全文获取类型
收费全文 | 2684篇 |
免费 | 246篇 |
专业分类
2930篇 |
出版年
2023年 | 7篇 |
2022年 | 16篇 |
2021年 | 36篇 |
2020年 | 23篇 |
2019年 | 37篇 |
2018年 | 58篇 |
2017年 | 43篇 |
2016年 | 86篇 |
2015年 | 115篇 |
2014年 | 135篇 |
2013年 | 147篇 |
2012年 | 198篇 |
2011年 | 197篇 |
2010年 | 150篇 |
2009年 | 138篇 |
2008年 | 176篇 |
2007年 | 165篇 |
2006年 | 133篇 |
2005年 | 129篇 |
2004年 | 133篇 |
2003年 | 138篇 |
2002年 | 129篇 |
2001年 | 23篇 |
2000年 | 18篇 |
1999年 | 26篇 |
1998年 | 36篇 |
1997年 | 32篇 |
1996年 | 27篇 |
1995年 | 39篇 |
1994年 | 26篇 |
1993年 | 36篇 |
1992年 | 34篇 |
1991年 | 21篇 |
1990年 | 21篇 |
1989年 | 24篇 |
1988年 | 20篇 |
1987年 | 9篇 |
1986年 | 11篇 |
1985年 | 14篇 |
1984年 | 9篇 |
1983年 | 9篇 |
1982年 | 10篇 |
1981年 | 13篇 |
1980年 | 11篇 |
1979年 | 6篇 |
1978年 | 10篇 |
1977年 | 11篇 |
1975年 | 6篇 |
1972年 | 6篇 |
1970年 | 7篇 |
排序方式: 共有2930条查询结果,搜索用时 0 毫秒
31.
Lucas Spohn Christiane Fichter Martin Werner Silke Lassmann 《Journal of cell communication and signaling》2016,10(1):41-47
Background: The EGF receptor is a therapeutic target in cancer cells, whereby mutations of EGFR and/or signalling members act as predictive markers. EGFR however also exhibits dynamic changes of subcellular localization, leading to STAT5 complex formation, nuclear translocation and induction of Aurora-A expression in squamous cancer cells. We previously described high EGFR and Aurora-A expression in esophageal cancer cells. Here, we investigated subcellular localization of EGFR and STAT5 in esophageal cancer cells. Results: Quantitative immunofluorescence analyses of four esophageal cancer cell lines reflecting esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) revealed that the subcellular localization of EGFR was shifted from a membranous to cytoplasmic localization upon EGF-stimulation in OE21 (ESCC) cells. Thereby, EGFR in part co-localized with E-Cadherin. In parallel, phosphorylated STAT5-Tyr694 appeared to increase in the nucleus and to decrease at the cell membrane. In three additional cell lines, EGFR was only marginally (Kyse-410/ESCC; OE19/EAC) and weakly (OE33, EAC) detectable at the cell membrane. Partial co-localization of EGFR and E-Cadherin occurred in OE33 cells. Post EGF-stimulation, EGFR was detected in the cytoplasm, resembling endosomal compartments. Furthermore, OE19 and OE33 exhibited nuclear STAT5-Tyr694 phosphorylation upon EGF-stimulation. None of the four cell lines showed nuclear EGFR expression and localization. Conclusion: In contrast to other (squamous) cancer cells, activation of EGFR in esophageal squamous cancer cells does not result in nuclear translocation of EGFR. Still, the subcellular localization of EGFR may influence STAT5-associated signaling pathways in esophageal cancer cells and hence possibly also the responses to ErbB, respective EGFR-targeted therapies. 相似文献
32.
33.
