全文获取类型
收费全文 | 40396篇 |
免费 | 103篇 |
国内免费 | 211篇 |
专业分类
系统科学 | 244篇 |
丛书文集 | 728篇 |
教育与普及 | 83篇 |
理论与方法论 | 158篇 |
现状及发展 | 18567篇 |
研究方法 | 1638篇 |
综合类 | 18675篇 |
自然研究 | 617篇 |
出版年
2013年 | 337篇 |
2012年 | 569篇 |
2011年 | 1218篇 |
2010年 | 252篇 |
2008年 | 713篇 |
2007年 | 791篇 |
2006年 | 800篇 |
2005年 | 779篇 |
2004年 | 795篇 |
2003年 | 723篇 |
2002年 | 752篇 |
2001年 | 1264篇 |
2000年 | 1155篇 |
1999年 | 794篇 |
1992年 | 762篇 |
1991年 | 578篇 |
1990年 | 655篇 |
1989年 | 634篇 |
1988年 | 592篇 |
1987年 | 678篇 |
1986年 | 652篇 |
1985年 | 785篇 |
1984年 | 652篇 |
1983年 | 517篇 |
1982年 | 459篇 |
1981年 | 503篇 |
1980年 | 622篇 |
1979年 | 1276篇 |
1978年 | 1044篇 |
1977年 | 1030篇 |
1976年 | 810篇 |
1975年 | 880篇 |
1974年 | 1189篇 |
1973年 | 1068篇 |
1972年 | 1071篇 |
1971年 | 1212篇 |
1970年 | 1559篇 |
1969年 | 1174篇 |
1968年 | 1115篇 |
1967年 | 1144篇 |
1966年 | 986篇 |
1965年 | 688篇 |
1964年 | 206篇 |
1959年 | 378篇 |
1958年 | 653篇 |
1957年 | 458篇 |
1956年 | 405篇 |
1955年 | 361篇 |
1954年 | 367篇 |
1948年 | 272篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
461.
Peutz-Jeghers syndrome (PJS, OMIM 175200) is an unusual inherited intestinal polyposis syndrome associated with distinct peri-oral
blue/black freckling [1–9]. Variable penetrance and clinical heterogeneity make it difficult to determine the exact frequency
of PJS [4]. PJS is a cancer predisposition syndrome. Affected individuals are at high risk for intestinal and extra-intestinal
cancers. In 1997, linkage studies mapped PJS to chromosome 19p [10, 11], and subsequently a serine/threonine kinase gene defect
(LKB1) was noted in a majority of PJS cases [12, 13]. A phenotypically similar syndrome has been produced in an LKB1 mouse
knockout model [14–18]. Several PJS kindred without LKB1 mutations have been described, suggesting other PJS loci [19–22].
The management of PJS is complex and evolving. New endoscopic technologies may improve management of intestinal polyposis.
Identification of specific genetic mutations and their targets will more accurately assess the clinical course, and help gage
the magnitude of cancer risk for affected individuals.
Received 20 February 2006; received after revision 5 May 2006; accepted 15 June 2006 相似文献
462.
Site- and state-specific lysine methylation of histones is catalyzed by a family of proteins that contain the evolutionarily
conserved SET domain and plays a fundamental role in epigenetic regulation of gene activation and silencing in all eukaryotes.
The recently determined three-dimensional structures of the SET domains from chromosomal proteins reveal that the core SET
domain structure contains a two-domain architecture, consisting of a conserved anti-parallel β-barrel and a structurally variable
insert that surround a unusual knot-like structure that comprises the enzyme active site. These structures of the SET domains,
either in the free state or when bound to cofactor S-adenosyl-L-homocysteine and/or histone peptide, mimicking an enzyme/cofactor/substrate complex, further yield the structural insights
into the molecular basis of the substrate specificity, methylation multiplicity and the catalytic mechanism of histone lysine
methylation.
Received 10 June 2006; accepted 22 August 2006 相似文献
463.
Blasig IE Winkler L Lassowski B Mueller SL Zuleger N Krause E Krause G Gast K Kolbe M Piontek J 《Cellular and molecular life sciences : CMLS》2006,63(4):505-514
Tight junctions seal intercellular clefts via membrane-related strands, hence, maintaining important organ functions. We investigated
the self-association of strand-forming transmembrane tight junction proteins. The regulatory tight junction protein occludin
was differently tagged and cotransfected in eucaryotic cells. These occludins colocalized within the plasma membrane of the
same cell, coprecipitated and exhibited fluorescence resonance energy transfer. Differently tagged strand-forming claudin-5
also colocalized in the plasma membrane of the same cell and showed fluorescence resonance energy transfer. This demonstrates
self-association in intact cells both of occludin and claudin-5 in one plasma membrane. In search of dimerizing regions of
occludin, dimerization of its cytosolic C-terminal coiledcoil domain was identified. In claudin-5, the second extracellular
loop was detected as a dimer. Since the transmembrane junctional adhesion molecule also is known to dimerize, the assumption
that homodimerization of transmembrane tight junction proteins may serve as a common structural feature in tight junction
assembly is supported.
