全文获取类型
收费全文 | 29821篇 |
免费 | 72篇 |
国内免费 | 74篇 |
专业分类
系统科学 | 138篇 |
丛书文集 | 363篇 |
教育与普及 | 57篇 |
理论与方法论 | 121篇 |
现状及发展 | 12815篇 |
研究方法 | 1182篇 |
综合类 | 14837篇 |
自然研究 | 454篇 |
出版年
2013年 | 249篇 |
2012年 | 368篇 |
2011年 | 835篇 |
2010年 | 157篇 |
2008年 | 426篇 |
2007年 | 510篇 |
2006年 | 538篇 |
2005年 | 512篇 |
2004年 | 597篇 |
2003年 | 481篇 |
2002年 | 481篇 |
2001年 | 996篇 |
2000年 | 957篇 |
1999年 | 584篇 |
1992年 | 538篇 |
1991年 | 433篇 |
1990年 | 460篇 |
1989年 | 487篇 |
1988年 | 434篇 |
1987年 | 434篇 |
1986年 | 490篇 |
1985年 | 572篇 |
1984年 | 440篇 |
1983年 | 423篇 |
1982年 | 363篇 |
1981年 | 363篇 |
1980年 | 397篇 |
1979年 | 967篇 |
1978年 | 782篇 |
1977年 | 739篇 |
1976年 | 573篇 |
1975年 | 695篇 |
1974年 | 966篇 |
1973年 | 766篇 |
1972年 | 802篇 |
1971年 | 960篇 |
1970年 | 1204篇 |
1969年 | 883篇 |
1968年 | 910篇 |
1967年 | 848篇 |
1966年 | 764篇 |
1965年 | 589篇 |
1964年 | 156篇 |
1959年 | 313篇 |
1958年 | 523篇 |
1957年 | 380篇 |
1956年 | 293篇 |
1955年 | 295篇 |
1954年 | 282篇 |
1948年 | 207篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
901.
Eukaryotic glycosylation: whim of nature or multipurpose tool? 总被引:13,自引:0,他引:13
Protein and lipid glycosylation is a ubiquitous phenomenon. The task of cataloguing the great structural variety of the glycan part has demanded considerable efforts over decades. This patient endeavor was imperative to discern the inherent rules of glycosylation which cannot affirm assumptions on a purely coincidental nature of this type of protein and lipid modification. These results together with theoretical considerations uncover a salient property of oligosaccharides. In comparison with amino acids and nucleotides, monosaccharides excel in their potential to serve as units of hardware for storing biological information. Thus, the view that glycan chains exclusively affect physiochemical properties of the conjugates is indubitably flawed. This original concept has been decisively jolted by the discovery of endogenous receptors (lectins) for distinct glycan epitopes which are as characteristic as a fingerprint or a signature for a certain protein (class) or cell type. Recent evidence documents that these binding proteins are even endowed with the capacity to select distinct low-energy conformers of the often rather flexible oligosaccharides, granting entry to a new level of regulation of ligand affinity by shifting conformer equilibria. The assessment of the details of this recognition by X-ray crystallography, nuclear magnetic resonance spectroscopy, microcalorimetry and custom-made derivatives is supposed to justify a guarded optimism in satisfying the need for innovative drug design in antiadhesion therapy, for example against viral or bacterial infections and unwanted inflammation. This review presents a survey of the structural aspects of glycosylation and of evidence to poignantly endorse the notion that carrier-attached glycan chains can partake in biological information transfer at the level of cell compartments, cells and organs. 相似文献
902.
903.
Kirkpatrick DT 《Cellular and molecular life sciences : CMLS》1999,55(3):437-449
Numerous proteins are involved in the nucleotide excision repair (NER) and DNA mismatch repair (MMR) pathways. The function
and specificity of these proteins during the mitotic cell cycle has been actively investigated, in large part due to the involvement
of these systems in human diseases. In contrast, comparatively little is known about their functioning during meiosis. At
least three repair pathways operate during meiosis in the yeast Saccharomyces cerevisiae to repair mismatches that occur as a consequence of heteroduplex formation in recombination. The first pathway is similar
to the one acting during postreplicative mismatch repair in mitotically dividing cells, while two pathways are responsible
for the repair of large loops during meiosis, using proteins from MMR and NER systems. Some MMR proteins also help prevent
recombination between diverged sequences during meiosis, and act late in recombination to affect the resolution of crossovers.
This review will discuss the current status of DNA mismatch repair and nucleotide excision repair proteins during meiosis,
especially in the yeast S. cerevisiae.
Received 21 September 1998; received after revision 23 November 1998; accepted 23 November 1998 相似文献
904.
In recent years, a number of cross-talk systems have been identified which feed into the insulin signalling cascade at the level of insulin receptor substrate (IRS) tyrosine phosphorylation, e.g., receptor and non-receptor tyrosine kinases and G-protein-coupled receptors. At the molecular level, a number of negative modulator and feedback systems somehow interacting with the beta-subunit (catecholamine-, phorbolester-, or tumor necrosis factor-alpha-induced serine/threonine phosphorylation, carboxy-terminal trimming by a thiol-dependent protease, association of inhibitory/regulatory proteins such as RAD, PC1, PED, alpha2-HS-glycoprotein) have been identified as candidate mechanisms for the impairment of insulin receptor function by elevations in the activity and/or amount of the corresponding modification enzymes/inhibitors. Both decreased responsiveness and sensitivity of the insulin receptor beta-subunit for insulin-induced tyrosine autophosphorylation have been demonstrated in several cellular and animal models of metabolic insulin resistance as well as in the adipose tissue and skeletal muscle of diabetic patients and obese Pima Indians compared to non-obese subjects. Therefore, induction of the insulin signalling cascade by bypassing the defective insulin receptor kinase may be useful for the therapy of non-insulin dependent diabetes mellitus. During the past two decades, phosphoinositolglycans (PIGs) of various origin have been demonstrated to exert potent insulin-mimetic metabolic effects upon incubation with cultured or isolated muscle and adipose cells. However, it remained to be elucidated whether these compounds actually manage to trigger insulin signalling and if so at which level of hierarchy within the signalling cascade the site of interference is located. Recent studies using isolated rat adipocytes and chemically synthesized PIG compounds point to IRS1/3 tyrosine phosphorylation by p59Lyn kinase as the site of cross-talk, the negative regulation of which by interaction with caveolin is apparently abrogated by PIG. This putative mechanism is thus compatible with the recently formulated caveolin signalling hypothesis, the supporting data for which are reviewed here. Though we have not obtained experimental evidence for the involvement of PIG in physiological insulin action, the potential cross-talk between insulin and PIG signalling, including the caveolae/detergent-insoluble glycolipid-enriched rafts as the compartments where the corresponding signalling components are concentrated, thus represent novel targets for signal transduction therapy. 相似文献
905.
906.
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
907.
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
908.
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
909.
910.
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