全文获取类型
收费全文 | 11633篇 |
免费 | 45篇 |
国内免费 | 71篇 |
专业分类
系统科学 | 61篇 |
丛书文集 | 29篇 |
教育与普及 | 21篇 |
理论与方法论 | 32篇 |
现状及发展 | 5434篇 |
研究方法 | 588篇 |
综合类 | 5456篇 |
自然研究 | 128篇 |
出版年
2012年 | 205篇 |
2011年 | 300篇 |
2010年 | 76篇 |
2009年 | 74篇 |
2008年 | 203篇 |
2007年 | 245篇 |
2006年 | 246篇 |
2005年 | 233篇 |
2004年 | 202篇 |
2003年 | 195篇 |
2002年 | 247篇 |
2001年 | 435篇 |
2000年 | 428篇 |
1999年 | 288篇 |
1992年 | 236篇 |
1991年 | 195篇 |
1990年 | 215篇 |
1989年 | 191篇 |
1988年 | 202篇 |
1987年 | 219篇 |
1986年 | 190篇 |
1985年 | 252篇 |
1984年 | 226篇 |
1983年 | 171篇 |
1982年 | 176篇 |
1981年 | 180篇 |
1980年 | 170篇 |
1979年 | 403篇 |
1978年 | 340篇 |
1977年 | 250篇 |
1976年 | 290篇 |
1975年 | 260篇 |
1974年 | 272篇 |
1973年 | 224篇 |
1972年 | 244篇 |
1971年 | 308篇 |
1970年 | 374篇 |
1969年 | 254篇 |
1968年 | 307篇 |
1967年 | 292篇 |
1966年 | 249篇 |
1965年 | 179篇 |
1964年 | 99篇 |
1959年 | 88篇 |
1958年 | 162篇 |
1957年 | 100篇 |
1956年 | 91篇 |
1955年 | 85篇 |
1954年 | 77篇 |
1948年 | 64篇 |
排序方式: 共有10000条查询结果,搜索用时 453 毫秒
591.
Rusznák Z Pocsai K Kovács I Pór A Pál B Bíró T Szücs G 《Cellular and molecular life sciences : CMLS》2004,61(12):1532-1542
In this work, the distributions of some acid-sensitive two-pore-domain K+ channels (TASK-1, TASK-2 and TASK-3) were investigated in the rat and human cerebellum. Astrocytes situated in rat cerebellar tissue sections were positive for TASK-2 channels. Purkinje cells were strongly stained and granule cells and astrocytes were moderately positive for TASK-3. Astrocytes isolated from the hippocampus, cerebellum and cochlear nucleus expressed TASK channels in a primary tissue culture. Our results suggest that TASK channel expression may be significant in the endoplasmic reticulum of the astrocytes. The human cerebellum showed weak TASK-2 immunolabelling. The pia mater, astrocytes, Purkinje and granule cells demonstrated strong TASK-1 and TASK-3 positivities. The TASK-3 labelling was stronger in general, but it was particularly intense in the Purkinje cells and pia mater.Received 25 February 2004; received after revision 19 April 2004; accepted 28 April 2004 相似文献
592.
Ubiquitin-proteasome pathway as a primary defender against TRAIL-mediated cell death 总被引:3,自引:0,他引:3
Kim S Choi K Kwon D Benveniste EN Choi C 《Cellular and molecular life sciences : CMLS》2004,61(9):1075-1081
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptotic cell death as well as expression of proinflammatory genes such as CXCL8 in malignant human astrocytoma cells. However, the molecular mechanisms that determine the fate of cells are not yet understood. The ubiquitin (Ub)-proteasome pathway regulates a wide range of cellular functions through degradation of various regulatory proteins; given this, we hypothesized that this pathway may play a central role in TRAIL-mediated signaling. We demonstrate here that inhibition of the Ub-proteasome pathway enhanced TRAIL-mediated cell death of human astrocytoma CRT-MG cells within hours by blocking degradation of active caspase-8 and -3. Proteasome inhibitors suppressed TRAIL-mediated activation of NF-B; however, inhibition of the NF-B pathway alone was not sufficient to enhance TRAIL-mediated cell death. Collectively, these results suggest that the Ub-proteasome pathway may play an important role as an antiapoptotic surveillance system by eliminating activated caspases as well as mediating NF-B-dependent signals.Received 30 December 2003; received after revision 9 February 2004; accepted 13 February 2004 相似文献
593.
