全文获取类型
收费全文 | 22875篇 |
免费 | 1088篇 |
国内免费 | 1005篇 |
专业分类
系统科学 | 1789篇 |
丛书文集 | 528篇 |
教育与普及 | 458篇 |
理论与方法论 | 335篇 |
现状及发展 | 968篇 |
研究方法 | 70篇 |
综合类 | 20812篇 |
自然研究 | 8篇 |
出版年
2024年 | 87篇 |
2023年 | 188篇 |
2022年 | 338篇 |
2021年 | 315篇 |
2020年 | 229篇 |
2019年 | 105篇 |
2018年 | 867篇 |
2017年 | 896篇 |
2016年 | 643篇 |
2015年 | 509篇 |
2014年 | 623篇 |
2013年 | 596篇 |
2012年 | 901篇 |
2011年 | 1611篇 |
2010年 | 1489篇 |
2009年 | 1232篇 |
2008年 | 1422篇 |
2007年 | 1592篇 |
2006年 | 720篇 |
2005年 | 771篇 |
2004年 | 677篇 |
2003年 | 701篇 |
2002年 | 830篇 |
2001年 | 768篇 |
2000年 | 653篇 |
1999年 | 895篇 |
1998年 | 689篇 |
1997年 | 716篇 |
1996年 | 643篇 |
1995年 | 527篇 |
1994年 | 541篇 |
1993年 | 447篇 |
1992年 | 357篇 |
1991年 | 355篇 |
1990年 | 287篇 |
1989年 | 259篇 |
1988年 | 230篇 |
1987年 | 142篇 |
1986年 | 58篇 |
1985年 | 20篇 |
1984年 | 9篇 |
1979年 | 4篇 |
1977年 | 2篇 |
1974年 | 2篇 |
1973年 | 3篇 |
1968年 | 2篇 |
1967年 | 3篇 |
1966年 | 2篇 |
1964年 | 3篇 |
1963年 | 3篇 |
排序方式: 共有10000条查询结果,搜索用时 328 毫秒
971.
Margherita Ratti Andrea Lampis Jens C. Hahne Rodolfo Passalacqua Nicola Valeri 《Cellular and molecular life sciences : CMLS》2018,75(22):4151-4162
Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient. 相似文献
972.
973.
Sei Yoshida Regina Pacitto Ken Inoki Joel Swanson 《Cellular and molecular life sciences : CMLS》2018,75(7):1227-1239
The growth and proliferation of metazoan cells are driven by cellular nutrient status and by extracellular growth factors. Growth factor receptors on cell surfaces initiate biochemical signals that increase anabolic metabolism and macropinocytosis, an actin-dependent endocytic process in which relatively large volumes of extracellular solutes and nutrients are internalized and delivered efficiently into lysosomes. Macropinocytosis is prominent in many kinds of cancer cells, and supports the growth of cells transformed by oncogenic K-Ras. Growth factor receptor signaling and the overall metabolic status of the cell are coordinated in the cytoplasm by the mechanistic target-of-rapamycin complex-1 (mTORC1), which positively regulates protein synthesis and negatively regulates molecular salvage pathways such as autophagy. mTORC1 is activated by two distinct Ras-related small GTPases, Rag and Rheb, which associate with lysosomal membranes inside the cell. Rag recruits mTORC1 to the lysosomal surface where Rheb directly binds to and activates mTORC1. Rag is activated by both lysosomal luminal and cytosolic amino acids; Rheb activation requires phosphoinositide 3-kinase, Akt, and the tuberous sclerosis complex-1/2. Signals for activation of Rag and Rheb converge at the lysosomal membrane, and several lines of evidence support the idea that growth factor-dependent endocytosis facilitates amino acid transfer into the lysosome leading to the activation of Rag. This review summarizes evidence that growth factor-stimulated macropinocytosis is essential for amino acid-dependent activation of mTORC1, and that increased solute accumulation by macropinocytosis in transformed cells supports unchecked cell growth. 相似文献
974.
975.
Lin Z Bei JX Shen M Li Q Liao Z Zhang Y Lv Q Wei Q Low HQ Guo YM Cao S Yang M Hu Z Xu M Wang X Wei Y Li L Li C Li T Huang J Pan Y Jin O Wu Y Wu J Guo Z He P Hu S Wu H Song H Zhan F Liu S Gao G Liu Z Li Y Xiao C Li J Ye Z He W Liu D Shen L Huang A Wu H Tao Y Pan X Yu B Tai ES Zeng YX Ren EC Shen Y Liu J Gu J 《Nature genetics》2012,44(1):73-77
To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis. 相似文献
976.
Zhang Z Lee JC Lin L Olivas V Au V LaFramboise T Abdel-Rahman M Wang X Levine AD Rho JK Choi YJ Choi CM Kim SW Jang SJ Park YS Kim WS Lee DH Lee JS Miller VA Arcila M Ladanyi M Moonsamy P Sawyers C Boggon TJ Ma PC Costa C Taron M Rosell R Halmos B Bivona TG 《Nature genetics》2012,44(8):852-860
Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer. 相似文献
977.
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
978.
979.
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
980.
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