全文获取类型
收费全文 | 533篇 |
免费 | 24篇 |
专业分类
557篇 |
出版年
2022年 | 6篇 |
2021年 | 5篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 8篇 |
2017年 | 2篇 |
2016年 | 11篇 |
2015年 | 16篇 |
2014年 | 28篇 |
2013年 | 23篇 |
2012年 | 32篇 |
2011年 | 22篇 |
2010年 | 18篇 |
2009年 | 18篇 |
2008年 | 37篇 |
2007年 | 27篇 |
2006年 | 25篇 |
2005年 | 34篇 |
2004年 | 38篇 |
2003年 | 28篇 |
2002年 | 29篇 |
2001年 | 4篇 |
2000年 | 13篇 |
1999年 | 7篇 |
1998年 | 10篇 |
1997年 | 10篇 |
1996年 | 4篇 |
1995年 | 4篇 |
1994年 | 12篇 |
1993年 | 6篇 |
1992年 | 6篇 |
1991年 | 4篇 |
1990年 | 6篇 |
1989年 | 7篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1986年 | 5篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 6篇 |
1982年 | 3篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1976年 | 5篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1967年 | 1篇 |
排序方式: 共有557条查询结果,搜索用时 0 毫秒
91.
Takashi Ohuchi Masayuki Seki Kazuto Kugou Shusuke Tada Kunihiro Ohta Takemi Enomoto 《DNA Repair》2009,8(6):690-696
Checkpoints are cellular surveillance and signaling pathways that regulate responses to DNA damage and perturbations of DNA replication. Here we show that high levels of sumoylated Rad52 are present in the mec1 sml1 and rad53 sml1 checkpoint mutants exposed to DNA-damaging agents such as methyl methanesulfonate (MMS) or the DNA replication inhibitor hydroxyurea (HU). The kinase-defective mutant rad53-K227A also showed high levels of Rad52 sumoylation. Elevated levels of Rad52 sumoylation occur in checkpoint mutants proceeding S phase being exposed DNA-damaging agent. Interestingly, chromatin immunoprecipitation (ChIP) on chip analyses revealed non-canonical chromosomal localization of Rad52 in the HU-treated rad53-K227A cells arrested in early S phase: Rad52 localization at dormant and early DNA replication origins. However, such unusual localization was not dependent on the sumoylation of Rad52. In addition, we also found that Rad52 could be highly sumoylated in the absence of Rad51. Double mutation of RAD51 and RAD53 exhibited the similar levels of Rad52 sumoylation to RAD53 single mutation. The significance and regulation mechanism of Rad52 sumoylation by checkpoint pathways will be discussed. 相似文献
92.
Dopaminergic neurons from the substantia nigra and the ventral tegmental area of the midbrain project to the caudate/putamen and nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic pathways. However, the mechanisms underlying the development of these pathways are not well understood. In the current study, the EphA5 receptor and its corresponding ligand, ephrin‐A5, were shown to regulate dopaminergic axon outgrowth and influence the formation of the midbrain dopaminergic pathways. Using a strain of mutant mice in which the EphA5 cytoplasmic domain was replaced with β‐galactosidase, EphA5 protein expression was detected in both the ventral tegmental area and the substantia nigra of the midbrain. Ephrin‐A5 was found in both the dorsolateral and the ventromedial regions of the striatum, suggesting a role in mediating dopaminergic axon‐target interactions. In the presence of ephrin‐A5, dopaminergic neurons extended longer neurites in in vitro coculture assays. Furthermore, in mice lacking ephrin‐A5, retrograde tracing studies revealed that fewer neurons sent axons to the striatum. These observations indicate that the interactions between ephrin‐A ligands and EphA receptors promote growth and targeting of the midbrain dopaminergic axons to the striatum. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2009 相似文献
93.
94.
