全文获取类型
收费全文 | 45986篇 |
免费 | 96篇 |
国内免费 | 117篇 |
专业分类
系统科学 | 354篇 |
丛书文集 | 1082篇 |
教育与普及 | 118篇 |
理论与方法论 | 244篇 |
现状及发展 | 20269篇 |
研究方法 | 1711篇 |
综合类 | 21727篇 |
自然研究 | 694篇 |
出版年
2013年 | 285篇 |
2012年 | 573篇 |
2011年 | 1300篇 |
2010年 | 247篇 |
2008年 | 745篇 |
2007年 | 778篇 |
2006年 | 838篇 |
2005年 | 826篇 |
2004年 | 774篇 |
2003年 | 829篇 |
2002年 | 753篇 |
2001年 | 1355篇 |
2000年 | 1236篇 |
1999年 | 803篇 |
1992年 | 797篇 |
1991年 | 676篇 |
1990年 | 715篇 |
1989年 | 667篇 |
1988年 | 692篇 |
1987年 | 712篇 |
1986年 | 689篇 |
1985年 | 855篇 |
1984年 | 699篇 |
1983年 | 589篇 |
1982年 | 493篇 |
1981年 | 511篇 |
1980年 | 665篇 |
1979年 | 1421篇 |
1978年 | 1213篇 |
1977年 | 1204篇 |
1976年 | 875篇 |
1975年 | 994篇 |
1974年 | 1370篇 |
1973年 | 1203篇 |
1972年 | 1221篇 |
1971年 | 1477篇 |
1970年 | 1942篇 |
1969年 | 1502篇 |
1968年 | 1367篇 |
1967年 | 1447篇 |
1966年 | 1254篇 |
1965年 | 907篇 |
1964年 | 243篇 |
1959年 | 571篇 |
1958年 | 850篇 |
1957年 | 668篇 |
1956年 | 572篇 |
1955年 | 503篇 |
1954年 | 561篇 |
1948年 | 334篇 |
排序方式: 共有10000条查询结果,搜索用时 10 毫秒
991.
The development and maturation of an oligodendroglial cell is comprised of three intimately related processes that include proliferation, differentiation, and myelination. Here we review how proliferation and differentiation are controlled by distinct molecular mechanisms and discuss whether differentiation is merely a default of inhibited proliferation. We then address whether differentiation and myelination can be uncoupled in a similar manner. This task is particularly challenging because an oligodendrocyte cannot myelinate without first differentiating, and these processes are therefore not mutually exclusive. Is it solely the presence of the axon that distinguishes a differentiated oligodendrocyte from a myelinating one? Uncoupling these two processes requires identifying specific signals that regulate myelination without affecting the differentiation process. We will review current understanding of the relationship between differentiation and myelination and discuss whether these two processes can truly be uncoupled. 相似文献
992.
Minagawa H Yoshida Y Kenmochi N Furuichi M Shimada J Kaneko H 《Cellular and molecular life sciences : CMLS》2007,64(1):77-81
Lactate oxidase is used in biosensors to measure the concentration of lactate in the blood and other body fluids. Increasing
the thermostability of lactate oxidase can significantly prolong the lifetime of these biosensors. We have previously obtained
a variant of lactate oxidase from Aerococcus viridans with two mutations (E160G/V198I) that is significantly more thermostable than the wild-type enzyme. Here we have attempted
to further improve the thermostability of E160G/V198I lactate oxidase using directed evolution. We made a mutant lactate oxidase
gene library by applying error-prone PCR and DNA shuffling, and screened for thermostable mutant lactate oxidase using a plate-based
assay. After three rounds of screening we obtained a thermostable mutant lactate oxidase, which has six mutations (E160G/V198I/G36S/T103S/A232S/F277Y).
The half-life of this lactate oxidase at 70 °C was about 2 times that of E160G/V198I and about 36 times that of the wild-type
enzyme. The amino acid mutation process suggests that the combined neutral mutations are important in protein evolution.
Received 15 September 2006; received after revision 21 October 2006; accepted 2 November 2006 相似文献
993.
Crnković-Mertens I Wagener N Semzow J Gröne EF Haferkamp A Hohenfellner M Butz K Hoppe-Seyler F 《Cellular and molecular life sciences : CMLS》2007,64(9):1137-1144
Cancer cells are typically characterized by apoptosis deficiency. In order to investigate a possible role for the anti-apoptotic
livin gene in renal cell cancer (RCC), we analyzed its expression in tumor tissue samples and in RCC-derived cell lines. In addition,
we studied the contribution of livin to the apoptotic resistance of RCC cells by RNA interference (RNAi). Livin gene expression was detected in a significant portion of RCC tumor tissue specimens (13/14, 92.9%) and tumor-derived cell
lines (12/15, 80.0%). Moreover, targeted inhibition of livin by RNAi markedly sensitized RCC cells towards proapoptotic stimuli, such as UV irradiation or the chemotherapeutic drugs
etoposide, 5-fluorouracil, and vinblastine. These effects were specific for livin expressing tumor cells. We conclude that livin can contribute significantly to the apoptosis resistance of RCC cells. Targeted inhibition of livin could represent a novel therapeutic strategy to increase the sensitivity of renal cancers towards pro-apoptotic agents.
Received 30 November 2006; received after revision 22 February 2007; accepted 20 March 2007 相似文献
994.
