全文获取类型
收费全文 | 31351篇 |
免费 | 47篇 |
国内免费 | 68篇 |
专业分类
系统科学 | 154篇 |
丛书文集 | 717篇 |
教育与普及 | 79篇 |
理论与方法论 | 200篇 |
现状及发展 | 13501篇 |
研究方法 | 1348篇 |
综合类 | 15098篇 |
自然研究 | 369篇 |
出版年
2013年 | 174篇 |
2012年 | 419篇 |
2011年 | 832篇 |
2010年 | 180篇 |
2008年 | 552篇 |
2007年 | 539篇 |
2006年 | 597篇 |
2005年 | 591篇 |
2004年 | 517篇 |
2003年 | 567篇 |
2002年 | 567篇 |
2001年 | 978篇 |
2000年 | 896篇 |
1999年 | 598篇 |
1992年 | 569篇 |
1991年 | 462篇 |
1990年 | 486篇 |
1989年 | 489篇 |
1988年 | 490篇 |
1987年 | 498篇 |
1986年 | 490篇 |
1985年 | 599篇 |
1984年 | 494篇 |
1983年 | 404篇 |
1982年 | 346篇 |
1981年 | 340篇 |
1980年 | 448篇 |
1979年 | 967篇 |
1978年 | 855篇 |
1977年 | 846篇 |
1976年 | 580篇 |
1975年 | 630篇 |
1974年 | 931篇 |
1973年 | 785篇 |
1972年 | 804篇 |
1971年 | 1017篇 |
1970年 | 1339篇 |
1969年 | 1004篇 |
1968年 | 945篇 |
1967年 | 988篇 |
1966年 | 829篇 |
1965年 | 609篇 |
1964年 | 148篇 |
1959年 | 360篇 |
1958年 | 522篇 |
1957年 | 443篇 |
1956年 | 366篇 |
1955年 | 316篇 |
1954年 | 363篇 |
1948年 | 193篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
991.
Evolution of bacterial pathogenesis 总被引:6,自引:0,他引:6
Ziebuhr W Ohlsen K Karch H Korhonen T Hacker J 《Cellular and molecular life sciences : CMLS》1999,56(9-10):719-728
The evolution of bacteria is associated with continuous generation of novel genetic variants. The major driving forces in this process are point mutations, genetic rearrangements, and horizontal gene transfer. A large number of human and animal bacterial pathogens have evolved the capacity to produce virulence factors that are directly involved in infection and disease. Additionally, many bacteria express resistance traits against antibiotics. Both virulence factors and resistance determinants are subject to intrastrain genetic and phenotypic variation. They are often encoded on unstable DNA regions. Thus, they can be readily transferred to bacteria of the same species or even to non-related prokaryotes. This review article focuses on the main mechanisms of bacterial microevolution responsible for the rapid emergence of variants with novel virulence and resistance properties. In addition, processes of macroevolution are described with special emphasis on gene transfer and fixation of adaptive mutations in the genome of pathogens. 相似文献
992.
Sarti P Silver RB Paroli L Nikonorov I Blanck TJ 《Cellular and molecular life sciences : CMLS》1999,56(11-12):1061-1069
Rat heart myocytes undergoing progressive damage demonstrate morphological changes of shortening and swelling followed by the formation of intracellular vacuoles and plasma membrane blebbing. The damaged myocytes displayed impaired N,N'-tetramethyl-p-phenyldiamine (TMPD) ascorbate-stimulated respiratory activity which was restored by the addition of reduced cytochrome c to the cell culture medium. To clarify the role played by cytochrome c in the impairment of cell respiration, polarographic, spectrophotometric and fluorescence as well as electron microscopy imaging experiments were performed. TMPD/ascorbate-stimulated respiratory activity returned to control levels, at approximately 20 microM cytochrome c, establishing the threshold below which the turnover rate by cytochrome c oxidase in the cell depends on cytochrome concentration. Mildly damaged cardiac myocytes, as indicated by cell shortening, retention of visible striations and free-fluorescein exclusion, together with the absence of lactate dehydrogenase leakage and exclusion of trypan blue, were able to oxidize exogenous cytochrome c and were permeable to fluorescein-conjugated cytochrome c. The results, while consistent with an early cytochrome c release observed at the beginning of cell death, elucidate the role played by cytochrome c in the kinetic control of mitochondrial electron transfer under pathological conditions, particularly those involving the terminal part of the respiratory chain. These data are the first to demonstrate that the sarcolemma of cardiac myocytes, damaged but still viable, is permeable to cytochrome c. 相似文献
993.
