全文获取类型
收费全文 | 28863篇 |
免费 | 82篇 |
国内免费 | 158篇 |
专业分类
系统科学 | 139篇 |
丛书文集 | 499篇 |
教育与普及 | 42篇 |
理论与方法论 | 100篇 |
现状及发展 | 13451篇 |
研究方法 | 1278篇 |
综合类 | 13198篇 |
自然研究 | 396篇 |
出版年
2013年 | 269篇 |
2012年 | 411篇 |
2011年 | 809篇 |
2010年 | 168篇 |
2008年 | 523篇 |
2007年 | 576篇 |
2006年 | 576篇 |
2005年 | 535篇 |
2004年 | 538篇 |
2003年 | 499篇 |
2002年 | 499篇 |
2001年 | 936篇 |
2000年 | 865篇 |
1999年 | 616篇 |
1992年 | 595篇 |
1991年 | 414篇 |
1990年 | 486篇 |
1989年 | 494篇 |
1988年 | 460篇 |
1987年 | 546篇 |
1986年 | 474篇 |
1985年 | 596篇 |
1984年 | 484篇 |
1983年 | 364篇 |
1982年 | 340篇 |
1981年 | 367篇 |
1980年 | 462篇 |
1979年 | 889篇 |
1978年 | 757篇 |
1977年 | 740篇 |
1976年 | 611篇 |
1975年 | 632篇 |
1974年 | 845篇 |
1973年 | 756篇 |
1972年 | 779篇 |
1971年 | 840篇 |
1970年 | 1073篇 |
1969年 | 813篇 |
1968年 | 820篇 |
1967年 | 795篇 |
1966年 | 681篇 |
1965年 | 472篇 |
1964年 | 156篇 |
1959年 | 249篇 |
1958年 | 440篇 |
1957年 | 292篇 |
1956年 | 259篇 |
1955年 | 246篇 |
1954年 | 239篇 |
1948年 | 162篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
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
992.
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
993.
994.
995.
The involvement of the renin-angiotensin system in the regulation of cell proliferation in the rat endometrium 总被引:1,自引:0,他引:1
Oestrogens are known to enhance angiotensin biosynthesis by increasing the elaboration of its precursor, angiotensinogen.
On the other hand, we found that inhibition of angiotensin-converting enzyme (ACE) suppressed the proliferative response of
the rat anterior pituitary gland to oestrogens. To answer the question whether the angiotensin system is involved in the control
of the cell proliferation of the uterine epithelium, the effects of an ACE inhibitor, enalapril maleate, and of angiotensins
II and IV, alone or together with losartan, an antagonist of angiotensin receptor type 1 (AT1), on endometrial epithelial
cell proliferation have been studied. The experiments were performed on ovariectomized female Wistar rats. In the first experiment
the animals were injected with a single dose of oestradiol benzoate or received an injection of solvent only. Half of the
oestrogen-treated rats were injected additionally with enalapril maleate (EN, twice daily). The incorporation of bromodeoxyuridine
(BrDU) into endometrial cell nuclei was used as an index of cell proliferation. It was found that oestradiol alone dramatically
increased the BrDU labelling index (LI) of endometrial cell nuclei, and this effect was partially blocked by the simultaneous
treatment with EN. In the second experiment, the animals were injected intraperitoneally with angiotensin II (AII), angiotensin
IV (AIV) or saline, alone or together with losartan. It was found that AIV induced an increase in the LI in uterine epithelium,
and this effect was not blocked by the simultaneous treatment with losartan. The increase in LI in uterine epithelium was
also observed in the rats treated with AII and with losartan. These findings suggest an involvement of angiotensin IV in the
control of uterine epithelium cell proliferation.
Received 12 October 1998; received after revision 6 January 1999; accepted 2 February 1999 相似文献
996.
Chemotherapy and immunotherapy of malignant glioma: molecular mechanisms and clinical perspectives 总被引:5,自引:0,他引:5
Despite the considerable progress in modern tumor therapy, the prognosis for patients with glioblastoma, the most frequent
malignant brain tumor, has not been substantially improved. Although cytoreductive surgery and radiotherapy are the mainstays
of treatment for malignant glioma at present, novel cytotoxic drugs and immunotherapeutic approaches hold great promise as
effective weapons against these malignancies. Thus, great efforts are being made to enhance antitumoral efficacy by combining
various cytotoxic agents, by novel routes of drug administration, or by combining anticancer drugs and immune modulators.
