全文获取类型
收费全文 | 4929篇 |
免费 | 400篇 |
国内免费 | 3篇 |
专业分类
5332篇 |
出版年
2024年 | 5篇 |
2023年 | 31篇 |
2022年 | 99篇 |
2021年 | 151篇 |
2020年 | 83篇 |
2019年 | 97篇 |
2018年 | 105篇 |
2017年 | 94篇 |
2016年 | 183篇 |
2015年 | 294篇 |
2014年 | 329篇 |
2013年 | 365篇 |
2012年 | 461篇 |
2011年 | 404篇 |
2010年 | 275篇 |
2009年 | 231篇 |
2008年 | 306篇 |
2007年 | 305篇 |
2006年 | 270篇 |
2005年 | 231篇 |
2004年 | 222篇 |
2003年 | 243篇 |
2002年 | 194篇 |
2001年 | 30篇 |
2000年 | 18篇 |
1999年 | 36篇 |
1998年 | 44篇 |
1997年 | 26篇 |
1996年 | 26篇 |
1995年 | 25篇 |
1994年 | 15篇 |
1993年 | 18篇 |
1992年 | 19篇 |
1991年 | 7篇 |
1989年 | 7篇 |
1988年 | 4篇 |
1987年 | 6篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1981年 | 3篇 |
1980年 | 3篇 |
1979年 | 4篇 |
1976年 | 3篇 |
1975年 | 5篇 |
1973年 | 4篇 |
1972年 | 6篇 |
1969年 | 4篇 |
1967年 | 3篇 |
1958年 | 2篇 |
1931年 | 2篇 |
排序方式: 共有5332条查询结果,搜索用时 15 毫秒
991.
Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors 总被引:4,自引:0,他引:4
Han Y Giroux A Grimm EL Aspiotis R Francoeur S Bayly CI Mckay DJ Roy S Xanthoudakis S Vaillancourt JP Rasper DM Tam J Tawa P Thornberry NA Paterson EP Garcia-Calvo M Becker JW Rotonda J Nicholson DW Zamboni RJ 《Bioorganic & medicinal chemistry letters》2004,14(3):805-808
The discovery of a series of potent, selective and reversible dipeptidyl caspase-3 inhibitors are reported. The iterative discovery process of using combinatorial chemistry, parallel synthesis, moleculare modelling and structural biology will be discussed. 相似文献
992.
Sophie Calderari Massimiliano Ria Christelle Gérard Tatiane C. Nogueira Olatz Villate Stephan C. Collins Helen Neil Nicolas Gervasi Christophe Hue Nicolas Suarez-Zamorano Cécilia Prado Miriam Cnop Marie-Thérèse Bihoreau Pamela J. Kaisaki Jean-Baptiste Cazier Cécile Julier Mark Lathrop Michel Werner Dominique Gauguier 《Genomics》2018,110(2):98-111
The GLIS family zinc finger 3 isoform (GLIS3) is a risk gene for Type 1 and Type 2 diabetes, glaucoma and Alzheimer's disease endophenotype. We identified GLIS3 binding sites in insulin secreting cells (INS1) (FDR q < 0.05; enrichment range 1.40–9.11 fold) sharing the motif wrGTTCCCArTAGs, which were enriched in genes involved in neuronal function and autophagy and in risk genes for metabolic and neuro-behavioural diseases. We confirmed experimentally Glis3-mediated regulation of the expression of genes involved in autophagy and neuron function in INS1 and neuronal PC12 cells. Naturally-occurring coding polymorphisms in Glis3 in the Goto-Kakizaki rat model of type 2 diabetes were associated with increased insulin production in vitro and in vivo, suggestive alteration of autophagy in PC12 and INS1 and abnormal neurogenesis in hippocampus neurons. Our results support biological pleiotropy of GLIS3 in pathologies affecting β-cells and neurons and underline the existence of trans?nosology pathways in diabetes and its co-morbidities. 相似文献
993.
994.
995.
The E3 ubiquitin ligase CHIP is involved in protein triage, serving as a co-chaperone for refolding as well as catalyzing ubiquitination of substrates. CHIP functions with both the stress induced Hsp70 and constitutive Hsc70 chaperones, and also plays a role in maintaining their balance in the cell. When the chaperones carry no client proteins, CHIP catalyzes their polyubiquitination and subsequent proteasomal degradation. Although Hsp70 and Hsc70 are highly homologous in sequence and similar in structure, CHIP mediated ubiquitination promotes degradation of Hsp70 with a higher efficiency than for Hsc70. Here we report a detailed and systematic investigation to characterize if there are significant differences in the CHIP in vitro ubiquitination of human Hsp70 and Hsc70. Proteomic analysis by mass spectrometry revealed that only 12 of 39 detectable lysine residues were ubiquitinated by UbcH5a in Hsp70 and only 16 of 45 in Hsc70. The only conserved lysine identified as ubiquitinated in one but not the other heat shock protein was K159 in Hsc70. Ubiquitination assays with K-R ubiquitin mutants showed that multiple Ub chain types are formed and that the distribution is different for Hsp70 versus Hsc70. CHIP ubiquitination with the E2 enzyme Ube2W is predominantly directed to the N-terminal amine of the substrate; however, some internal lysine modifications were also detected. Together, our results provide a detailed view of the differences in CHIP ubiquitination of these two very similar proteins, and show a clear example where substantial differences in ubiquitination can be generated by a single E3 ligase in response to not only different E2 enzymes but subtle differences in the substrate. 相似文献
996.
