cl(-) and H(+) antiport in the transporters-are contained wholly within each subunit of the homodimer. The near-normal function of a bacterial ClC transporter straitjacketed by covalent crosslinks across the dimer interface and the behaviour of a concatemeric human homologue argue that the transport cycle resides within each subunit and does not require rigid-body rearrangements between subunits. However, this evidence is only inferential, and because examples are known in which quaternary rearrangements of extramembrane ClC domains that contribute to dimerization modulate transport activity, we cannot declare as definitive a 'parallel-pathways' picture in which the homodimer consists of two single-subunit transporters operating independently. A strong prediction of such a view is that it should in principle be possible to obtain a monomeric ClC. Here we exploit the known structure of a ClC Cl(-)/H(+) exchanger, ClC-ec1 from Escherichia coli, to design mutants that destabilize the dimer interface while preserving both the structure and the transport function of individual subunits. The results demonstrate that the ClC subunit alone is the basic functional unit for transport and that cross-subunit interaction is not required for Cl(-)/H(+) exchange in ClC transporters.     

鸡溶菌酶A元件在大豆中对uidA基因瞬时表达的影响

本研究将报告基因uidA(β-葡糖苷酶基因)两侧各含有一个鸡溶菌酶A元件(chiMAR)的中间表达载体pLM9与不含chiMAR的中间表达载体pLM5经农杆菌介导转化大豆,以研究chiMAR对外源uidA基因瞬时表达的影响.结果表明,在大豆品种科丰6号和冀豆12中,chiMAR均能显著提高uidA基因的瞬时表达率(p<0.01),并且chiMAR对不同品种中uidA基因瞬时表达率的影响不同;在科丰6号中,chiMAR对uidA基因的瞬时表达量没有显著影响,但能够降低uidA基因瞬时表达的个体差异度;chiMAR可以显著降低uidA基因在冀豆12中的瞬时表达量(p<0.01),同时提高uidA基因瞬时表达的个体差异度.     

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10?12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10?11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10??) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10?11) and a tag SNP for NAT2 acetylation status (P = 4 × 10?11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.     

Light-induced liquid crystallinity

Liquid crystals are traditionally classified as thermotropic, lyotropic or polymeric, based on the stimulus that governs the organization and order of the molecular system. The most widely known and applied class of liquid crystals are a subset of thermotropic liquid crystals known as calamitic, in which adding heat can result in phase transitions from or into the nematic, cholesteric and smectic mesophases. Photoresponsive liquid-crystal materials and mixtures can undergo isothermal phase transitions if light affects the order parameter of the system within a mesophase sufficiently. In nearly all previous examinations, light exposure of photoresponsive liquid-crystal materials and mixtures resulted in order-decreasing photo-induced isothermal phase transitions. Under specialized conditions, an increase in order with light exposure has been reported, despite the tendency of the photoresponsive liquid-crystal system to reduce order in the exposed state. A direct, photo-induced transition from the isotropic to the nematic phase has been observed in a mixture of spiropyran molecules and a nematic liquid crystal. Here we report a class of naphthopyran-based materials that exhibit photo-induced conformational changes in molecular structure capable of yielding order-increasing phase transitions. Appropriate functionalization of the naphthopyran molecules leads to an exceedingly large order parameter in the open form, which results in a clear to strongly absorbing dichroic state. The increase in order with light exposure has profound implications in optics, photonics, lasing and displays and will merit further consideration for applications in solar energy harvesting. The large, photo-induced dichroism exhibited by the material system has been long sought in ophthalmic applications such as photochromic and polarized variable transmission sunglasses.