594.
Novel aspects of glypican glycobiology 总被引:5,自引:0,他引:5
Fransson LA Belting M Cheng F Jönsson M Mani K Sandgren S 《Cellular and molecular life sciences : CMLS》2004,61(9):1016-1024
Mutations in glypican genes cause dysmorphic and overgrowth syndromes in men and mice, abnormal development in flies and worms, and defective gastrulation in zebrafish and ascidians. All glypican core proteins share a characteristic pattern of 14 conserved cysteine residues. Upstream from the C-terminal membrane anchorage are 3–4 heparan sulfate attachment sites. Cysteines in glypican-1 can become nitrosylated by nitric oxide in a copper-dependent reaction. When glypican-1 is exposed to ascorbate, nitric oxide is released and participates in deaminative cleavage of heparan sulfate at sites where the glucosamines have a free amino group. This process takes place while glypican-1 recycles via a nonclassical, caveolin-1-associated route. Glypicans are involved in growth factor signalling and transport, e.g. of polyamines. Cargo can be unloaded from heparan sulfate by nitric oxide-dependent degradation. How glypican and its degradation products and the cargo exit from the recycling route is an enigma.Received 27 November 2003; received after revision 8 January 2004; accepted 13 January 2004 相似文献
595.
Tsyba L Rynditch AV Boeri E Jabbari K Bernardi G 《Cellular and molecular life sciences : CMLS》2004,61(6):721-726
The localization of HIV-1 proviruses in compositional DNA fractions from 27 AIDS patients during the chronic phase of the disease with depletion of CD4+ and different levels of viremia showed the following. (1) At low viremia, proviruses are predominantly localized in the GC-richest isochores, which are characterized by an open chromatin structure; this result mimics findings on HIV-1 integration in early infected cells in culture. (2) At higher viremia, an increased distribution of proviruses in GC-poor isochores (which match the GC poorness of HIV-1) was found; this suggests a selection of cells in which the isopycnic localization leads to a higher expression of proviruses and, in turn, to higher viremia. (3) At the highest viremia, integrations in GC-rich isochores are often predominant again, but generally not at the same level as in (1); this may be the consequence of new integrations from the extremely abundant RNA copies.Received 21 November 2003; received after revision 13 January 2004: accepted 15 January 2004 相似文献
596.
597.
An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice 总被引:19,自引:0,他引:19
Roy CN Custodio AO de Graaf J Schneider S Akpan I Montross LK Sanchez M Gaudino A Hentze MW Andrews NC Muckenthaler MU 《Nature genetics》2004,36(5):481-485
Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia. Hepcidin antimicrobial peptide (Hamp) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release. Hamp is part of the type II acute phase response and is thought to have a crucial regulatory role in sequestering iron in the context of ACD. Mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia. These data suggest a previously unidentified role for Hfe in innate immunity and ACD. 相似文献
598.
The knockout mouse project 总被引:1,自引:0,他引:1
Austin CP Battey JF Bradley A Bucan M Capecchi M Collins FS Dove WF Duyk G Dymecki S Eppig JT Grieder FB Heintz N Hicks G Insel TR Joyner A Koller BH Lloyd KC Magnuson T Moore MW Nagy A Pollock JD Roses AD Sands AT Seed B Skarnes WC Snoddy J Soriano P Stewart DJ Stewart F Stillman B Varmus H Varticovski L Verma IM Vogt TF von Melchner H Witkowski J Woychik RP Wurst W Yancopoulos GD Young SG Zambrowicz B 《Nature genetics》2004,36(9):921-924
Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain. 相似文献
599.
Davila S Furu L Gharavi AG Tian X Onoe T Qian Q Li A Cai Y Kamath PS King BF Azurmendi PJ Tahvanainen P Kääriäinen H Höckerstedt K Devuyst O Pirson Y Martin RS Lifton RP Tahvanainen E Torres VE Somlo S 《Nature genetics》2004,36(6):575-577
Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease. 相似文献
600.
Saleh M Vaillancourt JP Graham RK Huyck M Srinivasula SM Alnemri ES Steinberg MH Nolan V Baldwin CT Hotchkiss RS Buchman TG Zehnbauer BA Hayden MR Farrer LA Roy S Nicholson DW 《Nature》2004,429(6987):75-79
Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis. 相似文献