Infection of bacteria triggers innate immune defense reactions in Drosophila. So far, the only bacterial component known to be recognized by the insect innate immune system is peptidoglycan, one of
the most abundant constituents of the bacterial cell wall. Insects use peptidoglycan recognition proteins to detect peptidoglycan
and to activate innate immune responses. Such specialized peptidoglycan receptors appear to have evolved from phage enzymes
that hydrolyze bacterial cell walls. They are able to bind specific peptidoglycan molecules with distinct chemical moieties
and activate innate immune pathways by interacting with other signaling proteins. Recent X-ray crystallographic studies of
the peptidoglycan recognition proteins LCa, and LCx bound to peptidoglycan have provided structural insights into recognition
of peptidoglycan and activation of innate immunity in insects.
Received 28 December 2006; received after revision 2 February 2007; accepted 21 February 2007 相似文献
995.
The study of candidate genes over the past three decades has yielded notable successes in common-disease genetics. During
this time, however, interpretation of genetic association studies has been hampered by the use of clinical cohorts of inadequate
power and insufficient information on genetic variation in candidate genes. The unavailability of highthroughput and low-cost
genotyping technologies has also limited the scope of complex-disease genetic studies. More recently, however, the sequencing
and characterization of variation within the human genome has revolutionized genetic studies and enabled full genome-wide
scans for genes associated with disease. The identification of disease-associated (causative) genes has illuminated disease
mechanisms. The translation of this knowledge into direct clinical benefit in diagnosis, prognosis and therapy for an individual’s
disease still remains a challenge.
Received 11 September 2006; received after revision 17 December 2006; accepted 18 January 2007 相似文献
996.
Larrucea S Butta N Rodriguez RB Alonso-Martin S Arias-Salgado EG Ayuso MS Parrilla R 《Cellular and molecular life sciences : CMLS》2007,64(22):2965-2974
Podocalyxin (PODXL) is a mucin protein of the CD34 family expressed in kidney glomerular podocytes, vascular endothelium,
progenitor bone marrow and tumor cells. It is assumed that PODXL plays an anti-adherent role in kidney podocytes. CHO cells
stably expressing human PODXL (CHO-PODXL) or human tumor cells (Tera-1) inherently expressing PODXL showed increased adherence
to platelets. The adherence of cells was inhibited (70%) by blockers of platelet P-selectin, prevented by the soluble ectodomain
of human PODXL (PODXL-Δ) or by the arginine-glycine-aspartate (RGDS) peptide and partially impeded by inhibition of integrin
αVβ3/αVβ5, suggesting a coordinated action of P-selectin and integrins. Colocalization of platelet P-selectin and PODXL expressed
on CHO cells was demonstrated by confocal immunofluorescence. No adherence to platelets was observed when PODXL was expressed
in glycomutant CHO cells deficient in sialic acid.
Received 14 August 2007; received after revision 12 September 2007; accepted 13 September 2007 相似文献
997.
Periodic circadian (24-h) cycles play an important role in daily hormonal and behavioural rhythms. Usually our sleep/wake
cycle, temperature and melatonin rhythms are internally synchronized with a stable phase relationship. When there is a desynchrony
between the sleep/wake cycle and circadian rhythm, sleep disorders such as advanced and delayed sleep phase syndrome can arise
as well as transient chronobiologic disturbances, for example from jet lag and shift work. Appropriately timed bright light
is effective in re-timing the circadian rhythm and sleep pattern to a more desired time, ameliorating these disturbances.
Other less potent retiming effects may also be obtained from the judicious use of melatonin and exercise. 相似文献
998.
From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing 总被引:6,自引:1,他引:5
Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed. 相似文献
999.
Ras GTPases mediate a wide variety of cellular processes by converting a multitude of extracellular stimuli into specific biological responses including proliferation, differentiation and survival. In mammalian cells, three ras genes encode four Ras isoforms (H-Ras, K-Ras4A, K-Ras4B and N-Ras) that are highly homologous but functionally distinct. Differences between the isoforms, including their post-translational modifications and intracellular sorting, mean that Ras has emerged as an important model system of compartmentalised signalling and membrane biology. Ras isoforms in different subcellular locations are proposed to recruit distinct upstream and downstream accessory proteins and activate multiple signalling pathways. Here, we summarise data relating to isoform-specific signalling, its role in disease and the mechanisms promoting compartmentalised signalling. Further understanding of this field will reveal the role of Ras signalling in development, cellular homeostasis and cancer and may suggest new therapeutic approaches. 相似文献
1000.
Lindahl E Nyman U Melles E Sigmundsson K Ståhlberg M Wahren J Obrink B Shafqat J Joseph B Jörnvall H 《Cellular and molecular life sciences : CMLS》2007,64(4):479-486
Proinsulin C-peptide is known to bind specifically to cell membranes and to exert intracellular effects, but whether it is
internalized in target cells is unknown. In this study, using confocal microscopy and immunostained or rhodamine-labeled peptide,
we show that C-peptide is internalized and localized to the cytosol of Swiss 3T3 and HEK-293 cells. In addition, transport
into nuclei was found using the labeled peptide. The internalization was followed at 37°C for up to 1 h, and was reduced at
4°C and after preincubation with pertussis toxin. Hence, it is concluded to occur via an energy-dependent, pertussis toxin-sensitive
mechanism and without detectable degradation within the experimental time course. Surface plasmon resonance measurements demonstrated
binding of HEK-293 cell extract components to C-peptide, and subsequent elution of bound material revealed the components
to be intracellular proteins. The identification of C-peptide cellular internalization, intracellular binding proteins, absence
of rapid subsequent C-peptide degradation and apparent nuclear internalization support a maintained activity similar to that
of an intracrine peptide hormone. Hence, the data suggest the possibility of one further C-peptide site of action.
Received 31 October 2006; received after revision 27 December 2006; accepted 30 December 2006 相似文献