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.     

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.     

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。     

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。     

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.     

PI／TiO2纳米复合膜的H2／CH4和H2／N2分离性能

以可溶性聚酰亚胺为基质，经乙酸修饰后的钛酸丁酯为TiO2溶胶前体，NMP为共溶剂，采用溶胶—凝胶法可制得PI／TiO2纳米复合膜。采用XPS、TEM和气体透气性能测试等手段，对复合膜的结构和H2分离性能进行了表征。结果表明，复合膜中钛酸丁酯已转化为TiO2，PI与TiO2两相结合完好。TiO2以颗粒状均匀分布在PI基质中，其颗粒粒径约为10nm。复合膜的H2，N2和CH4透气系数随着TiO2含量的增加而明显增加。当TiO2含量为22．3％时，对H2的透气系数为14．1Barrer，对H2/N2和H2／CH4的分离系数分别为187．5和143．2，因此，该复合膜是一种较为理想的H2分离和回收膜材料。     

PI/TiO2纳米复合膜的H2/CH4和H2/N2分离性能

以可溶性聚酰亚胺为基质 ,经乙酸修饰后的钛酸丁酯为TiO2 溶胶前体 ,NMP为共溶剂 ,采用溶胶凝胶法可制得PI/TiO2 纳米复合膜。采用XPS、TEM和气体透气性能测试等手段 ,对复合膜的结构和H2 分离性能进行了表征。结果表明 ,复合膜中钛酸丁酯已转化为TiO2 ,PI与TiO2 两相结合完好。TiO2 以颗粒状均匀分布在PI基质中 ,其颗粒粒径约为 1 0nm。复合膜的H2 ,N2 和CH4 透气系数随着TiO2 含量的增加而明显增加。当TiO2 含量为2 2 3 %时 ,对H2 的透气系数为 1 4 .1Barrer,对H2 /N2 和H2 /CH4 的分离系数分别为 1 87.5和 1 4 3 .2 ,因此 ,该复合膜是一种较为理想的H2 分离和回收膜材料     

氢氧焰燃烧合成纳米SnO2/TiO2复合颗粒的形貌与结构

利用预混合氢氧焰燃烧合成了形态和结构不同的SnO2／TiO2复合纳米颗粒,颗粒呈多面体结构,形貌介于球形和立方方形之间,复合颗粒由同为四方晶系的SnO2和TiO2组成。在SnO2／TiO2复合颗粒中存在Sn—O—Ti键,没有出现相分离现象。复合颗粒表面的Ti：Sn(mol：mol,下同)比大于复合颗粒内部的Ti：Sn,而且复合颗粒内部Ti：Sn接近理论值。     

SiO_2/Ag/SiO_2/Au多层纳米壳中的法诺共振现象

利用等离子体杂化理论解释了SiO2/Ag/SiO2/Au多层纳米壳的法诺共振现象,并利用有限元方法系统地研究了其消光特性。结果表明:具有对称性的多层纳米壳结构可以实现法诺共振。进一步证实了SiO2/Ag/SiO2/Au多层纳米壳的法诺共振是由其内球壳和外球壳的偶极-偶极耦合杂化产生。通过选择合适的几何参数,SiO2/Ag/SiO2/Au多层纳米壳法诺共振的位置可以调谐至600~900nm。     

CaO-ZrO2-TiO2-Al2O3-B2O3-SiO2玻璃陶瓷的制备及化学稳定性研究

玻璃陶瓷是固化处理中、高放废物和α废物较为理想的候选材料之一。研究了特定条件下制备的CaO-ZrO2-TiO2-Al2O3-B2O3-SiO2体系玻璃陶瓷在水淬和空气中自然冷却的两种冷却制度对其结晶行为和显微结构的影响,用粉末浸泡实验方法测试了其化学稳定性。结果表明:自然冷却形成的玻璃陶瓷晶相主要是ZrSiO4和ZrTiO4;在25～70℃范围内,温度对玻璃陶瓷浸出率无明显影响,90℃下浸出率比25℃,40℃,70℃的浸出率高一个数量级;7 d元素总的归一化浸出为1.87 g/m2。     

四种原发恶性肿瘤中p16基因的缺失和突变研究

采用双重PCR、PCR－SSCP和序列分析方法,对31例非小细胞肺癌、15例食管癌、12例胃癌、9例乳腺癌共68例原发肿瘤组织标p16进行在肺癌、食管癌、胃癌、乳腺癌的缺失率分别为16％（5／31）、,20－％（3／15）,8％（1／13）,0（0／9）,2例突变：一例食管癌在第130位氨基酸密码由AGA变为ATA,编码的氨基酸由精氨酸变为异亮氨酸,一例肺癌第140位氨基酸的CGG处的C缺失,导致移码突变,p16基因在人类恶性肿瘤发生发展中起重要作用,是多肿瘤抑制基因。     

Pathways to neuronal injury and apoptosis in HIV-associated dementia

Human immunodeficiency virus-1 (HIV-1) can induce dementia with alarming occurrence worldwide. The mechanism remains poorly understood, but discovery in brain of HIV-1-binding sites (chemokine receptors) provides new insights. HIV-1 infects macrophages and microglia, but not neurons, although neurons are injured and die by apoptosis. The predominant pathway to neuronal injury is indirect through release of macrophage, microglial and astrocyte toxins, although direct injury by viral proteins might also contribute. These toxins overstimulate neurons, resulting in the formation of free radicals and excitotoxicity, similar to other neurodegenerative diseases. Recent advances in understanding the signalling pathways mediating these events offer hope for therapeutic intervention.