SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.     

Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)

Pelger-Hu?t anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia, infection and toxic drug reactions, and the evolution of neutrophil nuclear shape.     

Snake venom action: Are enzymes involved in it?

Summary Enzymes were the first clearly recognized components of snake venoms. When several more were discovered, attempts were made to correlate venom action with enzymic functions. The last few years have seen most successful efforts in the identification, isolation and structural elucidation of highly toxic polypeptides present in snake venoms, in particular of neurotoxins and membrane-active toxins. Following this development the polypeptides were called the true toxic components and the enzymes lost their previous central position in venom pharmacology. The time, therefore, has come to re-evaluate the role of enzymes in the complex interaction between snake and prey. While highly active polypeptides indeed dominate the action of hydrophiid venoms, they appear to play a lesser role in crotalid venom action as compared with enzyme components. Enzymes are involved in many levels of venom action, e. g. by serving as spreading factors, of by producing very active agents, such as bradykinin and lysolecithins in tissues of preys or predators. Some toxins, e. g. the membrane-active polypeptides appear to participate in the interaction between membrane phospholipids and venom phospholipases. The classical neurotoxin, -bungarotoxin, has been recognized as a powerful phospholipase. Several instances are known which indicate that some enzymes potentiate the toxic action of others; the analysis of a single enzyme may, therefore, not fully reveal its biofunction. For 3 enzymes, ophidianl-amino acid oxidase, ATPpyrophosphatase, and acetylcholinesterase, some of the problems pertaining to venom toxicity are discussed.     

A simple theoretical criterion of chemical carcinogenicity?

Summary The simple theoretical criterion for chemical carcinogenicity based on the average quasi-valence number is discussed and shown to be inappropriate as a reliable indicator of carcinogenicity of any organic compound.I thank very much Dr R. Gordon for reading the English text and also for a stimulating discussion.     

Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity

Expression of oncogenic Ras in primary human cells activates p53, thereby protecting cells from transformation. We show that in Ras-expressing IMR-90 cells, p53 is phosphorylated at Ser33 and Ser46 by the p38 mitogen-activated protein kinase (MAPK). Activity of p38 MAPK is regulated by the p53-inducible phosphatase PPM1D, creating a potential feedback loop. Expression of oncogenic Ras suppresses PPM1D mRNA induction, leaving p53 phosphorylated at Ser33 and Ser46 and in an active state. Retrovirus-mediated overexpression of PPM1D reduced p53 phosphorylation at these sites, abrogated Ras-induced apoptosis and partially rescued cells from cell-cycle arrest. Inactivation of p38 MAPK (the product of Mapk14) in vivo by gene targeting or by PPM1D overexpression expedited tumor formation after injection of mouse embryo fibroblasts (MEFs) expressing E1A+Ras into nude mice. The gene encoding PPM1D (PPM1D, at 17q22/q23) is amplified in human breast-tumor cell lines and in approximately 11% of primary breast tumors, most of which harbor wildtype p53. These findings suggest that inactivation of the p38 MAPK through PPM1D overexpression resulting from PPM1D amplification contributes to the development of human cancers by suppressing p53 activation.     

Cloning and expression of a rat D2 dopamine receptor cDNA

Dopamine receptors are classified into D1 and D2 subtypes on the basis of their pharmacological and biochemical characteristics. The D2 dopamine receptor has been implicated in the pathophysiology and treatment of movement disorders, schizophrenia and drug addiction. The D2 dopamine receptor interacts with guanine nucleotide-binding proteins to induce second messenger systems. Other members of the family of receptors that are coupled to G proteins share a significant similarity in primary amino-acid sequence and exhibit an archetypical topology predicted to consist of seven putative transmembrane domains. We have taken advantage of the expected nucleotide sequence similarities among members of this gene family to isolate genes coding for new receptors. Using the hamster beta 2-adrenergic receptor gene as a hybridization probe we have isolated related genes including a cDNA encoding the rat D2 dopamine receptor. This receptor has been characterized on the basis of three criteria: the deduced amino-acid sequence which reveals that it is a member of the family of G-protein-coupled receptors; the tissue distribution of the mRNA which parallels that of the D2 dopamine receptor; and the pharmacological profile of mouse fibroblast cells transfected with the cDNA.     

私营资本参与基础设施PPP项目的政府激励措施

政府往往需要提供激励措施才能吸引私营资本在基础设施公私合营(PPP)项目的投资。该文选取北京国家体育场等案例,归纳实际项目中的各种政府激励措施;并通过实证问卷调查私营部门的综合评价。结果表明:政府激励措施包括政府投资赞助、政府对融资的协助、政府担保、税收减免优惠和开发新市场;私营部门充分肯定各种激励措施的有效性,其中税收减免措施得分最高,政府投资赞助得分最低;而私营部门需客观评估政府激励措施,切勿索要不合理激励,以避免项目实施过程中出现因政府无法履行承诺而导致的项目中止或者失败。     

手性锌卟啉的合成及其与咪唑类配体配位反应热力学研究

以Ｌ－（＋）－酒石酸为手性源,合成了一类新型手性锌（Ⅱ）卟啉配合物,用元素分析,比旋光、紫外可见光谱等手段对产物及其中间体进行了表征,研究了这类卟啉与三种咪唑类配体轴位反应热力学性质,发现取代基的电子效应强烈地影响锌卟啉和配体的热力学性质,并用分子力学、半经验量化计算的方法对卟啉和配体的结构进行了优化和计算,得到和实验现象相一致的结果。