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951.
Transmitter-evoked local calcium release stabilizes developing dendrites 总被引:10,自引:0,他引:10
In the central nervous system, dendritic arborizations of neurons undergo dynamic structural remodelling during development. Processes are elaborated, maintained or eliminated to attain the adult pattern of synaptic connections. Although neuronal activity influences this remodelling, it is not known how activity exerts its effects. Here we show that neurotransmission-evoked calcium (Ca(2+)) release from intracellular stores stabilizes dendrites during the period of synapse formation. Using a ballistic labelling method to load cells with Ca(2+) indicator dyes, we simultaneously monitored dendritic activity and structure in the intact retina. Two distinct patterns of spontaneous Ca(2+) increases occurred in developing retinal ganglion cells--global increases throughout the arborization, and local 'flashes' of activity restricted to small dendritic segments. Blockade of local, but not global, activity caused rapid retraction of dendrites. This retraction was prevented locally by focal uncaging of caged Ca(2+) that triggered Ca(2+) release from internal stores. Thus, local Ca(2+) release is a mechanism by which afferent activity can selectively and differentially regulate dendritic structure across the developing arborization. 相似文献
952.
Rice LB 《Cellular and molecular life sciences : CMLS》2002,59(12):2023-2032
Among the more important problems in modern hospitals is the prevalence of bacterial pathogens expressing resistance to multiple
antimicrobial agents. The frequency of multiresistance suggests mechanisms by which bacterial species can concentrate and
efficiently exchange a variety of resistance determinants. Mechanisms by which this occurs include insertion of transposons
within transposons, coalescence through the activity of insertion sequences and the employment of integrons. In some instances,
more than one of these mechanisms is involved in creating large multiresistance genetic elements. The association of the elements
with transferable elements or transposons may promote rapid dissemination among clinical strains, and create further opportunities
for inclusion of additional resistance determinants. 相似文献
953.
The copines are a novel family of ubiquitous Ca(2+)-dependent, phospholipid-binding proteins. They contain two Ca(2+)- and phospholipid-binding domains known as 'C2 domains' present in proteins such as protein kinase C, phospholipase C and synaptotagmin. Copines are thought to be involved in membrane-trafficking phenomena because of their phospholipid-binding properties. They may also be involved in protein-protein interactions since they contain a domain similar to the protein-binding 'A domain' of integrins. The biochemistry, gene structure, tissue distribution and possible biological roles of copines are discussed, including recent observations with Arabidopsis that indicate that copines may be involved in cell division and growth. 相似文献
954.
Exposure to estrogens is a risk factor for breast and other human cancers. Initiation of breast, prostate and other cancers
has been hypothesized to result from reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA to
form depurinating adducts at the N-7 of guanine and N-3 of adenine by 1,4-Michael addition. The catechol of the carcinogenic
synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts
with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine. The catecholamine dopamine and the metabolite
catechol (1,2-dihydroxybenzene) of the leukemogen benzene can also be oxidized to their quinones, which react with DNA to
form predominantly analogous depurinating adducts. Apurinic sites formed by depurinating adducts are converted into tumor-initiating
mutations by error-prone repair. These mutations could initiate cancer by estrogens and benzene, and Parkinson's disease by
the neurotransmitter dopamine. These data suggest a unifying molecular mechanism of initiation for many cancers and neurodegenerative
diseases and lay the groundwork for designing strategies to assess risk and prevent these diseases.
Received 4 September 2001; received after revision 28 November 2001; accepted 2 December 2001 相似文献
955.
Bignold LP 《Cellular and molecular life sciences : CMLS》2002,59(6):950-958
Almost all solid malignancies exhibit complex cytological and architectural abnormalities, which vary from cell to cell and
area to area within the same tumour, and between tumours of the same type. The degrees of these abnormalities do not correlate
perfectly with the biological behaviour (especially growth rate and metastatic potential) among the various tumour types.
These features of tumours have long been considered to invalidate simple mutational or 'abnormal gene expression' (epigenetic)
theories of carcinogenesis. The 'mutator phenotype/clonal selection' hypothesis is based on the now well-established phenomenon
of genetic instability of cancer cells, and proposes that this instability is an essential requirement for the development
of tumours, and not an irrelevant side-effect of some other process. This paper argues that this hypothesis can provide a
satisfactory explanation for the diverse histological and biological features of solid malignancies. Further, because virtually
all solid tumours are histologically abnormal, genetic instability is likely to be essential for the malignant process. The
concepts of mutator phenotype and clonal selection are therefore supported.
Received 8 April 2002; accepted 25 April 2002 相似文献
956.
Rosenberg MJ Agarwala R Bouffard G Davis J Fiermonte G Hilliard MS Koch T Kalikin LM Makalowska I Morton DH Petty EM Weber JL Palmieri F Kelley RI Schäffer AA Biesecker LG 《Nature genetics》2002,32(1):175-179
The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth. 相似文献
957.
The knowledge of human genetic variation that will come from the human genome sequence makes feasible a polygenic approach to disease prevention, in which it will be possible to identify individuals as susceptible by their genotype profile and to prevent disease by targeting interventions to those at risk. There is doubt, however, regarding the magnitude of these genetic effects and thus the potential to apply them to either individuals or populations. We have therefore examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data are compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. By contrast, if currently identified risk factors for breast cancer were used to stratify the population, the half of the population at highest risk would account for only 62% of all cases. These results suggest that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases. 相似文献
958.
959.
Hoffmann K Dreger CK Olins AL Olins DE Shultz LD Lucke B Karl H Kaps R Müller D Vayá A Aznar J Ware RE Sotelo Cruz N Lindner TH Herrmann H Reis A Sperling K 《Nature genetics》2002,31(4):410-414
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. 相似文献
960.
Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors 总被引:5,自引:0,他引:5
Al-Tassan N Chmiel NH Maynard J Fleming N Livingston AL Williams GT Hodges AK Davies DR David SS Sampson JR Cheadle JP 《Nature genetics》2002,30(2):227-232
Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C-->A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans. 相似文献