Received 6 October 2005; received after revision 14 December 2005; accepted 27 December 2005
†These authors contributed equally to this work. 相似文献
464.
Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies 总被引:3,自引:0,他引:3
Borrell-Pagès M Zala D Humbert S Saudou F 《Cellular and molecular life sciences : CMLS》2006,63(22):2642-2660
Huntington’s disease (HD) is a neurodegenerative disorder that usually starts in middle age and is characterized by involuntary
movements (chorea), personality changes and dementia, leading to death within 10–20 years. The defective gene in HD contains
a trinucleotide CAG repeat expansion within its coding region that expresses a polyglutamine repeat in the protein huntingtin.
Together with the characteristic formation of aggregates in HD, aberrant protein interactions and several post-translational
modifications affect huntingtin during disease progression and lead to the dysfunction and death of selective neurons in the
brains of patients. The exact molecular mechanisms by which mutant huntingtin induces cell death are not completely understood
but may involve the gain of new toxic functions and the loss of the beneficial properties of huntingtin. This review focuses
on the cellular functions in which huntingtin is involved and how a better understanding of pathogenic pathways can lead to
new therapeutic approaches.
Received 24 May 2006; received after revision 5 July 2006; accepted 23 August 2006 相似文献
465.
Human β-defensins 总被引:1,自引:0,他引:1
Pazgier M Hoover DM Yang D Lu W Lubkowski J 《Cellular and molecular life sciences : CMLS》2006,63(11):1294-1313
466.
Nodal signals pattern vertebrate embryos 总被引:4,自引:0,他引:4
Vertebrate embryonic patterning requires several conserved inductive signals–including Nodal, Bmp, Wnt and Fgf signals. Nodal,
which is a member of the transforming growth factor β (TGFβ) superfamily, activates a signal transduction pathway that is
similar to that of other TGFβ members. Nodal genes, which have been identified in numerous vertebrate species, are expressed
in specific cell types and tissues during embryonic development. Nodal signal transduction has been shown to play a pivotal
role in inducing and patterning mesoderm and endoderm, and in regulating neurogenesis and left-right axis asymmetry. Antagonists,
which act at different steps in the Nodal signal transduction pathway, have been shown to tightly modulate the inductive activity
of Nodal.
Received 20 October 2005; received after revision 15 November 2005; accepted 25 November 2005 相似文献
467.
Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation
and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human
cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute
to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of
an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target,
and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft
models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently
being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight
some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer.
Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006 相似文献
468.
In human patients, blood coagulation disorders often associate with cancer, even in its early stages. Recently, in vitro and in vivo experimental models have shown that oncogene expression, or inactivation of tumour suppressor genes, upregulate genes that
control blood coagulation. These studies suggest that activation of blood clotting, leading to peritumoral fibrin deposition,
is instrumental in cancer development. Fibrin can indeed build up a provisional matrix, supporting the invasive growth of
neoplastic tissues and blood vessels. Interference with blood coagulation can thus be considered as part of a multifaceted
therapeutic approach to cancer.
Received 30 November 2005; received after revision 7 February 2005; accepted 8 February 2006 相似文献
469.
Bosch-Comas A Lindsten K Gonzàlez-Duarte R Masucci MG Marfany G 《Cellular and molecular life sciences : CMLS》2006,63(6):723-734
The biological functions of the more than one hundred genes coding for deubiquitinating enzymes in the human genome remain
mostly unknown. The USP25 gene, located at 21q11.2, encodes three protein isoforms produced by alternative splicing. While
two of the isoforms are expressed nearly ubiquituously, the expression of the longer USP25 isoform (USP25m) is restricted
to muscular tissues and is upregulated during myogenesis. USP25m interacts with three sarcomeric proteins: actin alpha-1 (ACTA1),
filamin C (FLNC), and myosin binding protein C1 (MyBPC1), which are critically involved in muscle differentiation and maintenance,
and have been implicated in the pathogenesis of severe myopathies. Biochemical analyses demonstrated that MyBPC1 is a short-lived
proteasomal substrate, and its degradation is prevented by over-expression of USP25m but not by other USP25 isoforms. In contrast,
ACTA1 and FLNC appear to be stable proteins, indicating that their interaction with USP25m is not related to their turnover
rate.
Received 7 November 2005; received after revision 7 January 2006; accepted 13 January 2006 相似文献
470.
On the basis of evidence collected from the literature, we propose a general model by which protein kinase (PK) A and the
different PKC isoforms can inversely affect cell growth. Molecular switches, which are able to direct the signal towards antiproliferative
or mitogenic pathways, are the different isoforms of Raf and PKC. Conflicting data are also reported and discussed in an attempt
to reconcile them.
Received 10 November 2005; received after revision 28 December 2005; accepted 3 January 2006 相似文献