Are elicitins cryptograms in plant-Oomycete communications? 总被引:13,自引:0,他引:13
Ponchet M Panabières F Milat M-L Mikes V Montillet JL Suty L Triantaphylides C Tirilly Y Blein JP 《Cellular and molecular life sciences : CMLS》1999,56(11-12):1020-1047
Stimulation of plant natural defenses is an important challenge in phytoprotection prospects. In that context, elicitins, which are small proteins secreted by Phytophthora and Pythium species, have been shown to induce a hypersensitive-like reaction in tobacco plants. Moreover, these plants become resistant to their pathogens, and thus this interaction constitutes an excellent model to investigate the signaling pathways leading to plant resistance. However, most plants are not reactive to elicitins, although they possess the functional signaling pathways involved in tobacco responses to elicitin. The understanding of factors involved in this reactivity is needed to develop agronomic applications. In this review, it is proposed that elicitins could interact with regulating cell wall proteins before they reach the plasma membrane. Consequently, the plant reactivity or nonreactivity status could result from the equilibrium reached during this interaction. The possibility of overexpressing the elicitins directly from genomic DNA in Pichia pastoris allows site-directed mutagenesis experiments and structure/function studies. The recent discovery of the sterol carrier activity of elicitins brings a new insight on their molecular activity. This constitutes a crucial property, since the formation of a sterol-elicitin complex is required to trigger the biological responses of tobacco cells and plants. Only the elicitins loaded with a sterol are able to bind to their plasmalemma receptor, which is assumed to be an allosteric calcium channel. Moreover, Phytophthora and Pythium do not synthesize the sterols required for their growth and their fructification, and elicitins may act as shuttles trapping the sterols from the host plants. Sequence analysis of elicitin genes from several Phytophthora species sheds unexpected light on the phylogenetic relationships among the genus, and suggests that the expression of elicitins is under tight regulatory control. Finally, general involvement of these lipid transfer proteins in the biology of Pythiaceae, and in plant defense responses, is discussed. A possible scheme for the coevolution between Phytophthora and tobacco plants is approached. 相似文献
994.
T cell activation is enhanced by the costimulatory interaction of B7 on antigen-presenting cells and CD28 on T cells, resulting
in long-term T cell proliferation, differentiation and production of large amounts of cytokines, such as interleukin (IL)-2.
CTLA-4 is a co-stimulation receptor that shares 31% homology with CD28 and binds B7 family members with higher affinity. CTLA-4
is transiently expressed intracellularly and on the cell surface following activation of T cells. We have studied the kinetics
of CTLA-4 expression and the effects of dexamethasone on CTLA-4 expression during T cell activation in cultures of mouse spleen
cells stimulated by a mixture of immobilized anti-CD3 and anti-CD28 monoclonal antibodies (anti-CD3/CD28 mAb) or concanavalin
A (ConA). CTLA-4 expression peaked on day 2 and returned to background levels after 7 days. Dexamethasone was found to potentiate
CTLA-4 expression in a dose-dependent manner with an EC50 effective concentration 50%) of about 10−8 M. In contrast, other immunosuppressive agents, such as rapamycin or cyclosporin A had no or an inhibitory effect on CTLA-4
expression, respectively. Dexamethasone also stimulated CD28 expression, but inhibited IL-2R expression during anti-CD3/CD28
mAb-induced mouse splenic T cell activation. Western blot analyses of lysates of activated mouse T cells showed that dexamethasone
increased CTLA-4 protein levels twofold during anti-CD3/CD28 mAb-induced activation. Dexamethasone also enhanced CTLA-4 messenger
RNA twofold as quantified by ribonuclease protection assay. The effects of dexamethasone on CTLA-4 expression were glucocorticoid-specific
and completely inhibited by the glucocorticoid receptor antagonist mifepristone (RU486), indicating that the effect of dexamethasone
on CTLA-4 expression is mediated through the glucocorticoid receptor. In conclusion, the immunosuppressive agent dexamethasone
actually stimulates CTLA-4 expression, which is involved in downregulation of T cell activation.
