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721.
A Design View on Research in Social Sciences 总被引:2,自引:2,他引:0
Research in social sciences has not had the same impact as research in natural sciences and several authors are critical of social science research methods. In order to elucidate this problem, the author analyzes the purpose of research in general and in social sciences in particular. The author makes reference to various research methods that are suggested and used in social sciences. Social science research differs from research in natural sciences. It differs not only in being dependent on actions of human individuals but also because systems in social sciences are a complex mixture of Hard and Soft systems. The paper argues that research in Human Activity Systems should focus on design. This view changes the research perspective and the demands on the research methods to be used. The author suggests a method based on focusing decision settings combined with Action Research. 相似文献
722.
The mitochondrial deoxyribonucleotide (dNTP) pool is separated from the cytosolic pool because the mitochondria inner membrane is impermeable to charged molecules. The mitochondrial pool is maintained by either import of cytosolic dNTPs through dedicated transporters or by salvaging deoxynucleosides within the mitochondria; apparently, enzymes of the de novo dNTP synthesis pathway are not present in the mitochondria. In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on the mitochondrial salvage pathway enzymes, the deoxyribonucleosides kinases. Two of the four human deoxyribonucleoside kinases, deoxyguanosine kinase (dGK) and thymidine kinase-2 (TK2), are expressed in mitochondria. Human dGK efficiently phosphorylates deoxyguanosine and deoxyadenosine, whereas TK2 phosphorylates deoxythymidine, deoxycytidine and deoxyuridine. Here we identify two mutations in TK2, histidine 90 to asparagine and isoleucine 181 to asparagine, in four individuals who developed devastating myopathy and depletion of muscular mitochondrial DNA in infancy. In these individuals, the activity of TK2 in muscle mitochondria is reduced to 14-45% of the mean value in healthy control individuals. Mutations in TK2 represent a new etiology for mitochondrial DNA depletion, underscoring the importance of the mitochondrial dNTP pool in the pathogenesis of mitochondrial depletion. 相似文献
723.
The mammalian sex-determining gene, SRY, was identified by positional cloning approximately 10 years ago. Since its discovery, intense research into this gene has been directed on two main fronts: elucidation of its function in development of the testis and examination of its singular evolutionary history. The role or SRY as the testis-determining factor (TDF) places it at a crucial point in the highly conserved morphogenetic process of vertebrate gonadogenesis. None of the genes that directly activate SRY nor any of its immediate downstream targets have yet been positively identified. Several genes, however, such as SF1, DAX1, and SOX9, whose spatial and temporal expression profiles overlap with that of SRY, are strongly implicated as co-regulators of gonadogenesis. Molecular genetic manipulation of these genes in mice has shown that they are indispensable to sexual development. Remarkably, its key position in this cascade of gene action has not protected SRY from strong yet poorly understood selective forces that have caused it to evolve rapidly in mammals. The evolution of SRY has been characterized not only by rapid sequence divergence within mammals, but also by structural changes such as intron insertion, gene amplification, and deletion. 相似文献
724.
Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. 总被引:49,自引:0,他引:49
A Brooks-Wilson M Marcil S M Clee L H Zhang K Roomp M van Dam L Yu C Brewer J A Collins H O Molhuizen O Loubser B F Ouelette K Fichter K J Ashbourne-Excoffon C W Sensen S Scherer S Mott M Denis D Martindale J Frohlich K Morgan B Koop S Pimstone J J Kastelein J Genest M R Hayden 《Nature genetics》1999,22(4):336-345
Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP). 相似文献
725.
A general approach to single-nucleotide polymorphism discovery 总被引:29,自引:0,他引:29
Marth GT Korf I Yandell MD Yeh RT Gu Z Zakeri H Stitziel NO Hillier L Kwok PY Gish WR 《Nature genetics》1999,23(4):452-456
Single-nucleotide polymorphisms (SNPs) are the most abundant form of human genetic variation and a resource for mapping complex genetic traits. The large volume of data produced by high-throughput sequencing projects is a rich and largely untapped source of SNPs (refs 2, 3, 4, 5). We present here a unified approach to the discovery of variations in genetic sequence data of arbitrary DNA sources. We propose to use the rapidly emerging genomic sequence as a template on which to layer often unmapped, fragmentary sequence data and to use base quality values to discern true allelic variations from sequencing errors. By taking advantage of the genomic sequence we are able to use simpler yet more accurate methods for sequence organization: fragment clustering, paralogue identification and multiple alignment. We analyse these sequences with a novel, Bayesian inference engine, POLYBAYES, to calculate the probability that a given site is polymorphic. Rigorous treatment of base quality permits completely automated evaluation of the full length of all sequences, without limitations on alignment depth. We demonstrate this approach by accurate SNP predictions in human ESTs aligned to finished and working-draft quality genomic sequences, a data set representative of the typical challenges of sequence-based SNP discovery. 相似文献
726.
The DNA sequence of human chromosome 22 总被引:75,自引:0,他引:75
Dunham I Shimizu N Roe BA Chissoe S Hunt AR Collins JE Bruskiewich R Beare DM Clamp M Smink LJ Ainscough R Almeida JP Babbage A Bagguley C Bailey J Barlow K Bates KN Beasley O Bird CP Blakey S Bridgeman AM Buck D Burgess J Burrill WD O'Brien KP 《Nature》1999,402(6761):489-495
Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome. 相似文献
727.
Comets are some of the most primitive bodies left over from the Solar System's early history. They may preserve both interstellar material and material from the proto-solar nebula, and so studies of their volatile components can provide clues about the evolution of gases and ices, as a collapsing molecular cloud transforms into a mature planetary system. Previous observations of emission from rotational transitions in molecules have averaged over large areas of the inner coma, and therefore include both molecules that sublimed from the nucleus and those that result from subsequent chemical processes in the coma Here we present high-resolution observations of emission from the molecules HNC, DCN and HDO associated with comet Hale-Bopp. Our data reveal arc-like structures-icy jets-offset from (but close to) the nucleus. The measured abundance ratios on 1-3" scales are substantially different from those on larger scales, and cannot be accounted for by models of chemical processes in the coma; they are, however, similar to the values observed in the cores of dense interstellar clouds and young stellar objects. We therefore propose that sublimation from millimetre-sized icy grains ejected from the nucleus provides access to relatively unaltered volatiles. The D/H ratios inferred from our data suggest that, by mass, Hale-Bopp (and by inference the outer regions of the early solar nebula) consists of > or =15-40% of largely unprocessed interstellar material. 相似文献
728.
S. O. Ooi K. Y. Sim M. C. M. Chung O. L. Kon 《Cellular and molecular life sciences : CMLS》1993,49(6-7):576-581
A substance with antiproliferative bioactivity in an aqueous extract ofCordyline terminalis was purified and identified by mass spectrometry to be the natural nucleoside, thymidine. 10–5M Thymidine inhibited EL4 cell replication and decreased cell viability after 12–24 h. The effect was highly specific for this nucleoside. Treated cell cultures showed a significant increase in S phase cells and a corresponding decrease in G1 phase cells. Nitrobenzylthioinosine (which prevented facilitated entry of thymidine) protected cells from the antiproliferative action of thymidine. A human breast cancer cell line (MCF7) was also growth-inhibited by 10–5M thymidine but a murine lymphoma cell line (K36) was not. Thus, submillimolar thymidine has effects on cell proliferation which are selective both with respect to specificity for the compound and for different tumour cell lines. 相似文献
729.
730.