全文获取类型
收费全文 | 21779篇 |
免费 | 1115篇 |
国内免费 | 698篇 |
专业分类
系统科学 | 1636篇 |
丛书文集 | 408篇 |
教育与普及 | 571篇 |
理论与方法论 | 378篇 |
现状及发展 | 967篇 |
研究方法 | 75篇 |
综合类 | 19554篇 |
自然研究 | 3篇 |
出版年
2024年 | 80篇 |
2023年 | 192篇 |
2022年 | 292篇 |
2021年 | 288篇 |
2020年 | 161篇 |
2019年 | 77篇 |
2018年 | 822篇 |
2017年 | 862篇 |
2016年 | 559篇 |
2015年 | 329篇 |
2014年 | 490篇 |
2013年 | 458篇 |
2012年 | 760篇 |
2011年 | 1445篇 |
2010年 | 1342篇 |
2009年 | 1036篇 |
2008年 | 1231篇 |
2007年 | 1558篇 |
2006年 | 649篇 |
2005年 | 649篇 |
2004年 | 590篇 |
2003年 | 539篇 |
2002年 | 504篇 |
2001年 | 499篇 |
2000年 | 524篇 |
1999年 | 892篇 |
1998年 | 862篇 |
1997年 | 872篇 |
1996年 | 765篇 |
1995年 | 697篇 |
1994年 | 681篇 |
1993年 | 522篇 |
1992年 | 487篇 |
1991年 | 449篇 |
1990年 | 388篇 |
1989年 | 359篇 |
1988年 | 286篇 |
1987年 | 207篇 |
1986年 | 107篇 |
1985年 | 38篇 |
1984年 | 8篇 |
1983年 | 6篇 |
1982年 | 3篇 |
1980年 | 3篇 |
1979年 | 5篇 |
1978年 | 3篇 |
1974年 | 2篇 |
1972年 | 4篇 |
1971年 | 2篇 |
1970年 | 2篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
921.
Ong CK Subimerb C Pairojkul C Wongkham S Cutcutache I Yu W McPherson JR Allen GE Ng CC Wong BH Myint SS Rajasegaran V Heng HL Gan A Zang ZJ Wu Y Wu J Lee MH Huang D Ong P Chan-on W Cao Y Qian CN Lim KH Ooi A Dykema K Furge K Kukongviriyapan V Sripa B Wongkham C Yongvanit P Futreal PA Bhudhisawasdi V Rozen S Tan P Teh BT 《Nature genetics》2012,44(6):690-693
Opisthorchis viverrini-related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini-related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8-3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of genome stability. This study provides insight into the mutational landscape contributing to O. viverrini-related CCA. 相似文献
922.
Steinbusch LK Schwenk RW Ouwens DM Diamant M Glatz JF Luiken JJ 《Cellular and molecular life sciences : CMLS》2011,68(15):2525-2538
Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose
transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored
in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well
as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly
affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized
at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate
uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences
in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved
in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both
GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking
components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development
of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy. 相似文献
923.
924.
Gires O 《Cellular and molecular life sciences : CMLS》2011,68(24):4009-4022
Tumor-initiating cells (TICs) have emerged as the driving force of carcinomas, which appear as hierarchically structured.
TICs as opposed to the tumor bulk display tumor forming potential, which is linked to a certain degree of self-renewal and
differentiation, both major features of stem cells. Markers such as CD44, CD133, CD24, EpCAM, CD166, Lgr5, CD47, and ALDH
have been described, which allow for the prospective enrichment of TICs. It is conspicuous that the same markers allow for
an enrichment of TICs in various entities and, on the other hand, that different combinations of these markers were independently
reported for the same tumor entity. Potential functions of these markers in the regulation of TIC phenotypes remained somewhat
neglected although they might give insights in common molecular themes of TICs. The present review discusses major TIC markers
with respect to their function and potential contributions to the tumorigenic phenotype of TICs. 相似文献
925.
Thomae AW Baltin J Pich D Deutsch MJ Ravasz M Zeller K Gossen M Hammerschmidt W Schepers A 《Cellular and molecular life sciences : CMLS》2011,68(22):3741-3756
In eukaryotes, binding of the six-subunit origin recognition complex (ORC) to DNA provides an interactive platform for the
sequential assembly of pre-replicative complexes. This process licenses replication origins competent for the subsequent initiation
step. Here, we analyze the contribution of human Orc6, the smallest subunit of ORC, to DNA binding and pre-replicative complex
formation. We show that Orc6 not only interacts with Orc1–Orc5 but also with the initiation factor Cdc6. Biochemical and imaging
experiments reveal that this interaction is required for licensing DNA replication competent. Furthermore, we demonstrate
that Orc6 contributes to the interaction of ORC with the chaperone protein HMGA1a (high mobility group protein A1a). Binding
of human ORC to replication origins is not specified at the level of DNA sequence and the functional organization of origins
is poorly understood. We have identified HMGA1a as one factor that might direct ORC to AT-rich heterochromatic regions. The
systematic analysis of the interaction between ORC and HMGA1a revealed that Orc6 interacts with the acidic C-terminus of HMGA1a
and also with its AT-hooks. Both domains support autonomous replication if targeted to DNA templates. As such, Orc6 functions
at different stages of the replication initiation process. Orc6 can interact with ORC chaperone proteins such as HMGA1a to
facilitate chromatin binding of ORC and is also an essential factor for pre-RC formation. 相似文献
926.
927.
Terhi Vihervaara Riikka-Liisa Uronen Gerd Wohlfahrt Ingemar Björkhem Elina Ikonen Vesa M. Olkkonen 《Cellular and molecular life sciences : CMLS》2011,68(3):537-551
ORP1L is an oxysterol binding homologue that regulates late endosome (LE) positioning. We show that ORP1L binds several oxysterols
and cholesterol, and characterize a mutant, ORP1L Δ560–563, defective in oxysterol binding. While wild-type ORP1L clusters
LE, ORP1L Δ560–563 induces LE scattering, which is reversed by disruption of the endoplasmic reticulum (ER) targeting FFAT
motif, suggesting that it is due to enhanced LE–ER interactions. Endosome motility is reduced upon overexpression of ORP1L.
Both wild-type ORP1L and the Δ560–563 mutant induce the recruitment of both dynactin and kinesin-2 on LE. Most of the LE decorated
by overexpressed ORP1L fail to accept endocytosed dextran or EGF, and the transfected cells display defective degradation
of internalized EGF. ORP1L silencing in macrophage foam cells enhances endosome motility and results in inhibition of [3H]cholesterol efflux to apolipoprotein A-I. These data demonstrate that LE motility and functions in both protein and lipid
transport are regulated by ORP1L. 相似文献
928.
929.
Zafirova B Wensveen FM Gulin M Polić B 《Cellular and molecular life sciences : CMLS》2011,68(21):3519-3529
NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties,
expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor
properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes
stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage.
Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that
this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D
functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation. 相似文献
930.
Ververis K Rodd AL Tang MM El-Osta A Karagiannis TC 《Cellular and molecular life sciences : CMLS》2011,68(24):4101-4114
Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid
(Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that
histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies
such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies,
involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified
that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in
cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase
inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes.
Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum histone deacetylase inhibitors
tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained
nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight
the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination
therapies for cancer. 相似文献