Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.     

Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2

Coumarin derivatives such as warfarin represent the therapy of choice for the long-term treatment and prevention of thromboembolic events. Coumarins target blood coagulation by inhibiting the vitamin K epoxide reductase multiprotein complex (VKOR). This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the post-translational gamma-carboxylation of several blood coagulation factors. Despite extensive efforts, the components of the VKOR complex have not been identified. The complex has been proposed to be involved in two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2; Online Mendelian Inheritance in Man (OMIM) 607473), and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR; OMIM 122700). Here we identify, by using linkage information from three species, the gene vitamin K epoxide reductase complex subunit 1 (VKORC1), which encodes a small transmembrane protein of the endoplasmic reticulum. VKORC1 contains missense mutations in both human disorders and in a warfarin-resistant rat strain. Overexpression of wild-type VKORC1, but not VKORC1 carrying the VKCFD2 mutation, leads to a marked increase in VKOR activity, which is sensitive to warfarin inhibition.     

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.     

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.     

Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa.

The murine retinal degeneration slow (rds) gene is a semidominant mutation with a phenotype having rod and cone photoreceptors that develop abnormally and then slowly degenerate. The phenotype is a possible model for retinitis pigmentosa, one of the scores of hereditary human retinal degenerations, which is also characterized by photoreceptor degeneration. We report here three mutations of the human homologue of the rds gene (RDS) that cosegregate with autosomal dominant retinitis pigmentosa in separate families. Our results indicate that some cases of autosomal dominant retinitis pigmentosa are due to mutations at the RDS locus.     

Fine mapping of the dominant glandless Gene Gl2^e in Sea-island cotton （Gossypium barbadense L.）

Gle2 is a mutant gene that controls glandless trait in cotton plants and seeds. It is an important gene resource to gossypol-free cottonseed breeding. The objective of this research was to develop SSR markers tightly linked with Gle2 by using the F2 segregating population containing 1599 plants derived from the cross of G. hirsutum genetic standard line TM-1 and G. barbadense glandless mutant line Hai-1. Genetic analysis suggested that the Gle2 was an incomplete dominant gene. Based on the backbone of genetic linkage map from G. hirsutum × G. barbadense BC1 published by our laboratory,Gle2 was lo-cated between CIR362 and NAU2251b,NAU3860b,STV033,with a genetic distance 9.27 and 0.96 cM,respectively. This result is useful for cloning Gle2 gene by map-based cloning method.     

Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease)

"Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease. To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.     

KRAS、BRAF及PIK3CA基因突变与转移性结直肠癌的关系

 为了联合检测并分析KRAS、BRAF和PIK3CA突变与临床病理指标之间的关系,探讨基因突变在结直肠癌(CRC)发生、发展中的生物学意义,收集第四军医大学西京消化病医院及兰州军区兰州总医院2008—2009年入院治疗的150例结直肠癌患者的癌组织标本,提取DNA行PCR扩增后,采用焦磷酸测序法联合检测KRAS、BRAF及PIK3CA基因的突变率,统计分析基因突变与患者临床病理(包括患者的年龄、性别、肿瘤位置、Dukes'分期、TNM分期、组织病理学分型及转移)之间的关系。结果表明,在150例患者中,KRAS突变率为32%(48/150),BRAF突变率为8%(12/150),PIK3CA突变突变率为12%(18/150),其中9号外显子突变率为6%(9/150),20号外显子突变率为6%(9/150)。KRAS和PIK3CA的突变与患者的Dukes'分期关系密切,KRAS、BRAF和PIK3CA的突变与CRC患者的年龄、性别、肿瘤位置、组织病理学分型之间无明显的关系。     

天然水体中优势菌种非活性细胞吸附Pb2+和Cd2+的热力学及动力学研究

研究了长春市伊通河天然水体中优势菌种非活性细胞对Pb²⁺和Cd²⁺吸附规律, 发现非活性细胞对Pb²⁺和Cd²⁺的吸附符合Langm uir和Freundlich热力学方程. 非活性细胞吸附Pb²⁺和Cd²⁺的动力学过程分为快速阶段和慢速阶段, 其中慢速阶段符合二级吸附速率动力学方程.     

2070t/h超临界对冲火焰锅炉飞灰含碳量偏高原因分析

针对湖南某电厂2 070t/h超临界对冲火焰锅炉燃用运行煤种出现的飞灰含碳量偏高的现象,对其锅炉进行了热态调整试验,研究了炉膛氧量、负荷、燃尽风量和煤粉细度的变化对飞灰含碳量的影响。研究结果表明,炉膛氧量、负荷、燃尽风量和煤粉细度的变化对飞灰含碳量有较大影响。负荷增加、煤粉细度减小,飞灰含碳量降低;燃尽风量和炉膛氧量过低或过高都会使飞灰含碳量升高,运行中炉膛氧量和燃尽风量存在一个最佳值;而且,燃尽风对飞灰含碳量的影响与负荷有关。依此对该锅炉运行进行优化调整,使飞灰含碳量降低到4.5%以下。     

Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy

X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium, because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.     

天然水体中优势菌种非活性细胞对Pb２＋和Cd２＋的吸附及其影响因素

研究了长春市伊通河天然水体中优势菌种非活性细胞对Pb^２＋和Cd ^２＋ 的吸附及其影响因素. 发现细菌生物量对非活性细胞吸附Pb^２＋的影响比对Cd^２＋ 的影响大； 细菌对Pb^２＋的吸附 在pH=4.5时吸附量最大， 而对Cd^２＋的吸附在pH=6.0时吸附量最大； 细菌对Pb^２＋和Cd^２＋的吸附在30 ℃最大； 当Pb^２＋和Cd２＋共存时， Pb^２＋对细菌吸附Cd^２＋的影响不显著， 细菌对Pb２＋的吸附量随Cd^２＋浓度的增大而减少.     

论北京平谷新生代盆地的成因*

通过对北京市东北部平谷新生代盆地地层岩性、水文条件、深部构造、微小地震和盆地形态特征综合分析,提出平谷盆地并非第四纪断陷盆地,而是岩溶塌陷盆地的新认识。综合研究认为平谷盆地内基岩断裂可能大量发育;但新生代夏垫-马坊断裂带并没有在平谷盆地内发育;造成平谷盆地新生代断裂密布假象的原因是基岩埋藏古地貌;平谷盆地古溶洞形成时代可能为上新世-早更新世,盆地可能在早更新世发生塌陷,形成最初的盆地雏形。     

转基因动物模型在ALS发病机制研究及药物疗效观察中的应用

肌萎缩性脊髓侧索硬化症（Amyotrophic Lateral Sclerosis）简称为ALS,是严重危害患者身心健康的神经退行性疾病。本文简述了ALS的研究近况,着重介绍了转基因动物在该病机理研究和治疗性药物筛选方面的重要作用,转基因动物的使用和典型模型动物的商品化大大促进了该领域的研究进程。     

关于Euler-致型方程x^2-D1y^2=2s^2和x^2-D2y^2=-2t^2

设D1，D2是无平方因子正整数，该文给出了方程组x^2-D1y^2=2s^2和x^2-D2y^2=-2t^2有本原整数解(x，y，s，t)的必要条件。