Sindermann JR Babij P Klink JC Köbbert C Plenz G Ebbing J Fan L March KL 《American journal of physiology. Heart and circulatory physiology》2002,283(6):H2714-H2724
To study the effects of enhanced smooth muscle cell (SMC) proliferation on arterial vessel geometry in the absence of vessel trauma, we developed a transgenic mouse model expressing SV40 large T antigen under control of the 2.3-kb smooth muscle-myosin heavy chain promoter. Transgenic mice studied at ages from 3 to 13 wk showed a 3.2-fold increase in arterial wall SMC density, with 28% of SMC exhibiting proliferative cell nuclear antigen staining, confirming enhanced SMC proliferation, which was accompanied by two- to threefold increases in arterial wall areas (P < 0.05). Remarkably, despite increased vessel wall mass, the lumen area was not compromised, but rather was increased. A tightly conserved linear relationship was found between arterial circumference and wall thickness with slopes of 0.036 for both transgenics (r = 0.93, P < 0.01) and controls (r = 0.77, P < 0.01), suggesting the hypothesis that the conservation of wall stress functions as a primary determinant of adaptive arterial remodeling. This establishes a new model of adaptive vessel remodeling occurring in response to a proliferative input in the absence of mechanical injury or primary flow perturbation. 相似文献
34.
BiPPred: Combined sequence‐ and structure‐based prediction of peptide binding to the Hsp70 chaperone BiP 下载免费PDF全文
Manuel Glaser Atanas Patronov Harpreet Shah Katrin Christiane Back Marina Angelika Daake Johannes Buchner Iris Antes 《Proteins》2016,84(10):1390-1407
Substrate binding to Hsp70 chaperones is involved in many biological processes, and the identification of potential substrates is important for a comprehensive understanding of these events. We present a multi‐scale pipeline for an accurate, yet efficient prediction of peptides binding to the Hsp70 chaperone BiP by combining sequence‐based prediction with molecular docking and MMPBSA calculations. First, we measured the binding of 15mer peptides from known substrate proteins of BiP by peptide array (PA) experiments and performed an accuracy assessment of the PA data by fluorescence anisotropy studies. Several sequence‐based prediction models were fitted using this and other peptide binding data. A structure‐based position‐specific scoring matrix (SB‐PSSM) derived solely from structural modeling data forms the core of all models. The matrix elements are based on a combination of binding energy estimations, molecular dynamics simulations, and analysis of the BiP binding site, which led to new insights into the peptide binding specificities of the chaperone. Using this SB‐PSSM, peptide binders could be predicted with high selectivity even without training of the model on experimental data. Additional training further increased the prediction accuracies. Subsequent molecular docking (DynaDock) and MMGBSA/MMPBSA‐based binding affinity estimations for predicted binders allowed the identification of the correct binding mode of the peptides as well as the calculation of nearly quantitative binding affinities. The general concept behind the developed multi‐scale pipeline can readily be applied to other protein‐peptide complexes with linearly bound peptides, for which sufficient experimental binding data for the training of classical sequence‐based prediction models is not available. Proteins 2016; 84:1390–1407. © 2016 Wiley Periodicals, Inc. 相似文献
35.
The Susceptibility of Pseudomonas aeruginosa Strains from Cystic Fibrosis Patients to Bacteriophages
Christiane Essoh Yann Blouin Guillaume Loukou Arsher Cablanmian Serge Lathro Elizabeth Kutter Hoang Vu Thien Gilles Vergnaud Christine Pourcel 《PloS one》2013,8(4)
Phage therapy may become a complement to antibiotics in the treatment of chronic Pseudomonas aeruginosa infection. To design efficient therapeutic cocktails, the genetic diversity of the species and the spectrum of susceptibility to bacteriophages must be investigated. Bacterial strains showing high levels of phage resistance need to be identified in order to decipher the underlying mechanisms. Here we have selected genetically diverse P. aeruginosa strains from cystic fibrosis patients and tested their susceptibility to a large collection of phages. Based on plaque morphology and restriction profiles, six different phages were purified from “pyophage”, a commercial cocktail directed against five different bacterial species, including P. aeruginosa. Characterization of these phages by electron microscopy and sequencing of genome fragments showed that they belong to 4 different genera. Among 47 P. aeruginosa strains, 13 were not lysed by any of the isolated phages individually or by pyophage. We isolated two new phages that could lyse some of these strains, and their genomes were sequenced. The presence/absence of a CRISPR-Cas system (Clustered Regularly Interspaced Short Palindromic Repeats and Crisper associated genes) was investigated to evaluate the role of the system in phage resistance. Altogether, the results show that some P. aeruginosa strains cannot support the growth of any of the tested phages belonging to 5 different genera, and suggest that the CRISPR-Cas system is not a major defence mechanism against these lytic phages. 相似文献
36.
