全文获取类型
收费全文 | 1558篇 |
免费 | 105篇 |
国内免费 | 3篇 |
出版年
2023年 | 7篇 |
2022年 | 12篇 |
2021年 | 20篇 |
2020年 | 13篇 |
2019年 | 10篇 |
2018年 | 20篇 |
2017年 | 24篇 |
2016年 | 37篇 |
2015年 | 65篇 |
2014年 | 61篇 |
2013年 | 82篇 |
2012年 | 96篇 |
2011年 | 116篇 |
2010年 | 70篇 |
2009年 | 57篇 |
2008年 | 91篇 |
2007年 | 73篇 |
2006年 | 71篇 |
2005年 | 72篇 |
2004年 | 58篇 |
2003年 | 85篇 |
2002年 | 83篇 |
2001年 | 9篇 |
2000年 | 8篇 |
1999年 | 18篇 |
1998年 | 24篇 |
1997年 | 17篇 |
1996年 | 17篇 |
1995年 | 16篇 |
1994年 | 18篇 |
1993年 | 15篇 |
1992年 | 11篇 |
1991年 | 11篇 |
1989年 | 15篇 |
1988年 | 14篇 |
1987年 | 9篇 |
1986年 | 11篇 |
1985年 | 10篇 |
1984年 | 10篇 |
1983年 | 10篇 |
1982年 | 9篇 |
1981年 | 17篇 |
1979年 | 9篇 |
1978年 | 9篇 |
1977年 | 7篇 |
1975年 | 9篇 |
1973年 | 7篇 |
1970年 | 7篇 |
1965年 | 8篇 |
1963年 | 6篇 |
排序方式: 共有1666条查询结果,搜索用时 16 毫秒
151.
Michael C Madigan Ryan M McEnaney Ankur J Shukla Guiying Hong Eric E Kelley Margaret M Tarpey Mark Gladwin Brian S Zuckerbraun Edith Tzeng 《Molecular medicine (Cambridge, Mass.)》2015,21(1):313-322
Chronic, nonhealing wounds result in patient morbidity and disability. Reactive oxygen species (ROS) and nitric oxide (NO) are both required for normal wound repair, and derangements of these result in impaired healing. Xanthine oxidoreductase (XOR) has the unique capacity to produce both ROS and NO. We hypothesize that XOR contributes to normal wound healing. Cutaneous wounds were created in C57Bl6 mice. XOR was inhibited with dietary tungsten or allopurinol. Topical hydrogen peroxide (H2O2, 0.15%) or allopurinol (30 μg) was applied to wounds every other day. Wounds were monitored until closure or collected at d 5 to assess XOR expression and activity, cell proliferation and histology. The effects of XOR, nitrite, H2O2 and allopurinol on keratinocyte cell (KC) and endothelial cell (EC) behavior were assessed. We identified XOR expression and activity in the skin and wound edges as well as granulation tissue. Cultured human KCs also expressed XOR. Tungsten significantly inhibited XOR activity and impaired healing with reduced ROS production with reduced angiogenesis and KC proliferation. The expression and activity of other tungsten-sensitive enzymes were minimal in the wound tissues. Oral allopurinol did not reduce XOR activity or alter wound healing but topical allopurinol significantly reduced XOR activity and delayed healing. Topical H2O2 restored wound healing in tungsten-fed mice. In vitro, nitrite and H2O2 both stimulated KC and EC proliferation and EC migration. These studies demonstrate for the first time that XOR is abundant in wounds and participates in normal wound healing through effects on ROS production. 相似文献
152.
153.