Ivan Laprevotte Sophie Brouillet Christophe Terzian Alain Hénaut 《Journal of molecular evolution》1997,44(2):214-225
A computer-assisted analysis was made of 24 complete nucleotide sequences selected from the vertebrate retroviruses to represent
the ten viral groups. The conclusions of this analysis extend and strengthen the previously made hypothesis on the Moloney
murine leukemia virus: The evolution of the nucleotide sequence appears to have occurred mainly through at least three overlapping
levels of duplication: (1) The distributions of overrepresented (3–6)-mers are consistent with the universal rule of a trend
toward TG/CT excess and with the persistence of a certain degree of symmetry between the two strands of DNA. This suggests
one or several original tandemly repeated sequences and some inverted duplications. (2) The existence of two general core
consensuses at the level of these (3–6)-mers supports the hypothesis of a common evolutionary origin of vertebrate retroviruses.
Consensuses more specific to certain sequences are compatible with phylogenetic trees established independently. The consensuses
could correspond to intermediary evolutionary stages. (3) Most of the (3–6)-mers with a significantly higher than average
frequency appear to be internally repeated (with monomeric or oligomeric internal iterations) and seem to be at least partly
the cause of the bias observed by other researchers at the level of retroviral nucleotide composition. They suggest a third
evolutionary stage by slippage-like stepwise local duplications.
Received: 3 January 1996 / Accepted: 27 March 1996 相似文献
997.
Notch genes encode evolutionarily conserved large, single transmembrane receptors, which regulate many cell fate decisions and differentiation processes during fetal and postnatal life. Multiple Notch receptors and ligands are expressed in both developing and adult epidermis and hair follicles. Proliferation and differentiation of these two ectodermal-derived structures have been proposed to be controlled in part by the Notch pathway. Whether Notch signaling is involved in postnatal hair homeostasis is currently unknown. Here, we investigate and compare the role of the Notch1 receptor during embryonic hair follicle development and postnatal hair homeostasis using Cre-loxP based tissue specific and inducible loss-of-function approaches. During embryonic development, tissue-specific ablation of Notch1 does not perturb formation and patterning of hair follicle placodes. However, Notch1 deficient hair follicles invaginate prematurely into the dermis. Embryonic as well as postnatal inactivation of Notch1 shortly after birth or in adult mice results in almost complete hair loss followed by cyst formation. The first hair cycle of Notch1 deficient mice is characterized by shortened anagen and a premature entry into catagen. These data show that Notch1 is essential for late stages of hair follicle development during embryogenesis as well as for post-natal hair follicle development and hair homeostasis. 相似文献
998.
999.
Sophie Winkler Rupert Derler Bernd Gesslbauer Elmar Krieger Andreas J. Kungl 《Biochimica et Biophysica Acta (BBA)/General Subjects》2019,1863(3):528-533
Background
Binding of chemokines to glycosaminoglycans (GAGs) is a crucial step in leukocyte recruitment to inflamed tissues.Methods
A disaccharide compositional analysis of the HS dp6 fraction in combination with MS analysis of the CCL2-depleted dp6 fraction was the basis for target GAG ligand structure suggestions. Four experimentally-derived heparan sulfate hexasaccharides, two potentially chemokine-specific and two unspecific, have been docked to CCL2. Subsequent 300?ns molecular dynamics simulations were used to improve the docked complexes.Results
Hexasaccharides with four sulfations and no acetylations are suggested for selective and high affinity chemokine binding. Using the Antithromin-III/heparin complex as positive control for docking, we were able to recover the correct complex structure only if the previously liganded ATIII structure was used as input. Since the liganded structure is not known for a CCL2-GAG complex, we investigated if molecular dynamics simulations could improve initial docking results. We found that all four GAG oligosaccharides ended up in close contact with the known binding residues after about 100?ns simulation time.Conclusions
A discrimination of specific vs. unspecific CCL2 GAG ligands is not possible by this approach. Long-time molecular dynamics simulations are, however, well suited to capture the delicate enthalpy/entropy balance of GAG binding and improve results obtained from docking.General significance
With the comparison of two methods, MS-based ligand identification and molecular modelling, we have shown the current limitations of our molecular understanding of complex ligand binding which is could be due to the numerical inaccessibility of ligand-induced protein conformational changes. 相似文献1000.
Antonia Sophie Wenners Keyur Mehta Sibylle Loibl Hyerim Park Berit Mueller Norbert Arnold Sigrid Hamann Joerg Weimer Beyhan Ataseven Silvia Darb-Esfahani Christian Schem Christoph Mundhenke Fariba Khandan Christoph Thomssen Walter Jonat Hans-Juergen Holzhausen Gunther von Minckwitz Carsten Denkert Maret Bauer 《PloS one》2012,7(10)
In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC. 相似文献