Immunotherapeutic approaches include cytotoxic cytokines, targeted antibodies, and vaccination strategies. However, the success
of most of these experimental therapies is prevented by the marked molecular resistance of glioma cells to diverse cytotoxic
agents or by glioma-associated immunosuppression. One promising experimental strategy to target glioma is the employment of
death ligands such as CD95 (Fas/Apo1) ligand or Apo2 ligand (TRAIL). Specific proapoptotic approaches may overcome many of
the obvious obstacles to a satisfactory management of malignant brain tumors.
Received 8 March 1999; received after revision 27 May 1999; accepted 14 June 1999 相似文献
997.
Cell surface heparan sulfate proteoglycans are involved in several aspects of the lipoprotein metabolism. Most of the biological activities of these proteoglycans are mediated via interactions of their heparan sulfate moieties with various protein ligands, including lipoproteins and lipases. The binding of lipoproteins to heparan sulfate is largely determined by their apoprotein composition, and apoproteins B and E display the highest affinity for heparan sulfate. Interactions of lipoproteins with heparan sulfate are important for the cellular uptake and turnover of lipoproteins, in part by enhancing the accessibility of lipoproteins to lipoprotein receptors and lipases. Apoprotein B may interact with receptors without involving heparan sulfate. Heparan sulfate has been further implicated in presentation and stabilization of lipoprotein lipase and hepatic lipase on cell surfaces and in the transport of lipoprotein lipase from extravascular cells to the luminal surface of the endothelia. In atherosclerosis, heparan sulfate is intimately involved in several events important to the pathophysiology of the disease. Heparan sulfate thus binds and regulates the activity of growth factors, cytokines, superoxide dismutase and antithrombin, which contribute to aberrant cell proliferation, migration and matrix production, scavenging of reactive oxygen radicals and thrombosis. In this review we discuss the various roles of heparan sulfate proteoglycans in vascular biology, with emphasis on interactions of heparan sulfate with lipoproteins and lipases and the molecular basis of such interactions. 相似文献
998.
Glycine: a new anti-inflammatory immunonutrient 总被引:7,自引:0,他引:7
999.
The Pendred syndrome gene encodes a chloride-iodide transport protein 总被引:24,自引:0,他引:24
Pendred syndrome is the most common form of syndromic deafness and characterized by congenital sensorineural hearing loss and goitre. This disorder was mapped to chromosome 7 and the gene causing Pendred syndrome (PDS) was subsequently identified by positional cloning. PDS encodes a putative transmembrane protein designated pendrin. Pendrin is closely related to a family of sulfate transport proteins that includes the rat sulfate-anion transporter (encoded by Sat-1; 29% amino acid sequence identity), the human diastrophic dysplasia sulfate transporter (encoded by DTD; 32%) and the human sulfate transporter 'downregulated in adenoma' (encoded by DRA; 45%). On the basis of this homology and the presence of a slightly modified sulfate-transporter signature sequence comprising its putative second transmembrane domain, pendrin has been proposed to function as a sulfate transporter. We were unable to detect evidence of sulfate transport following the expression of pendrin in Xenopus laevis oocytes by microinjection of PDS cRNA or in Sf9 cells following infection with PDS-recombinant baculovirus. The rates of transport for iodide and chloride were significantly increased following the expression of pendrin in both cell systems. Our results demonstrate that pendrin functions as a transporter of chloride and iodide, but not sulfate, and may provide insight into thyroid physiology and the pathophysiology of Pendred syndrome. 相似文献
1000.
Jansen G Thijssen KL Werner P van der Horst M Hazendonk E Plasterk RH 《Nature genetics》1999,21(4):414-419
Caenorhabditis elegans is the first animal whose genomic sequence has been determined. One of the new possibilities in post-sequence genetics is the analysis of complete gene families at once. We studied the family of heterotrimeric G proteins. C. elegans has 20 Galpha, 2 Gbeta and 2 Ggamma genes. There is 1 homologue of each of the 4 mammalian classes of Galpha genes, G(i)/G(o)alpha, G(s)alpha , G(q)alpha and G12alpha, and there are 16 new alpha genes. Although the conserved Galpha subunits are expressed in many neurons and muscle cells, GFP fusions indicate that 14 new Galpha genes are expressed almost exclusively in a small subset of the chemosensory neurons of C. elegans. We generated loss-of-function alleles using target-selected gene inactivation. None of the amphid-expressed genes are essential for viability, and only four show any detectable phenotype (chemotaxis defects), suggesting extensive functional redundancy. On the basis of functional analysis, the 20 genes encoding Galpha proteins can be divided into two groups: those that encode subunits affecting muscle activity (homologues of G(i)/G(o)alpha, G(s)alpha and G(q)), and those (14 new genes) that encode proteins most likely involved in perception. 相似文献