Sehati S Clement MH Martins J Xu L Longo VD Valentine JS Gralla EB 《Free radical biology & medicine》2011,50(11):1591-1598
Yeast lacking copper-zinc superoxide dismutase (sod1?) have a number of oxygen-dependent defects, including auxotrophies for lysine and methionine and sensitivity to oxygen. Here we report additional defects in metabolic regulation. Under standard growth conditions with glucose as the carbon source, yeast undergo glucose repression in which mitochondrial respiration is deemphasized, energy is mainly derived from glycolysis, and ethanol is produced. When glucose is depleted, the diauxic shift is activated, in which mitochondrial respiration is reemphasized and stress resistance increases. We find that both of these programs are adversely affected by the lack of Sod1p. Key events in the diauxic shift do not occur and sod1? cells do not utilize ethanol and stop growing. The ability to shift to growth on ethanol is gradually lost as time in culture increases. In early stages of culture, sod1? cells consume more oxygen and have more mitochondrial mass than wild-type cells, indicating that glucose repression is not fully activated. These changes are at least partially dependent on the activity of the Hap2,3,4,5 complex, as indicated by CYC1-lacZ reporter assays. These changes may indicate a role for superoxide in metabolic signaling and regulation and/or a role for glucose derepression in defense against oxidative stress. 相似文献
154.
Kinzel O Alfieri A Altamura S Brunetti M Bufali S Colaceci F Ferrigno F Filocamo G Fonsi M Gallinari P Malancona S Hernando JI Monteagudo E Orsale MV Palumbi MC Pucci V Rowley M Sasso R Scarpelli R Steinkühler C Jones P 《Bioorganic & medicinal chemistry letters》2011,21(15):4429-4435
The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development. 相似文献
155.
Edith Katsnelson Uzi Motro Marcus W. Feldman Arnon Lotem 《Proceedings. Biological sciences / The Royal Society》2011,278(1705):582-589
Social foragers can use either a ‘producer’ strategy, which involves searching for food, or a ‘scrounger’ strategy, which involves joining others'' food discoveries. While producers rely on personal information and past experience, we may ask whether the tendency to forage as a producer is related to being a better learner. To answer this question, we hand-raised house sparrow (Passer domesticus) nestlings that upon independence were given an individual-learning task that required them to associate colour signal and food presence. Following the testing phase, all fledglings were released into a shared aviary, and their social-foraging tendencies were measured. We found a significant positive correlation between individual''s performance in the individual-learning task and subsequent tendency to use searching (producing) behaviour. Individual-learning score was negatively correlated with initial fear of the test apparatus and with body weight. However, the correlation between individual learning and searching remained significant after controlling for these variables. Since it was measured before the birds entered a social group, individual-learning ability could not be the outcome of being a producer. However, the two traits may be initially associated, or individual learning could facilitate producing behaviour. To our knowledge, this is the first evidence that associates individual-learning abilities with social-foraging strategies in animal groups. 相似文献
156.
García-Medina S Razo-Estrada C Galar-Martinez M Cortéz-Barberena E Gómez-Oliván LM Alvarez-González I Madrigal-Bujaidar E 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2011,153(1):113-118
Few studies have been made in regard to the effect of aluminum on the molecular and cellular structure and function of aquatic organisms; therefore, in the present report we determined the genotoxic and cytotoxic effects induced by the metal on the lymphocytes of carp (Cyprinus carpio). Three groups of fish were exposed to 0.05, 120, and 239 mg/L of aluminum (Al), respectively, by using Al2 (SO4)3·7H2O, and another group was included as control. The cells obtained were studied with the comet assay, flow cytometry, and the TUNEL method. With the first method we found a concentration and time dependent, significant increase in the amount of DNA damage induced by Al, and a higher damage when we evaluated the level of oxidized DNA. By applying flow cytometry we established that the metal induced a DNA content increase and ploidy modifications as well as apoptosis and disturbances of the cell cycle progression. With the last method we determined a significant increase in the amount of apoptotic cells, mainly in the 72–96 h period. Our results established that Al caused deleterious DNA and cellular effects in the tested organism, and they suggested the pertinence of evaluating toxicity induced by the metal in organisms living in contaminated water bodies. 相似文献
157.
158.