Received 19 May 1999; received after revision 13 July 1999; accepted 13 July 1999 相似文献
995.
Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1 总被引:8,自引:0,他引:8
Aminoff M Carter JE Chadwick RB Johnson C Gräsbeck R Abdelaal MA Broch H Jenner LB Verroust PJ Moestrup SK de la Chapelle A Krahe R 《Nature genetics》1999,21(3):309-313
Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic anaemia, as well as neurological symptoms that may be the only manifestations. At the cellular level, MGA1 is characterized by selective intestinal vitamin B12 (B12, cobalamin) malabsorption. MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries and Norway, and highest in Finland (0.8/100,000). We previously mapped the MGA1 locus by linkage analysis in Finnish and Norwegian families to a 6-cM region on chromosome 10p12.1 (ref. 8). A functional candidate gene encoding the intrinsic factor (IF)-B12 receptor, cubilin, was recently cloned; the human homologue, CUBN, was mapped to the same region. We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families. Our genetic and molecular data indicate that mutations in CUBN cause MGA1. 相似文献
996.
High-resolution mapping of quantitative trait loci in outbred mice 总被引:21,自引:0,他引:21
Screening the whole genome of a cross between two inbred animal strains has proved to be a powerful method for detecting genetic loci underlying quantitative behavioural traits, but the level of resolution offered by quantitative trait loci (QTL) mapping is still too coarse to permit molecular cloning of the genetic determinants. To achieve high-resolution mapping, we used an outbred stock of mice for which the entire genealogy is known. The heterogeneous stock (HS) was established 30 years ago from an eight-way cross of C57BL/6, BALB/c, RIII, AKR, DBA/2, I, A/J and C3H inbred mouse strains. At the time of the experiment reported here, the HS mice were at generation 58, theoretically offering at least a 30-fold increase in resolution for QTL mapping compared with a backcross or an F2 intercross. Using the HS mice we have mapped a QTL influencing a psychological trait in mice to a 0.8-cM interval on chromosome 1. This method allows simultaneous fine mapping of multiple QTLs, as shown by our report of a second QTL on chromosome 12. The high resolution possible with this approach makes QTLs accessible to positional cloning. 相似文献
997.
Lanford PJ Lan Y Jiang R Lindsell C Weinmaster G Gridley T Kelley MW 《Nature genetics》1999,21(3):289-292
The mammalian cochlea contains an invariant mosaic of sensory hair cells and non-sensory supporting cells reminiscent of invertebrate structures such as the compound eye in Drosophila melanogaster. The sensory epithelium in the mammalian cochlea (the organ of Corti) contains four rows of mechanosensory hair cells: a single row of inner hair cells and three rows of outer hair cells. Each hair cell is separated from the next by an interceding supporting cell, forming an invariant and alternating mosaic that extends the length of the cochlear duct. Previous results suggest that determination of cell fates in the cochlear mosaic occurs via inhibitory interactions between adjacent progenitor cells (lateral inhibition). Cells populating the cochlear epithelium appear to constitute a developmental equivalence group in which developing hair cells suppress differentiation in their immediate neighbours through lateral inhibition. These interactions may be mediated through the Notch signalling pathway, a molecular mechanism that is involved in the determination of a variety of cell fates. Here we show that genes encoding the receptor protein Notch1 and its ligand, Jagged 2, are expressed in alternating cell types in the developing sensory epithelium. In addition, genetic deletion of Jag2 results in a significant increase in sensory hair cells, presumably as a result of a decrease in Notch activation. These results provide direct evidence for Notch-mediated lateral inhibition in a mammalian system and support a role for Notch in the development of the cochlear mosaic. 相似文献
998.
Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease 总被引:16,自引:0,他引:16
Sakuntabhai A Ruiz-Perez V Carter S Jacobsen N Burge S Monk S Smith M Munro CS O'Donovan M Craddock N Kucherlapati R Rees JL Owen M Lathrop GM Monaco AP Strachan T Hovnanian A 《Nature genetics》1999,21(3):271-277
Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis. 相似文献
999.
1000.