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51.
52.
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis 总被引:1,自引:0,他引:1
International Multiple Sclerosis Genetics Consortium;Wellcome Trust Case Control Consortium Sawcer S Hellenthal G Pirinen M Spencer CC Patsopoulos NA Moutsianas L Dilthey A Su Z Freeman C Hunt SE Edkins S Gray E Booth DR Potter SC Goris A Band G Oturai AB Strange A Saarela J Bellenguez C Fontaine B Gillman M Hemmer B Gwilliam R Zipp F Jayakumar A Martin R Leslie S Hawkins S Giannoulatou E D'alfonso S Blackburn H Martinelli Boneschi F Liddle J Harbo HF Perez ML Spurkland A Waller MJ Mycko MP 《Nature》2011,476(7359):214-219
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. 相似文献
53.
Languages vary widely but not without limit. The central goal of linguistics is to describe the diversity of human languages and explain the constraints on that diversity. Generative linguists following Chomsky have claimed that linguistic diversity must be constrained by innate parameters that are set as a child learns a language. In contrast, other linguists following Greenberg have claimed that there are statistical tendencies for co-occurrence of traits reflecting universal systems biases, rather than absolute constraints or parametric variation. Here we use computational phylogenetic methods to address the nature of constraints on linguistic diversity in an evolutionary framework. First, contrary to the generative account of parameter setting, we show that the evolution of only a few word-order features of languages are strongly correlated. Second, contrary to the Greenbergian generalizations, we show that most observed functional dependencies between traits are lineage-specific rather than universal tendencies. These findings support the view that-at least with respect to word order-cultural evolution is the primary factor that determines linguistic structure, with the current state of a linguistic system shaping and constraining future states. 相似文献
54.
Summary Sprague-Dawley rats made neutropenic by60Co irradiation or cyclophosphamide treatment retained a limited capacity for mounting a local leukocyte mobilization (LLM) response. Rats irradiated with 700 rad60Co lacked an LLM. Rats treated with 100 mg/kg cyclophosphamide showed no LLM following an initial low response when assayed originally.We wish to thank Mr Dane Walden for excellent technical assistance. This work was supported by Armed Forces Radiobiology Research Institute, Defense Nuclear Agency, under Research Work Unit MJ 60212. The views presented in this paper are those of the authors. No endorsement of the Defense Nuclear Agency has been given or should be inferred. 相似文献
55.
Summary Using the ammoniacal silver stain, Cabot rings were identified in peripheral blood erythrocytes from patients with severe untreated pernicious anemia. Ultrastructural studies of these erythrocytes showed silver deposits in partial loops and figure-eight forms, indicating that arginine rich histone may be a prominent component of the Cabot ring.Supported in part by the Elizabeth Roodvoets Memorial Grant for Cancer Research of the American Cancer Society (No. CI-79) and by National Cancer Institute Grant USPHS No. CA 14428-02. 相似文献
56.
Cancer cells have diverse biological capabilities that are conferred by numerous genetic aberrations and epigenetic modifications. Today's powerful technologies are enabling these changes to the genome to be catalogued in detail. Tomorrow is likely to bring a complete atlas of the reversible and irreversible alterations that occur in individual cancers. The challenge now is to work out which molecular abnormalities contribute to cancer and which are simply 'noise' at the genomic and epigenomic levels. Distinguishing between these will aid in understanding how the aberrations in a cancer cell collaborate to drive pathophysiology. Past successes in converting information from genomic discoveries into clinical tools provide valuable lessons to guide the translation of emerging insights from the genome into clinical end points that can affect the practice of cancer medicine. 相似文献
57.
58.
A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse 总被引:37,自引:0,他引:37
Nolan PM Peters J Strivens M Rogers D Hagan J Spurr N Gray IC Vizor L Brooker D Whitehill E Washbourne R Hough T Greenaway S Hewitt M Liu X McCormack S Pickford K Selley R Wells C Tymowska-Lalanne Z Roby P Glenister P Thornton C Thaung C Stevenson JA Arkell R Mburu P Hardisty R Kiernan A Erven A Steel KP Voegeling S Guenet JL Nickols C Sadri R Nasse M Isaacs A Davies K Browne M Fisher EM Martin J Rastan S Brown SD Hunter J 《Nature genetics》2000,25(4):440-443
As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics. 相似文献
59.
Summary A table presents the number of hours required for binding to reach 80% and 95% of the equilibrium value for a noncooperative, single site ligand binding system. A 2nd table provides the fraction of binding sites occupied and the fraction of the total ligand bound at equilibrium under the same conditions. 相似文献
60.
Tottey S Waldron KJ Firbank SJ Reale B Bessant C Sato K Cheek TR Gray J Banfield MJ Dennison C Robinson NJ 《Nature》2008,455(7216):1138-1142
Metals are needed by at least one-quarter of all proteins. Although metallochaperones insert the correct metal into some proteins, they have not been found for the vast majority, and the view is that most metalloproteins acquire their metals directly from cellular pools. However, some metals form more stable complexes with proteins than do others. For instance, as described in the Irving-Williams series, Cu(2+) and Zn(2+) typically form more stable complexes than Mn(2+). Thus it is unclear what cellular mechanisms manage metal acquisition by most nascent proteins. To investigate this question, we identified the most abundant Cu(2+)-protein, CucA (Cu(2+)-cupin A), and the most abundant Mn(2+)-protein, MncA (Mn(2+)-cupin A), in the periplasm of the cyanobacterium Synechocystis PCC 6803. Each of these newly identified proteins binds its respective metal via identical ligands within a cupin fold. Consistent with the Irving-Williams series, MncA only binds Mn(2+) after folding in solutions containing at least a 10(4) times molar excess of Mn(2+) over Cu(2+) or Zn(2+). However once MncA has bound Mn(2+), the metal does not exchange with Cu(2+). MncA and CucA have signal peptides for different export pathways into the periplasm, Tat and Sec respectively. Export by the Tat pathway allows MncA to fold in the cytoplasm, which contains only tightly bound copper or Zn(2+) (refs 10-12) but micromolar Mn(2+) (ref. 13). In contrast, CucA folds in the periplasm to acquire Cu(2+). These results reveal a mechanism whereby the compartment in which a protein folds overrides its binding preference to control its metal content. They explain why the cytoplasm must contain only tightly bound and buffered copper and Zn(2+). 相似文献