全文获取类型
收费全文 | 17216篇 |
免费 | 42篇 |
国内免费 | 53篇 |
专业分类
系统科学 | 253篇 |
丛书文集 | 444篇 |
教育与普及 | 36篇 |
理论与方法论 | 50篇 |
现状及发展 | 7948篇 |
研究方法 | 726篇 |
综合类 | 7706篇 |
自然研究 | 148篇 |
出版年
2012年 | 203篇 |
2011年 | 410篇 |
2010年 | 97篇 |
2009年 | 94篇 |
2008年 | 272篇 |
2007年 | 344篇 |
2006年 | 289篇 |
2005年 | 298篇 |
2004年 | 271篇 |
2003年 | 325篇 |
2002年 | 260篇 |
2001年 | 609篇 |
2000年 | 609篇 |
1999年 | 344篇 |
1992年 | 328篇 |
1991年 | 253篇 |
1990年 | 298篇 |
1989年 | 271篇 |
1988年 | 262篇 |
1987年 | 276篇 |
1986年 | 284篇 |
1985年 | 338篇 |
1984年 | 242篇 |
1983年 | 219篇 |
1982年 | 200篇 |
1981年 | 238篇 |
1980年 | 261篇 |
1979年 | 568篇 |
1978年 | 463篇 |
1977年 | 469篇 |
1976年 | 351篇 |
1975年 | 374篇 |
1974年 | 583篇 |
1973年 | 455篇 |
1972年 | 413篇 |
1971年 | 510篇 |
1970年 | 656篇 |
1969年 | 573篇 |
1968年 | 492篇 |
1967年 | 528篇 |
1966年 | 439篇 |
1965年 | 330篇 |
1964年 | 86篇 |
1959年 | 198篇 |
1958年 | 293篇 |
1957年 | 192篇 |
1956年 | 172篇 |
1955年 | 167篇 |
1954年 | 159篇 |
1948年 | 87篇 |
排序方式: 共有10000条查询结果,搜索用时 46 毫秒
901.
Lincoln AJ Wickramasinghe D Stein P Schultz RM Palko ME De Miguel MP Tessarollo L Donovan PJ 《Nature genetics》2002,30(4):446-449
In a wide variety of animal species, oocyte maturation is arrested temporarily at prophase of meiosis I (ref. 1). Resumption of meiosis requires activation of cyclin-dependent kinase-1 (CDK1, p34cdc2), one component of maturation-promoting factor (MPF). The dual specificity phosphatases Cdc25a, Cdc25b and Cdc25c are activators of cyclin-dependent kinases; consequently, they are postulated to regulate cell-cycle progression in meiosis and mitosis as well as the DNA-damage response. We generated Cdc25b-deficient (Cdc25b-/-) mice and found that they are viable. As compared with wildtype cells, fibroblasts from Cdc25b-/- mice grew vigorously in culture and arrested normally in response to DNA damage. Female Cdc25b-/- mice were sterile, and Cdc25b-/- oocytes remained arrested at prophase with low MPF activity. Microinjection of wildtype Cdc25b mRNA into Cdc25b-/- oocytes caused activation of MPF and resumption of meiosis. Thus, Cdc25b-/- female mice are sterile because of permanent meiotic arrest resulting from the inability to activate MPF. Cdc25b is therefore essential for meiotic resumption in female mice. Mice lacking Cdc25b provide the first genetic model for studying the mechanisms regulating prophase arrest in vertebrates. 相似文献
902.
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer 总被引:26,自引:0,他引:26
Tomlinson IP Alam NA Rowan AJ Barclay E Jaeger EE Kelsell D Leigh I Gorman P Lamlum H Rahman S Roylance RR Olpin S Bevan S Barker K Hearle N Houlston RS Kiuru M Lehtonen R Karhu A Vilkki S Laiho P Eklund C Vierimaa O Aittomäki K Hietala M Sistonen P Paetau A Salovaara R Herva R Launonen V Aaltonen LA;Multiple Leiomyoma Consortium 《Nature genetics》2002,30(4):406-410
903.
Protecting against promiscuity: the regulatory role of insulators 总被引:11,自引:0,他引:11
904.
The superoxide-generating NADPH oxidase: structural aspects and activation mechanism 总被引:31,自引:0,他引:31
Vignais PV 《Cellular and molecular life sciences : CMLS》2002,59(9):1428-1459
Flavocytochrome b
558
is the catalytic core of the respiratory-burst oxidase, an enzyme complex that catalyzes the NADPH-dependent reduction of
O2 into the superoxide anion O2
- in phagocytic cells. Flavocytochrome b
558
is anchored in the plasma membrane. It is a heterodimer that consists of a large glycoprotein gp91phox (phox for phagocyte oxidase) (β subunit) and a small protein p22phox (α subunit). The other components of the respiratory-burst oxidase are water-soluble
proteins of cytosolic origin, namely p67phox, p47phox, p40phox and Rac. Upon cell stimulation, they assemble with the membrane-bound
flavocytochrome b
558
which becomes activated and generates O2
-. A defect in any of the genes encoding gp91phox, p22phox, p67phox or p47phox results in chronic granulomatous disease, a
genetic disorder characterized by severe and recurrent infections, illustrating the role of O2
- and the derived metabolites H2O2 and HOCl in host defense against invading microorganisms. The electron carriers, FAD and hemes b, and the binding site for NADPH are confined to the gp91phox subunit of flavocytochrome b
558
. The p22phox subunit serves as a docking site for the cytosolic phox proteins. This review provides an overview of current
knowledge on the structural organization of the O2
--generating flavocytochrome b
558
, its kinetics, its mechanism of activation and the regulation of its biosynthesis. Homologues of gp91phox, called Nox and
Duox, are present in a large variety of non-phagocytic cells. They exhibit modest O2
--generating oxidase activity, and some act as proton channels. Their role in various aspects of signal transduction is currently
under investigation and is briefly discussed.
