全文获取类型
收费全文 | 1244篇 |
免费 | 72篇 |
专业分类
1316篇 |
出版年
2024年 | 2篇 |
2023年 | 7篇 |
2022年 | 22篇 |
2021年 | 42篇 |
2020年 | 12篇 |
2019年 | 28篇 |
2018年 | 58篇 |
2017年 | 36篇 |
2016年 | 48篇 |
2015年 | 64篇 |
2014年 | 89篇 |
2013年 | 98篇 |
2012年 | 96篇 |
2011年 | 107篇 |
2010年 | 60篇 |
2009年 | 41篇 |
2008年 | 84篇 |
2007年 | 71篇 |
2006年 | 64篇 |
2005年 | 56篇 |
2004年 | 48篇 |
2003年 | 42篇 |
2002年 | 44篇 |
2001年 | 7篇 |
2000年 | 5篇 |
1999年 | 6篇 |
1998年 | 8篇 |
1997年 | 5篇 |
1996年 | 7篇 |
1995年 | 9篇 |
1994年 | 3篇 |
1993年 | 5篇 |
1992年 | 4篇 |
1991年 | 4篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1964年 | 1篇 |
1962年 | 1篇 |
排序方式: 共有1316条查询结果,搜索用时 0 毫秒
91.
Protein synthesis on the ribosome involves a number of external protein factors that bind at its functional sites. One key factor is the elongation factor G (EF-G) that facilitates the translocation of transfer RNAs between their binding sites, as well as advancement of the messenger RNA by one codon. The details of the EF-G/ribosome diffusional encounter and EF-G association pathway still remain unanswered. Here, we applied Brownian dynamics methodology to study bimolecular association in the bacterial EF-G/70S ribosome system. We estimated the EF-G association rate constants at 150 and 300 mM monovalent ionic strengths and obtained reasonable agreement with kinetic experiments. We have also elucidated the details of EF-G/ribosome association paths and found that positioning of the L11 protein of the large ribosomal subunit is likely crucial for EF-G entry to its binding site. 相似文献
92.
Gustav ?stner Veronica Lindstr?m Per Hjort Christensen Maciej Kozak Magnus Abrahamson Anders Grubb 《The Journal of biological chemistry》2013,288(23):16438-16450
The pathophysiological process in amyloid disorders usually involves the transformation of a functional monomeric protein via potentially toxic oligomers into amyloid fibrils. The structure and properties of the intermediary oligomers have been difficult to study due to their instability and dynamic equilibrium with smaller and larger species. In hereditary cystatin C amyloid angiopathy, a cystatin C variant is deposited in arterial walls and cause brain hemorrhage in young adults. In the present investigation, we use redox experiments of monomeric cystatin C, stabilized against domain swapping by an intramolecular disulfide bond, to generate stable oligomers (dimers, trimers, tetramers, decamers, and high molecular weight oligomers). These oligomers were characterized concerning size by gel filtration, polyacrylamide gel electrophoresis, and mass spectrometry, shape by electron and atomic force microscopy, and, function by assays of their capacity to inhibit proteases. The results showed the oligomers to be highly ordered, domain-swapped assemblies of cystatin C and that the oligomers could not build larger oligomers, or fibrils, without domain swapping. The stabilized oligomers were used to induce antibody formation in rabbits. After immunosorption, using immobilized monomeric cystatin C, and elution from columns with immobilized cystatin C oligomers, oligomer-specific antibodies were obtained. These could be used to selectively remove cystatin C dimers from biological fluids containing both dimers and monomers. 相似文献
93.
Nowak-Stępniowska A Wiktorska K Małecki M Romiszewska A Padzik-Graczyk A 《Acta biochimica Polonica》2011,58(4):497-505
Porphyrin photosensitizers tend to localize in mitochondria. The depolarization of mitochondrial membrane is one of the early stages of apoptosis and Laser Scanning Fluorescence Microscopy allows to determine changes in transmembrane mitochondrial potential under influence of PDT depending on the kind of photosensitizer (PP(Arg)(2), Hp(Arg)(2)), the energy dose (5, 10, 30 and 50 J/cm(2)) and time periods (24 and 48 hours after irradiation) in the LNCaP (lymphonodal metastasis of prostate carcinoma, the androgen dependent cell line). Cyototoxicity induced by PP(Arg)(2)- and Hp(Arg)(2)-based PDT depending on energy dose and time after irradiation in prostate carcinoma is determined with MTT. Generally, it was shown that lower energy doses induce greater changes in transmembrane mitochondrial potential. Hp(Arg)(2)-based PDT was more effective causing greater mitochondrial membrane depolarization and cell viability decrease in comparison to PP(Arg)(2)-mediated PDT (in the case of maximal nontoxic photosensitizer doses used). 相似文献
94.
