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991.
Brain and vascular cells form a functionally integrated signalling network that is known as the neurovascular unit (NVU). The signalling (autocrine, paracrine and juxtacrine) between different elements of this unit, especially in humans, is difficult to disentangle in vivo. Developing representative in vitro models is therefore essential to better understand the cellular interactions that govern the neurovascular environment. We here describe a novel approach to assay these cellular interactions by combining a human adult cerebral microvascular endothelial cell line (hCMEC/D3) with a fetal ganglionic eminence-derived neural stem cell (hNSC) line. These cell lines provide abundant homogeneous populations of cells to produce a consistently reproducible in vitro model of endothelial morphogenesis and the ensuing NVU. Vasculature-like structures (VLS) interspersed with patches of differentiating neural cells only occurred when hNSCs were seeded onto a differentiated endothelium. These VLS emerged within 3 days of coculture and by day 6 were stabilizing. After 7 days of coculture, neuronal differentiation of hNSCs was increased 3-fold, but had no significant effect on astrocyte or oligodendrocyte differentiation. ZO1, a marker of adherens and tight junctions, was highly expressed in both undifferentiated and differentiated endothelial cells, but the adherens junction markers CD31 and VE-cadherin were significantly reduced in coculture by approximately 20%. A basement membrane, consisting of laminin, vitronectin, and collagen I and IV, separated the VLS from neural patches. This simple assay can assist in elucidating the cellular and molecular signaling involved in the formation of VLS, as well as the enhancement of neuronal differentiation through endothelial signaling. 相似文献
992.
Kuan-Han Lee Yeh-Long Chen Bor-Ruey Huang Qing-Yu Zhu Ting-Chao Chou Cherng-Chyi Tzeng 《Nucleosides, nucleotides & nucleic acids》2013,32(6):1407-1416
Abstract A direct alkylation of trimethylsilylated pyrimidines and azapyrimidines with 1-azido-3-benzyloxy-2-chloromethoxypropane gave acyclic analogues of AZT in a good overall yield. None of the compounds exhibited significant antiviral activity against human immunodeficiency virus and herpes simplex virus. 相似文献
993.
Alexander A. Krayevsky Natalie B. Tarussova Qing-Yu Zhu Pedro Vidal Ting-Chao Chou Penny Baron 《Nucleosides, nucleotides & nucleic acids》2013,32(2-4):177-196
Abstract A number of nucleoside 5′-hydrogerphosphonates and nucleoside 5′-methylphosphonates were prepared, to study their ability to inhibit replication of HIV-1. Two compounds, the 5′-hydrogenphosphonate of 3′-azido-3′-deoxythymidine (AZT-HP, IVc) and of 3′-deoxy-3′-fluorothymidine (FLT-HP, IVa), exhibit potent anti-HIV-1 activity with selectivity indices similar to or better than those of their parent nucleosides. 相似文献
994.
Mao-Meng Tiao Chia-Wei Liou Li-Tung Huang Pei-Wen Wang Tsu-Kung Lin Jin-Bor Chen Yao-Min Chou Ying-Hsien Huang Hung-Yu Lin Chao-Long Chen Jiin-Haur Chuang 《PLoS genetics》2013,9(8)
Mitochondrial dysfunction has been implicated in the pathogenesis of biliary atresia (BA). This study aimed to determine whether a specific mitochondrial DNA haplogroup is implicated in the pathogenesis and prognosis of BA. We determined 40 mitochondrial single nucleotide polymorphisms in 15 major mitochondrial haplogroups by the use of 24-plex PCR and fluorescent beads combined with sequence-specific oligonucleotide probes in 71 patients with BA and in 200 controls in the Taiwanese population of ethnic Chinese background. The haplogroup B4 and E prevalence were significantly lower and higher respectively, in the patients with BA than in the controls (odds ratios, 0.82 [p = 0.007] and 7.36 [p = 0.032] respectively) in multivariate logistic-regression analysis. The 3-year survival rate with native liver was significantly lower in haplogroup E than the other haplogroups (P = 0.037). A cytoplasmic hybrid (cybrid) was obtained from human 143B osteosarcoma cells devoid of mtDNA (ρ0 cell) and was fused with specific mtDNA bearing E and B4 haplogroups donated by healthy Taiwanese subjects. Chenodeoxycholic acid treatment resulted in significantly lower free radical production, higher mitochondrial membrane potential, more viable cells, and fewer apoptotic cybrid B4 cells than parental 143B and cybrid E cells. Bile acid treatment resulted in a significantly greater protective mitochondrial reaction with significantly higher mitochondrial DNA copy number and mitofusin 1 and 2 concentrations in cybrid B4 and parental cells than in cybrid E cells. The results of the study suggested that the specific mitochondrial DNA haplogroups B4 and E were not only associated with lower and higher prevalence of BA respectively, in the study population, but also with differential susceptibility to hydrophobic bile acid in the cybrid harboring different haplogroups. 相似文献
995.