Sachin Patil Lilly M. Saleena Yong-Wah Kim Edith Weber Hermann von Grafenstein 《International journal of peptide research and therapeutics》2011,17(2):137-145
Peptides are important naturally occurring ligands of MHC molecules. X-ray crystallographic studies have enabled extensive characterization of such peptide ligands. Yet structural and dynamic changes of these peptides in the MHC bound state are not well understood. These conformational transitions are key to understanding the function of MHC molecules and for the development of peptide-based therapeutics. Employing NMR for such studies can fill this gap but it requires the availability of peptides labeled with NMR-active nuclei. Here we report production of nine-mer MHC-binding peptides for use in high resolution NMR studies. The method utilizes a fusion protein approach of attaching the peptide to an easily expressed bacterial protein. The fusion protein construct design allows for rapid purification of the fusion protein and avoids chemical modification of the peptide as a result of the cleavage reaction. The methods developed here allow for rapid cloning of additional MHC binding peptides without significant molecular biology effort. 8?C10 mg of mature freeze dried peptides can be obtained from 1 liter of minimal media, sufficient for NMR experimentation. Six uniformly 15N-labeled peptides have been successfully expressed in bacteria and NMR spectra with the expected number of well-resolved signals were recorded. The results obtained here will make peptide-MHC complexes amenable to structural analysis which has not been possible previously. 相似文献
159.
The chromosomal passenger complex (CPC), containing Aurora B kinase, Inner Centromere Protein, Survivin, and Borealin, regulates chromosome condensation and interaction between kinetochores and microtubules at metaphase, then relocalizes to midzone microtubules at anaphase and regulates central spindle organization and cytokinesis. However, the precise role(s) played by the CPC in anaphase have been obscured by its prior functions in metaphase. Here we identify a missense allele of Drosophila Survivin that allows CPC localization and function during metaphase but not cytokinesis. Analysis of mutant cells showed that Survivin is essential to target the CPC and the mitotic kinesin-like protein 1 orthologue Pavarotti (Pav) to the central spindle and equatorial cell cortex during anaphase in both larval neuroblasts and spermatocytes. Survivin also enabled localization of Polo kinase and Rho at the equatorial cortex in spermatocytes, critical for contractile ring assembly. In neuroblasts, in contrast, Survivin function was not required for localization of Rho, Polo, or Myosin II to a broad equatorial cortical band but was required for Myosin II to transition to a compact, fully constricted ring. Analysis of this "separation-of-function" allele demonstrates the direct role of Survivin and the CPC in cytokinesis and highlights striking differences in regulation of cytokinesis in different cell systems. 相似文献
160.
Almåsbak H Rian E Hoel HJ Pulè M Wälchli S Kvalheim G Gaudernack G Rasmussen AM 《Cytotherapy》2011,13(5):629-640
Background aimsT cells can be redirected to reject cancer by retroviral transduction with a chimeric antigen receptor (CAR) or by administration of a bispecific T cell engager (BiTE). We demonstrate that transfection of T cells with messenger (m) RNA coding for CAR is an alternative strategy.MethodsWe describe the pre-clinical evaluation of a method based on transient modification of expanded T cells with a CD19 CAR directed against B-cell malignancies. CAR mRNA was generated under cell-free conditions in a scalable process using recombinant RNA polymerase. Efficient and non-toxic square-wave electroporation was used to load the mRNA into the cytoplasm of T cells with no risk of insertional mutagenesis.ResultsAfter transfection > 80% of T cells were viable, with 94% CAR expression. Transfected T cells were cytolytic to CD19+ targets and produced interferon (IFN)-γ in response. Killing of CD19+ target cells was demonstrated even at day 8 with undetectable CAR expression. Increasing the concentration of mRNA resulted in higher surface CAR expression, better killing and more IFN-γ release but at the expense of increased activation-induced cell death. Finally, we demonstrated that a second transgene could be introduced by co-electroporation of CXCR4 or CCR7 with CAR to also modify chemotactic responses.ConclusionsWe advocate the transient redirection approach as well suited to meet safety aspects for early phase studies, prior to trials using stably transduced cells once CAR has been proven safe. The simplicity of this methodology also facilitates rapid screening of candidate targets and novel receptors in pre-clinical studies. 相似文献