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81.
It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.  相似文献   
82.
More than 5 million single-nucleotide polymorphisms (SNPs) with minor-allele frequency greater than 10% are expected to exist in the human genome. Some of these SNPs may be associated with risk of developing common diseases. To assess the power of currently available SNPs to detect such associations, we resequenced 50 genes in two ethnic samples and measured patterns of linkage disequilibrium between the subset of SNPs reported in dbSNP and the complete set of common SNPs. Our results suggest that using all 2.7 million SNPs currently in the database would detect nearly 80% of all common SNPs in European populations but only 50% of those common in the African American population and that efficient selection of a minimal subset of SNPs for use in association studies requires measurement of allele frequency and linkage disequilibrium relationships for all SNPs in dbSNP.  相似文献   
83.
Pelli DG  Farell B  Moore DC 《Nature》2003,423(6941):752-756
Do we recognize common objects by parts, or as wholes? Holistic recognition would be efficient, yet people detect a grating of light and dark stripes by parts. Thus efficiency falls as the number of stripes increases, in inverse proportion, as explained by probability summation among independent feature detectors. It is inefficient to detect correlated components independently. But gratings are uncommon artificial stimuli that may fail to tap the full power of visual object recognition. Familiar objects become special as people become expert at judging them, possibly because the processing becomes more holistic. Letters and words were designed to be easily recognized, and, through a lifetime of reading, our visual system presumably has adapted to do this as well as it possibly can. Here we show that in identifying familiar English words, even the five most common three-letter words, observers have the handicap predicted by recognition by parts: a word is unreadable unless its letters are separately identifiable. Efficiency is inversely proportional to word length, independent of how many possible words (5, 26 or thousands) the test word is drawn from. Human performance never exceeds that attainable by strictly letter- or feature-based models. Thus, everything seen is a pattern of features. Despite our virtuosity at recognizing patterns and our expertise from reading a billion letters, we never learn to see a word as a feature; our efficiency is limited by the bottleneck of having to rigorously and independently detect simple features.  相似文献   
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Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.  相似文献   
86.
Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.  相似文献   
87.
Franklin D 《Science news》1984,126(16):245
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Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.  相似文献   
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