Fujimoto K Morisaki D Yoshida M Namba T Hye-Sook K Wataya Y Kourai H Kakuta H Sasaki K 《Bioorganic & medicinal chemistry letters》2006,16(10):2758-2760
The in vitro antimalarial activity of bis-pyridinium salts, N,N'-hexamethylenebis(4-carbamoyl-1-decylpyridinium bromide) and their derivatives, against the Plasmodium falciparum FCR-3 strain (ATCC 30932, chloroquine-sensitive) was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 3.5microM to 10nM. The chain length of the N1-alkyl moiety was found to be very beneficial in terms of antimalarial activity, and in this series of compounds, the most appropriate N1-alkyl chain length was found to be eight. 相似文献
95.
Bahrudin U Morikawa K Takeuchi A Kurata Y Miake J Mizuta E Adachi K Higaki K Yamamoto Y Shirayoshi Y Yoshida A Kato M Yamamoto K Nanba E Morisaki H Morisaki T Matsuoka S Ninomiya H Hisatome I 《Journal of molecular biology》2011,413(4):857-878
Cardiac arrhythmogenesis is regulated by channel proteins whose protein levels are in turn regulated by the ubiquitin-proteasome system (UPS). We have previously reported on UPS impairment induced by E334K cardiac myosin-binding protein C (cMyBPC), which causes hypertrophic cardiomyopathy (HCM) accompanied by arrhythmia. We hypothesized that UPS impairment induced by E334K cMyBPC causes accumulation of cardiac channel proteins, leading to electrophysiological dysfunction. Wild-type or E334K cMyBPC was overexpressed in HL-1 cells and primary cultured neonatal rat cardiac myocytes. The expression of E334K cMyBPC suppressed cellular proteasome activities. The protein levels of Kv1.5, Nav1.5, Hcn4, Cav3.2, Cav1.2, Serca, RyR2, and Ncx1 were significantly higher in cells expressing E334K cMyBPC than in wild type. They further increased in cells pretreated with MG132 and had longer protein decays. The channel proteins retained the correct localization. Cells expressing E334K cMyBPC exhibited higher Ca2+ transients and longer action potential durations (APDs), accompanied by afterdepolarizations and higher apoptosis. Those augments of APD and Ca2+ transients were recapitulated by a simulation model. Although a Ca2+ antagonist, azelnidipine, neither protected E334K cMyBPC from degradation nor affected E334K cMyBPC incorporation into the sarcomere, it normalized the APD and Ca2+ transients and partially reversed the levels of those proteins regulating apoptosis, thereby attenuating apoptosis. In conclusion, UPS impairment caused by E334K cMyBPC may modify the levels of channel proteins, leading to electrophysiological dysfunction. Therefore, UPS impairment due to a mutant cMyBPC may partly contribute to the observed clinical arrhythmias in HCM patients. 相似文献
96.
Masaaki Niino Nobuhiro Mifune Tatsuo Kohriyama Masahiro Mori Takashi Ohashi Izumi Kawachi Yuko Shimizu Hikoaki Fukaura Ichiro Nakashima Susumu Kusunoki Katsuichi Miyamoto Kazuto Yoshida Takashi Kanda Kyoichi Nomura Takashi Yamamura Fumihito Yoshii Jun-ichi Kira Shunya Nakane Kazumasa Yokoyama Makoto Matsui Yusei Miyazaki Seiji Kikuchi 《BMC neurology》2014,14(1):1-8
Background
Cognitive impairment could affect quality of life for patients with multiple sclerosis (MS), and cognitive function may be correlated with several factors such as depression and fatigue. This study aimed to evaluate cognitive function in Japanese patients with MS and the association between cognitive function and apathy, fatigue, and depression.Methods
The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was performed in 184 Japanese patients with MS and 163 healthy controls matched for age, gender, and education. The Apathy Scale (AS), Fatigue Questionnaire (FQ), and Beck Depression Inventory Second Edition (BDI-II) were used to evaluate apathy, fatigue, and depression, respectively. Student’s t-test was used to compare MS patients and healthy controls. Correlations between two factors were assessed using the Pearson correlation test, and multiple regression analysis was used to evaluate how much each factor affected the BRB-N score.Results
In all BRB-N tests, patients with MS scored significantly lower than controls, and the effect size of symbol digit modalities test was the highest among the 9 tests of the BRB-N. Patients with MS had higher AS (p?<?0.001), FQ (p?<?0.0001), and BDI-II (p?<?0.0001) scores than controls. In patients with MS, scores on most of the BRB-N tests correlated with scores on the AS and BDI-II; however, there was little correlation between scores on the BRB-N tests and those on the FQ.Conclusions
Cognitive function was impaired, particularly information-processing speed, and decreased cognitive function was correlated with apathy and depression in Japanese patients with MS. Despite the association between cognitive variables and depression/apathy, cognitive function was impaired beyond the effect of depression and apathy. However, subjective fatigue is not related with cognitive impairment. Taken together, this suggests that different therapeutic approaches are needed to improve subjective fatigue and cognition, and thereby quality of life, in patients with MS. 相似文献97.