Kwang-Yu Chang Shan-Yin Tsai Shang-Hung Chen Hsiao-Hui Tsou Chia-Jui Yen Ko-Jiunn Liu Hsun-Lang Fang Hung-Chang Wu Bin-Fay Chuang Shao-Wen Chou Careen K Tang Shyun-Yeu Liu Pei-Jung Lu Ching-Yu Yen Jang-Yang Chang 《Journal of biomedical science》2013,20(1):43
Background
Dysregulated epidermal growth factor receptor (EGFR)-phosphoinositide-3-kinase (PI3K)-AKT signaling is considered pivotal for oral cancer, and the pathway is a potential candidate for therapeutic targeting.Results
A total of 108 archival samples which were from surgically resected oral cancer were examined. Immunohistochemical staining showed the protein expression of membranous wild-type EGFR and cytoplasmic phosphorylated AKT was detected in 63.9% and 86.9% of the specimens, respectively. In 49.1% of the samples, no phosphatase and tensin homolog (PTEN) expression was detected. With regard to the EGFR variant III (EGFRvIII), 75.0% of the samples showed positive expression for moderate to severe staining, 31.5% of which had high expression levels. Real-time polymerase chain reaction assays for gene copy number assessment of PIK3CA revealed that 24.8% of the samples had alterations, and of EGFR showed that 49.0% had amplification. Direct sequencing of PIK3CA gene showed 2.3% of the samples had a hotspot point mutation. Statistical assessment showed the expression of the EGFRvIII correlated with the T classification and TNM stage. The Kaplan-Meier analyses for patient survival showed that the individual status of phosphorylated AKT and EGFRvIII led to significant differences in survival outcome. The multivariate analysis indicated that phosphorylated AKT, EGFRvIII expression and disease stage were patient survival determinants.Conclusions
Aberrations in the EGFR-PI3K-AKT pathway were frequently found in oral cancers. EGFRvIII and phosphorylated AKT were predictors for the patient survival and clinical outcome. 相似文献996.
Srikanth Nagalla Jeff W Chou Mark C Willingham Jimmy Ruiz James P Vaughn Purnima Dubey Timothy L Lash Stephen J Hamilton-Dutoit Jonas Bergh Christos Sotiriou Michael A Black Lance D Miller 《Genome biology》2013,14(4):R34
Background
Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified.Results
To investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes.Conclusions
These findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications. 相似文献997.
998.
Huang JK Chou CT Chang HT Shu SS Kuo CC Tsai JY Liao WC Wang JL Lin KL Lu YC Chen IS Liu SI Ho CM Jan CR 《Journal of receptor and signal transduction research》2011,31(3):247-255
Effect of the carcinogen thapsigargin on human prostate cancer cells is unclear. This study examined if thapsigargin altered basal [Ca2?](i) levels in suspended PC3 human prostate cancer cells by using fura-2 as a Ca2?-sensitive fluorescent probe. Thapsigargin at concentrations between 10?nM and 10 μM increased [Ca2?](i) in a concentration-dependent fashion. The Ca2? signal was reduced partly by removing extracellular Ca2? indicating that Ca2? entry and release both contributed to the [Ca2?](i) rise. This Ca2? influx was inhibited by suppression of phospholipase A2, but not by inhibition of store-operated Ca2? channels or by modulation of protein kinase C activity. In Ca2?-free medium, pretreatment with the endoplasmic reticulum Ca2? pump inhibitor 2,5-di-(t-butyl)-1,4-hydroquinone (BHQ) nearly abolished thapsigargin-induced Ca2? release. Conversely, pretreatment with thapsigargin greatly reduced BHQ-induced [Ca2?](i) rise, suggesting that thapsigargin released Ca2? from the endoplasmic reticulum. Inhibition of phospholipase C did not change thapsigargin-induced [Ca2?](i) rise. At concentrations of 1-10 μM, thapsigargin induced cell death that was partly reversed by chelation of Ca2? with BAPTA/AM. Annexin V/propidium iodide staining data suggest that apoptosis was partly responsible for thapsigargin-induced cell death. Together, in PC3 human prostate cancer cells, thapsigargin induced [Ca2?](i) rises by causing phospholipase C-independent Ca2? release from the endoplasmic reticulum and Ca2? influx via phospholipase A2-sensitive Ca2? channels. Thapsigargin also induced cell death via Ca2?-dependent pathways and Ca2?-independent apoptotic pathways. 相似文献
999.
Hsu JM Chen CT Chou CK Kuo HP Li LY Lin CY Lee HJ Wang YN Liu M Liao HW Shi B Lai CC Bedford MT Tsai CH Hung MC 《Nature cell biology》2011,13(2):174-181
Epidermal growth factor receptor (EGFR) can undergo post-translational modifications, including phosphorylation, glycosylation and ubiquitylation, leading to diverse physiological consequences and modulation of its biological activity. There is increasing evidence that methylation may parallel other post-translational modifications in the regulation of various biological processes. It is still not known, however, whether EGFR is regulated by this post-translational event. Here, we show that EGFR Arg?1175 is methylated by an arginine methyltransferase, PRMT5. Arg?1175 methylation positively modulates EGF-induced EGFR trans-autophosphorylation at Tyr?1173, which governs ERK activation. Abolishment of Arg?1175 methylation enhances EGF-stimulated ERK activation by reducing SHP1 recruitment to EGFR, resulting in augmented cell proliferation, migration and invasion of EGFR-expressing cells. Therefore, we propose a model in which the regulatory crosstalk between PRMT5-mediated Arg?1175 methylation and EGF-induced Tyr?1173 phosphorylation attenuates EGFR-mediated ERK activation. 相似文献
1000.
Invasive lobular cancer (ILC) tends to be significantly larger in size with significantly more positive lymph nodes, whereas ILC has a significantly more favorable outcome, compared to stage-matched invasive ductal carcinoma (IDC). The mechanism accounting for such differences remains elusive. Based on morphological, immunohistochemical, and molecular studies of over 1,000 cases of human breast cancers, we hypothesize that the differences may result from the structural and/or functional differences of their surrounding myoepithelial cell layers, which dictate lobular and ductal tumor cells to follow different pathways of invasion or metastasis. The background, rationale, supportive data, and implications of our hypothesis are presented and discussed. 相似文献