Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.     

Gamma-secretase gene mutations in familial acne inversa

Acne inversa (AI), also known as hidradenitis suppurativa, is a chronic, recurrent, inflammatory disease of hair follicles that often runs in families. We studied six Chinese families with features of AI as well as additional skin lesions on back, face, nape, and waist and found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN, the genes encoding essential components of the γ-secretase multiprotein complex. Our results identify the γ-secretase component genes as the culprits for a subset of familial AI, implicate the γ-secretase-Notch pathway in the molecular pathogenesis of AI, and demonstrate that familial AI can be an allelic disorder of early-onset familial Alzheimer's disease.     

Absence of duplication of chromosome 21 genes in familial and sporadic Alzheimer's disease

The possibility that Alzheimer's disease (AD) is caused by overexpression or duplication of one or more genes on chromosome 21 has been raised by the observation of AD-like neuropathologic changes in individuals with Down syndrome and by the mapping of both the defect for familial AD and the amyloid beta protein gene to this autosome. Possible duplication on chromosome 21 was investigated in both familial and sporadic AD by means of restriction fragment length polymorphisms for the amyloid and SODI loci, as well as for DNA markers in the vicinity of the familial AD defect and in the critical Down syndrome region of chromosome 21. No evidence of increased DNA dosage was observed in either brain or leukocytes of patients with inherited or sporadic forms of AD. Duplication of these regions is therefore not a frequent event in either form of AD. Furthermore, no significant allelic association was detected between AD and any of the loci, including the amyloid and SODI genes, providing no support for the hypothesis that defects in these specific genes are the primary cause of AD.     

Amyotrophic lateral sclerosis: effect of serum on anterior horn cells in tissue culture

A high proportion of diluted serums of patients with amyotrophic lateral sclerosis were toxic to the anterior horn cells of the mouse in tissue culture. This is not a general cytotoxicity, since apparently only the neurons were killed. Serums from other degenerative neurological diseases were inactive.     

Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms

Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.     

含 P43 启动子 aiiA 基因重组枯草芽孢杆菌的构建与表达…

细菌群体可以通过响应N-酰基高丝氨酸内酯(N-acyl-homoserine lactones, AHLs)激活某些致病基因的表达,而芽胞杆菌可以表达AiiA(Autoinducer inactivation)蛋白降解病原菌的AHLs从而减低损害。为构建外源高效表达AiiA蛋白的工程菌,利用AiiA蛋白降解AHLs分子来防治细菌性植物病害,通过搭桥PCR扩增P43-aiiA联合片段,连接pHY300PLK载体,构建P43-aiiA-C11枯草芽孢杆菌菌株,验证其AiiA酶活。结果成功克隆得到P43-aiiA片段,经鉴定P43-aiiA-pHY300PLK成功转入C11菌株,通过AiiA活性检测,野生菌株组指示菌全部变蓝,3个平行实验组的蓝色指示菌至条状培养基中间变浅,至下端全部为白色菌落,说明实验所构建的P43-aiiA-C11菌株具有高于野生型C11菌株的淬灭酶活性,能明显降解信号分子。与野生型菌株相比,构建菌株P43-aiiA-C11表达产物具有显著降解AHLs的能力,研究结果为推动植物病害防治提供了重要理论基础。     

Altered telomeres in tumors with ATRX and DAXX mutations

The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.     

Neuronal activity in the lateral intraparietal area and spatial attention

Although the parietal cortex has been implicated in the neural processes underlying visual attention, the nature of its contribution is not well understood. We tracked attention in the monkey and correlated the activity of neurons in the lateral intraparietal area (LIP) with the monkey's attentional performance. The ensemble activity in LIP across the entire visual field describes the spatial and temporal dynamics of a monkey's attention. Activity subtending a single location in the visual field describes the attentional priority at that area but does not predict that the monkey will actually attend to or make an eye movement to that location.     

Adaptive mutations in bacteria: high rate and small effects

Evolution by natural selection is driven by the continuous generation of adaptive mutations. We measured the genomic mutation rate that generates beneficial mutations and their effects on fitness in Escherichia coli under conditions in which the effect of competition between lineages carrying different beneficial mutations is minimized. We found a rate on the order of 10(-5) per genome per generation, which is 1000 times as high as previous estimates, and a mean selective advantage of 1%. Such a high rate of adaptive evolution has implications for the evolution of antibiotic resistance and pathogenicity.     

Central trigeminal structures and the lateral hypothalamic syndrome in the rat

Extrahypothalamic lesions of central trigeminal structures produce a syndrome of aphagia, adipsia, finickiness, and food spillage. The similarity of these effects to the lateral hypothalamic syndrome and the location of trigeminal structures within the diencephalon suggest that some components of the lateral hypothalamic syndrome are due to incidental damage to trigeminal fibers of passage.     

Dissociation of impairment after lateral and medial prefrontal lesions in dogs

Dogs were trained before operation on a go, no-go test with symmetrical reinforcement. Lesions situated on the medial surface of the prefrontal cortex caused slight or no impairment in retention, whereas removal of the lateral prefrontal cortex induced severe and long-lasting impairment. The lateral prefrontal cortex is probably related to selection of the proper instrumental responses to corresponding stimuli.     