Schroeder CP Goeldner EM Schulze-Forster K Eickhoff CA Holtermann P Heidecke H 《Biological trace element research》2004,99(1-3):17-25
Selenite is frequently used in combination with cancer chemotherapeutic agents to reduce side effects. However, the cytoprotective
activity of selenite may also reduce the efficacy of chemotherapeutic drugs on tumor cells. This study was designed to examine
the effects of selenite combined with cytotoxic agents used in clinical protocols [e.g., doxorubicine, docetaxel, 5-fluorouracil
(5-FU), methotrexate (MTX), mafosphamide, mitomycin C, gemcitabine, etoposide, cisplatin, irinotecan, and oxaliplatin] on
the proliferation of various carcinoma cell types. The data demonstrated that selenite had no marked effects on the antiproliferative
activity of docetaxel, doxorubicine, 5-FU, MTX, and mafosphamide in MDA-MB-231 breast cancer cells. Likewise, no consistent
changes were observed in A549 lung cancer cell proliferation when selenite was combined with cisplatin, etoposide, gemcitabine,
or mitomycin C. On the other hand, selenite potentiated the cytotoxicity of 5-FU, oxaliplatin, and irinotecan in HCT116 colon
cancer cells by approx 1.1-fold, 2.7-fold, and 2.6-fold, respectively. In SW620 colon cancer cells, selenite induced a 1.5-fold
and 4.3-fold increase of the antiproliferative activity of 5-FU and oxaliplatin, respectively. Whereas irinotecan showed no
effects on SW620 cell growth, a combination with selenite resulted in 23% inhibition. Our results indicate that selenite did
not reduce the antiproliferative activity of chemotherapeutic agents in vitro. In addition, selenite was able to increase
the inhibitory activity of docetaxel in A549 lung cancer cells, and of 5-FU, oxaliplatin, and irinotecan in HCT116 and SW620
colon cancer cells implying selenite is potentially useful as an adjuvant chemotherapeutic agent. 相似文献
37.
38.
Edward B. Blanchard Maria L. Peters Christiane Hermann Shannon M. Turner Todd C. Buckley Kristine Barton Mark P. Dentinger 《Applied psychophysiology and biofeedback》1997,22(4):227-245
In order to test for the specific therapeutic effects of thermal biofeedback (TBF) for hand warming on vascular headache (HA),
70 patients with chronic vascular HA were randomly assigned to TBF for hand warming, TBF for hand cooling, TBF for stabilization
of hand temperature, or biofeedback to suppress alpha in the EEG. Patients in each condition initially had high levels of
expectation of therapeutic benefit and found the treatment rationales highly credible. Participants in each condition received
12 treatment sessions on a twice-per-week basis. Based on daily HA diary data gathered for 4 weeks prior to treatment and
4 weeks after treatment, HA Index was significantly (p=.003) reduced as was HA medication consumption. There were no differential
reducations in HA Index or Medication Index among the four conditions. Global self-reports of improvement gathered at the
end of the post-treatment monitoring period also did not differ among the four conditions. We were unable to demonstrate a
specific effect of TBF for hand warming on vascular HA activity. 相似文献
39.
Christiane Lacombe Viviane Viallard Stphane Schaak Herv Paris 《Biology of the cell / under the auspices of the European Cell Biology Organization》1996,88(3):123-129
Summary— As evidenced by pertussis toxin-catalysed [32P]ADP-ribosylation, immunoblotting and Northern blot, the human adenocarcinoma intestinal cell line Caco-2 expresses Gi2 and Gi3 proteins. The localization of these two Gis within the cell was investigated by using subcellular fractionation and confocal microscopy on intact cell layer. A brush-border rich fraction and a pellet containing the remaining cellular membranes were prepared. [32P]ADP-ribosylation and immunoblotting demonstrated the presence of both αi2 and αi3 in these two preparations. Immunofluorescence studies performed on intact cells grown on Transwell filters and viewed by confocal microscopy further confirmed the localization of αi3-subunit on basolateral as well as on apical membranes. In contrast, αi2-subunit was shown to accumulate mainly in the intra-cellular compartment while only faint staining of the plasma membrane was detectable. Based upon double-labelling experiments with antibody against rough endoplasmic reticulum (RER), there is a strong possibility that intra-cellular sites of αi2-subunit correspond to association with RER membranes. 相似文献