Received 28 May 2002; received after revision 20 June 2002; accepted 24 June 2002 相似文献
905.
Role of hydrogen peroxide and oxidative stress in healing responses 总被引:11,自引:0,他引:11
Rojkind M Domínguez-Rosales JA Nieto N Greenwel P 《Cellular and molecular life sciences : CMLS》2002,59(11):1872-1891
906.
Our understanding of how immune responses are generated and regulated drives the design of possible immunotherapies for cancer
patients. For that reason, we first describe briefly the actual immunological theories and their common perspectives about
cancer vaccine development. Second, we describe cancer vaccines that are able to induce tumor-specific immune responses in
cancer patients. However, these responses are not always followed by tumor rejection. At the end of the review, we discuss
two possible reasons that might explain this dichotomy of cancer immunology. First, the immune response generated, although
detectable, may not be quantitatively sufficient to reject the tumor. Second, the tumor microenvironment may modulate tumor
cell susceptibility to the systemic immune response induced by the immunization. Finally, we discuss what, in our opinion,
might be the best way to improve cancer vaccine strategies and how the relationship between the tumor and its surroundings
might be studied in more details.
Received 21 June 2001; received after revision 15 August 2001; accepted 15 August 2001 相似文献
907.
Cellular and molecular aspects of drugs of the future: meropenem 总被引:1,自引:0,他引:1
Cottagnoud P 《Cellular and molecular life sciences : CMLS》2002,59(11):1928-1933
Meropenem, first synthesized in the late eighties, has become one of the most important beta-lactam antibiotics of the carbapenem subclass used for the treatment of a variety of life-threatening infections. Due to its unique chemical structure, meropenem is not inactivated by the kidney dehydropeptidase I and the majority of microbial beta-lactamases. Its antimicrobial activity is based on its high affinity for the majority of cell wall-synthesizing enzymes, the so-called penicillin-binding proteins, of Gram-positive and -negative bacteria. However, bacteria have evolved several approaches to resist meropenem: (i) by reducing the affinity of the penicillin-binding proteins for the antibiotics, (ii) by decreasing the permeability of the outer membrane of Gram-negative bacteria, (iii) by using efflux pumps, and (iv) by activating zinc-dependent carbapenemases. Meropenem has a low toxicity profile and, in contrast to imipenem, no central nervous system toxicity. 相似文献
908.
Bignold LP 《Cellular and molecular life sciences : CMLS》2002,59(6):950-958
Almost all solid malignancies exhibit complex cytological and architectural abnormalities, which vary from cell to cell and
area to area within the same tumour, and between tumours of the same type. The degrees of these abnormalities do not correlate
perfectly with the biological behaviour (especially growth rate and metastatic potential) among the various tumour types.
These features of tumours have long been considered to invalidate simple mutational or 'abnormal gene expression' (epigenetic)
theories of carcinogenesis. The 'mutator phenotype/clonal selection' hypothesis is based on the now well-established phenomenon
of genetic instability of cancer cells, and proposes that this instability is an essential requirement for the development
of tumours, and not an irrelevant side-effect of some other process. This paper argues that this hypothesis can provide a
satisfactory explanation for the diverse histological and biological features of solid malignancies. Further, because virtually
all solid tumours are histologically abnormal, genetic instability is likely to be essential for the malignant process. The
concepts of mutator phenotype and clonal selection are therefore supported.
Received 8 April 2002; accepted 25 April 2002 相似文献
909.
Maechler P 《Cellular and molecular life sciences : CMLS》2002,59(11):1803-1818
Mitochondrial metabolism is crucial for the coupling of glucose recognition to the exocytosis of the insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP, which is the main coupling messenger in insulin secretion. However, the subsequent Ca2+ signal in the cytosol is necessary but not sufficient for full development of sustained insulin secretion. Hence, mitochondria generate ATP and other coupling factors serving as fuel sensors for the control of the exocytotic process. Numerous studies have sought to identify the factors that mediate the amplifying pathway over the Ca2+ signal in glucose-stimulated insulin secretion. Predominantly, these factors are nucleotides (GTP, ATP, cAMP, NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and glutamate. Hence, the classical neurotransmitter glutamate receives a novel role, that of an intracellular messenger or co-factor in insulin secretion. This scenario further highlights the importance of glutamate dehydrogenase, a mitochondrial enzyme well recognized to play a key role in the control of insulin secretion. Therefore, additional putative messengers of mitochondrial origin are likely to participate in insulin secretion. 相似文献
910.
The knowledge of human genetic variation that will come from the human genome sequence makes feasible a polygenic approach to disease prevention, in which it will be possible to identify individuals as susceptible by their genotype profile and to prevent disease by targeting interventions to those at risk. There is doubt, however, regarding the magnitude of these genetic effects and thus the potential to apply them to either individuals or populations. We have therefore examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data are compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. By contrast, if currently identified risk factors for breast cancer were used to stratify the population, the half of the population at highest risk would account for only 62% of all cases. These results suggest that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases. 相似文献