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21.
Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain 总被引:10,自引:0,他引:10
T Lund L O'Reilly P Hutchings O Kanagawa E Simpson R Gravely P Chandler J Dyson J K Picard A Edwards 《Nature》1990,345(6277):727-729
Insulin-dependent diabetes mellitus (IDDM) is a disease with an autoimmune aetiology. The inbred non-obese diabetic (NOD) mouse strain provides a good animal model of the human disease and genetic analysis suggests that, as in man, at least one of the several genes controlling the development of IDDM is linked to the major histocompatibility complex. The NOD mouse does not express I-E owing to a deletion in the promoter region of the I-E alpha-chain gene, and the sequence of NOD I-A beta-chain in the first external domain is unique with His 56 and Ser 57 replacing Pro and Asp, respectively, at these positions. There has been considerable interest in the role amino acid 57 might have in conferring susceptibility to autoimmune diseases, including IDDM. The presence of a charged residue (such as Asp) at this position might affect the conformation of the peptide binding groove. But it could be assumed that Pro 56 gives rise to a different conformation of I-A beta-chain than does His 56. We therefore constructed transgenic NOD mice in which the transgene encoded a modified A beta nod with Pro 56, and studied its effect on the development of IDDM in this mouse strain. Previous studies have suggested that NOD mice expressing I-E as a result of the introduction of an I-E alpha-chain (E alpha) transgene are protected from the development of insulitis and hence IDDM. To explore further the protective effect of this molecule we constructed a second class of transgenic NOD mouse carrying an E alpha d transgene. Both transgenes protected the mice from IDDM, but this was not associated with a complete deletion of any T cells expressing commonly used T-cell receptor V beta genes. 相似文献
22.
Generation of a functional mammary gland from a single stem cell 总被引:1,自引:0,他引:1
Shackleton M Vaillant F Simpson KJ Stingl J Smyth GK Asselin-Labat ML Wu L Lindeman GJ Visvader JE 《Nature》2006,439(7072):84-88
The existence of mammary stem cells (MaSCs) has been postulated from evidence that the mammary gland can be regenerated by transplantation of epithelial fragments in mice. Interest in MaSCs has been further stimulated by their potential role in breast tumorigenesis. However, the identity and purification of MaSCs has proved elusive owing to the lack of defined markers. We isolated discrete populations of mouse mammary cells on the basis of cell-surface markers and identified a subpopulation (Lin-CD29hiCD24+) that is highly enriched for MaSCs by transplantation. Here we show that a single cell, marked with a LacZ transgene, can reconstitute a complete mammary gland in vivo. The transplanted cell contributed to both the luminal and myoepithelial lineages and generated functional lobuloalveolar units during pregnancy. The self-renewing capacity of these cells was demonstrated by serial transplantation of clonal outgrowths. In support of a potential role for MaSCs in breast cancer, the stem-cell-enriched subpopulation was expanded in premalignant mammary tissue from MMTV-wnt-1 mice and contained a higher number of MaSCs. Our data establish that single cells within the Lin-CD29hiCD24+ population are multipotent and self-renewing, properties that define them as MaSCs. 相似文献
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24.
Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase 总被引:8,自引:0,他引:8
Simpson MA Cross H Proukakis C Priestman DA Neville DC Reinkensmeier G Wang H Wiznitzer M Gurtz K Verganelaki A Pryde A Patton MA Dwek RA Butters TD Platt FM Crosby AH 《Nature genetics》2004,36(11):1225-1229
We identified an autosomal recessive infantile-onset symptomatic epilepsy syndrome associated with developmental stagnation and blindness. Assuming a founder effect in a large Old Order Amish pedigree, we carried out a genome-wide screen for linkage and identified a single region of homozygosity on chromosome 2p12-p11.2 spanning 5.1 cM (maximum lod score of 6.84). We sequenced genes in the region and identified a nonsense mutation in SIAT9, which is predicted to result in the premature termination of the GM3 synthase enzyme (also called lactosylceramide alpha-2,3 sialyltransferase). GM3 synthase is a member of the sialyltransferase family and catalyzes the initial step in the biosynthesis of most complex gangliosides from lactosylceramide. Biochemical analysis of plasma glycosphingolipids confirmed that affected individuals lack GM3 synthase activity, as marked by a complete lack of GM3 ganglioside and its biosynthetic derivatives and an increase in lactosylceramide and its alternative derivatives. Although the relationship between defects in ganglioside catabolism and a range of lysosomal storage diseases is well documented, this is the first report, to our knowledge, of a disruption of ganglioside biosynthesis associated with human disease. 相似文献
25.
Scientists have sequenced the human genome and identified most of its genes. Now it is time to use these genomic data, and the high-throughput technology developed to generate them, to tackle major health problems such as cancer. To accelerate our understanding of this disease and to produce targeted therapies, further basic mutational and functional genomic information is required. A systematic and coordinated approach, with the results freely available, should speed up progress. This will best be accomplished through an international academic and pharmaceutical oncogenomics initiative. 相似文献
26.
R. K. Callow N. C. Johnston J. Simpson 《Cellular and molecular life sciences : CMLS》1959,15(11):421-422
Zusammenfassung Die Mandibulardrüsen der Honigbienen-Arbeiterinnen enthalten 10-Hydroxy-2-decensäure. Es wird angenommen, dass diese Drüsen die Quelle der im Weisel- und Arbeiterinnenlarvenfutter vorkommenden 10-Hydroxy-2-decensäure sind. 相似文献
27.
The superfused rat cuneate nucleus has been used to investigate the sensitivity of primary afferent terminals and of evoked primary afferent depolarization (PAD) to alterations in extracellular K+ and Cl- ions levels. Results indicate that PAD is caused by an efflux of Cl- from primary afferent terminals rather than by an increase in extracellular K+. 相似文献
28.
Expression of murine H-2Kb histocompatibility antigen in cells transformed with cloned H-2 genes 总被引:21,自引:0,他引:21
A L Mellor L Golden E Weiss H Bullman J Hurst E Simpson R F James A R Townsend P M Taylor W Schmidt J Ferluga L Leben M Santamaria G Atfield H Festenstein R A Flavell 《Nature》1982,298(5874):529-534
Cosmids containing H-2 histocompatibility antigen genes of the H-2b haplotype have been isolated. One of these genes expresses a 45,000 molecular weight protein, indistinguishable from H-2Kb when introduced into mouse L cells. These H-2Kb transformed L cells can be killed by allospecific anti-H-2Kb cytotoxic T cells. Moreover, when infected with influenza virus, they can be killed by an H-2Kb-restricted, influenza virus-specific cytotoxic T cell line. These results show that expression of the H-2Kb gene product on the L-cell surface is sufficient to make it a target for specific T-cell killing. 相似文献
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30.
Hybrid cell lines with T-cell characteristics. 总被引:10,自引:0,他引:10