Hyperphagia in rats with cuts between the ventromedial and lateral hypothalamus

Bilateral cuts between the ventromedial and lateral hypothalamus in female rats consistently produced hyperphagia. Hyperphagia occurred slightly less reliably when one of the cuts entered the ventromedial hypothalamus and only infrequently if one entered the lateral hypothalamus. The results are consistent with other evidence that suggests that fibers originating medially stop eating by inhibiting cells in the lateral hypothalamus.     

Multiple sclerosis: correlation between immunoglobulin-G in cerebrospinal fluid and brain

There is a positive correlation between the concentration of immunoglobulin-G in plaques of demyelination due to multiple sclerosis (as well as in white matter of normal appearance) and the concentration of this globulin in the cerebrospinal fluid. The tentative conclusion drawn from these results was that, in patients with multiple sclerosis, the increase in immuno-globulin-G in the cerebrospinal fluid is a reflection of an excess of this globulin in the brain.     

NO诱导IAA和O2.-积累于侧根尖端促进水稻侧根生长

为了探讨NO和超氧阴离子对水稻种子根侧根生长的影响,以DR5-GUS标记IAA的转基因水稻为材料,种子催芽萌发后,用含有不同浓度的NO供体、NO合成酶抑制剂和清除剂溶液来培养萌发3 d的水稻幼苗,在培养的第3 d和第5 d分别测量初生根长度和初生根上侧根数量,并通过DAF-2DA对NO、GUS对IAA和NBT对超氧阴离子（O₂·^-）染色后,在显微镜下观察NO、IAA和O₂·^-在侧根的定位,分析与NO合成相关的基因表达。结果表明,NO和IAA主要分布在根中柱的维管束部分以及侧根起始形成处和侧根根尖,O₂·^-只极性分布在侧根起始部位和侧根根尖。当NO合成受到抑制或清除时,NO、IAA和O₂·^-在侧根的积累量明显减少,侧根数量及初生根长度也均显著下降。荧光定量PCR分析发现,外源的NO供体SNP处理均能显著诱导水稻OsNIA1和OsNIA2基因表达,而NO合成酶抑制剂处理则抑制OsNIA1和OsNIA2基因表达。基于我...     

Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas

Previous studies have demonstrated that allelic deletions of the short arm of chromosome 17 occur in over 75% of colorectal carcinomas. Twenty chromosome 17p markers were used to localize the common region of deletion in these tumors to a region contained within bands 17p12 to 17p13.3. This region contains the gene for the transformation-associated protein p53. Southern and Northern blot hybridization experiments provided no evidence for gross alterations of the p53 gene or surrounding sequences. As a more rigorous test of the possibility that p53 was a target of the deletions, the p53 coding regions from two tumors were analyzed; these two tumors, like most colorectal carcinomas, had allelic deletions of chromosome 17p and expressed considerable amounts of p53 messenger RNA from the remaining allele. The remaining p53 allele was mutated in both tumors, with an alanine substituted for valine at codon 143 of one tumor and a histidine substituted for arginine at codon 175 of the second tumor. Both mutations occurred in a highly conserved region of the p53 gene that was previously found to be mutated in murine p53 oncogenes. The data suggest that p53 gene mutations may be involved in colorectal neoplasia, perhaps through inactivation of a tumor suppressor function of the wild-type p53 gene.     

K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension

Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na(+)) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca(2+)) entry, the signal for aldosterone production and cell proliferation. Similarly, we identify an inherited KCNJ5 mutation that produces increased Na(+) conductance in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia. These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K(+) channel selectivity in constitutive cell proliferation and hormone production.     

Facile detection of mitochondrial DNA mutations in tumors and bodily fluids

Examination of human bladder, head and neck, and lung primary tumors revealed a high frequency of mitochondrial DNA (mtDNA) mutations. The majority of these somatic mutations were homoplasmic in nature, indicating that the mutant mtDNA became dominant in tumor cells. The mutated mtDNA was readily detectable in paired bodily fluids from each type of cancer and was 19 to 220 times as abundant as mutated nuclear p53 DNA. By virtue of their clonal nature and high copy number, mitochondrial mutations may provide a powerful molecular marker for noninvasive detection of cancer.     

葡萄二次果的贮藏和酿酒特性研究

比较了葡萄品种巨峰和雷司令二交果与一次果的贮藏和酿酒特性。巨峰葡萄二次果在贮藏期果内还原糖含酸量、可溶性固形物含量的变化趋势与一次果完全相反;果梗耐拉力、果粒耐压力显著高于一次果,而袋内ＣＯ２浓度、落粒率却显著低于一次果,显著池优良的耐贮性。雷司令二次果的酒中富含必需氨基酸和Ｚｎ,但酒中苹果酸过高。此外二次果粒小,出汁率低,株产低。     

Neural connections between the lateral geniculate nucleus and visual cortex in vitro

Neural connections were established in cocultures of rat visual cortex (VC) and lateral geniculate nucleus (LGN), which were isolated in early infancy. Morphological and electrophysiological studies showed that the cortical laminar organization of afferent and efferent connections in the coculture preparations was similar to that in the adult VC. The results indicate the existence of intrinsic mechanisms in VC and LGN that guide the formation of synaptic connections with the appropriate targets.