Amy A. Irving Kazuto Yoshimi Marcia L. Hart Taybor Parker Linda Clipson Madeline R. Ford Takashi Kuramoto William F. Dove James M. Amos-Landgraf 《Disease models & mechanisms》2014,7(11):1215-1225
Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer.KEY WORDS: APC, Allelic series, Animal models, Colorectal cancer 相似文献
98.
Isogai M Kawamoto Y Inahata K Fukada H Sugimoto K Tada T 《Bioorganic & medicinal chemistry letters》2011,21(10):3021-3024
Bimolecular fluorescence complementation (BiFC) assay has been used widely to visualize protein-protein interactions in cells. However, there is a problem that fluorescent protein fragments have an ability to associate with each other independent of an interaction between proteins fused to the fragments. To facilitate the BiFC assay, we have attempted to determine the structure and characteristics of reassembled fluorescent protein, Venus. The anion-exchange chromatography showed an oligomer and a monomer of reassembled Venus. Our results suggested that the oligomer was formed by β-strands swapping without any serious steric clashes and was converted to the monomer. Crystal structure of reassembled Venus had an 11-stranded β-barrel fold, typical of GFP-derived fluorescent proteins. Based on the structural features, we have mutated to β-strand 7 and measured Tm values. The results have revealed that the mutation influences the thermal stability of reassembled fluorescent complex. 相似文献
99.
Wouter L. W. Hazenbos Kimberly K. Kajihara Richard Vandlen J. Hiroshi Morisaki Sophie M. Lehar Mark J. Kwakkenbos Tim Beaumont Arjen Q. Bakker Qui Phung Lee R. Swem Satish Ramakrishnan Janice Kim Min Xu Ishita M. Shah Binh An Diep Tao Sai Andrew Sebrell Yana Khalfin Angela Oh Chris Koth S. Jack Lin Byoung-Chul Lee Magnus Strandh Klaus Koefoed Peter S. Andersen Hergen Spits Eric J. Brown Man-Wah Tan Sanjeev Mariathasan 《PLoS pathogens》2013,9(10)
Infection of host tissues by Staphylococcus aureus and S. epidermidis requires an unusual family of staphylococcal adhesive proteins that contain long stretches of serine-aspartate dipeptide-repeats (SDR). The prototype member of this family is clumping factor A (ClfA), a key virulence factor that mediates adhesion to host tissues by binding to extracellular matrix proteins such as fibrinogen. However, the biological siginificance of the SDR-domain and its implication for pathogenesis remain poorly understood. Here, we identified two novel bacterial glycosyltransferases, SdgA and SdgB, which modify all SDR-proteins in these two bacterial species. Genetic and biochemical data demonstrated that these two glycosyltransferases directly bind and covalently link N-acetylglucosamine (GlcNAc) moieties to the SDR-domain in a step-wise manner, with SdgB appending the sugar residues proximal to the target Ser-Asp repeats, followed by additional modification by SdgA. GlcNAc-modification of SDR-proteins by SdgB creates an immunodominant epitope for highly opsonic human antibodies, which represent up to 1% of total human IgG. Deletion of these glycosyltransferases renders SDR-proteins vulnerable to proteolysis by human neutrophil-derived cathepsin G. Thus, SdgA and SdgB glycosylate staphylococcal SDR-proteins, which protects them against host proteolytic activity, and yet generates major eptopes for the human anti-staphylococcal antibody response, which may represent an ongoing competition between host and pathogen. 相似文献
100.