Tomasz B. Owczarek Jaros?aw Suchanski Bartosz Pula Alicja M. Kmiecik Marek Chadalski Aleksandra Jethon Piotr Dziegiel Maciej Ugorski 《PloS one》2013,8(12)
It was recently proposed that UDP-galactose:ceramide galactosyltransferase (UGT8), enzyme responsible for synthesis of galactosylceramide (GalCer), is a significant index of tumor aggressiveness and a potential marker for the prognostic evaluation of lung metastases in breast cancer. To further reveal the role of UGT8 and GalCer in breast cancer progression, tumorigenicity and metastatic potential of control MDA-MB-231 cells (MDA/LUC) and MDA-MB-231 cells (MDA/LUC-shUGT8) with highly decreased expression of UGT8 and GalCer after stable expression of shRNA directed against UGT8 mRNA was studied in vivo in athymic nu/nu mice. Control MDA/LUC cells formed tumors and metastatic colonies much more efficiently in comparison to MDA/LUC-shUGT8 cells with suppressed synthesis of GalCer after their, respectively, orthotopic and intracardiac transplantation. These findings indicate that UGT8 and GalCer have a profound effect on tumorigenic and metastatic properties of breast cancer cells. In accordance with this finding, immunohistochemical staining of tumor specimens revealed that high expression of UGT8 accompanied by accumulation of GalCer in MDA-MB-231 cells is associated with a much higher proliferative index and a lower number of apoptotic cells in comparison to the MDA/LUC-shUGT8 cells. In addition, it was found that expression of UGT8 in MDA-MB-231 cells increased their resistance to apoptosis induced by doxorubicin in vitro. Therefore, these data suggest that accumulation of GalCer in tumor cells inhibits apoptosis, which would facilitates metastatic cells to survive in the hostile microenvironment of tumor in target organ. 相似文献
95.
David Corwin Clay Holdsworth Russell C. Rockne Andrew D. Trister Maciej M. Mrugala Jason K. Rockhill Robert D. Stewart Mark Phillips Kristin R. Swanson 《PloS one》2013,8(11)
Purpose
To demonstrate a method of generating patient-specific, biologically-guided radiotherapy dose plans and compare them to the standard-of-care protocol.Methods and Materials
We integrated a patient-specific biomathematical model of glioma proliferation, invasion and radiotherapy with a multiobjective evolutionary algorithm for intensity-modulated radiation therapy optimization to construct individualized, biologically-guided plans for 11 glioblastoma patients. Patient-individualized, spherically-symmetric simulations of the standard-of-care and optimized plans were compared in terms of several biological metrics.Results
The integrated model generated spatially non-uniform doses that, when compared to the standard-of-care protocol, resulted in a 67% to 93% decrease in equivalent uniform dose to normal tissue, while the therapeutic ratio, the ratio of tumor equivalent uniform dose to that of normal tissue, increased between 50% to 265%. Applying a novel metric of treatment response (Days Gained) to the patient-individualized simulation results predicted that the optimized plans would have a significant impact on delaying tumor progression, with increases from 21% to 105% for 9 of 11 patients.Conclusions
Patient-individualized simulations using the combination of a biomathematical model with an optimization algorithm for radiation therapy generated biologically-guided doses that decreased normal tissue EUD and increased therapeutic ratio with the potential to improve survival outcomes for treatment of glioblastoma. 相似文献96.
Andrzej Matyja Krzysztof Gil Artur Pasternak Krystyna Sztefko Mariusz Gajda Krzysztof A. Tomaszewski Maciej Matyja Jerzy A. Walocha Jan Kulig Piotr Thor 《Journal of cellular and molecular medicine》2013,17(6):734-742
The major mechanisms of gallstone formation include biliary cholesterol hypersecretion, supersaturation and crystallization, mucus hypersecretion, gel formation and bile stasis. Gallbladder hypomotility seems to be a key event that triggers the precipitation of cholesterol microcrystals from supersaturated lithogenic bile. Telocytes, a new type of interstitial cells, have been recently identified in many organs, including gallbladder. Considering telocyte functions, it is presumed that these cells might be involved in the signalling processes. The purpose of this study was to correlate the quantity of telocytes in the gallbladder with the lithogenicity of bile. Gallbladder specimens were collected from 24 patients who underwent elective laparoscopic cholecystectomy for symptomatic gallstone disease. The control group consisted of 25 consecutive patients who received elective treatment for pancreatic head tumours. Telocytes were visualized in paraffin sections of gallbladders with double immunofluorescence using primary antibodies against c‐Kit (anti‐CD117) and anti‐mast cell tryptase. Cholesterol, phospholipid and bile acid levels were measured in gallbladder bile. The number of telocytes in the gallbladder wall was significantly lower in the study group than that in the control group (3.03 ± 1.43 versus 6.34 ± 1.66 cell/field of view in the muscularis propria, P < 0.001) and correlated with a significant increase in the cholesterol saturation index. The glycocholic and taurocholic acid levels were significantly elevated in the control subjects compared with the study group. The results suggest that bile composition may play an important role in the reduction in telocytes density in the gallbladder. 相似文献
97.
Barbara Pietrzak Anna Bednarska Magdalena Markowska Maciej Rojek Ewa Szymanska Miroslaw Slusarczyk 《Hydrobiologia》2013,715(1):125-134
The combined effect of external environment and energy allocation strategy of the organism on longevity can be exceptional. In a cold oligotrophic fishless habitat, individual Daphnia can live for over a year, several times the usual Daphnia lifespan. This extreme lifespan is in part a consequence of the overwintering strategy which includes storing resources and delaying reproduction until another spring. Yet, contrasting strategies may be applied by Daphnia, resulting in over twofold differences in lifespan within a single habitat. We identify physiological mechanisms mediating such differences in longevity in closely related Daphnia of two lineages coexisting within a high altitude lake, testing the predictions that long-lived animals stay in colder waters and have lower metabolic rates, irrespective of temperature. Vertical distribution of the animals was assessed during three summer stratification seasons, and metabolic activity was measured as oxygen consumption and RNA:DNA ratio. The results not only support our predictions but also reveal that habitat choice is dependent on reproductive status rather than genotype. The young individuals of the overwintering lineage may delay reproduction in part by staying in colder waters than the reproducing adults, which together with low intrinsic metabolic rates may underlie the longevity of Daphnia of this lineage. 相似文献
98.
99.