全文获取类型
收费全文 | 586篇 |
免费 | 51篇 |
出版年
2023年 | 10篇 |
2022年 | 13篇 |
2021年 | 21篇 |
2020年 | 18篇 |
2019年 | 11篇 |
2018年 | 26篇 |
2017年 | 13篇 |
2016年 | 32篇 |
2015年 | 44篇 |
2014年 | 38篇 |
2013年 | 38篇 |
2012年 | 49篇 |
2011年 | 44篇 |
2010年 | 33篇 |
2009年 | 34篇 |
2008年 | 35篇 |
2007年 | 25篇 |
2006年 | 20篇 |
2005年 | 18篇 |
2004年 | 16篇 |
2003年 | 34篇 |
2002年 | 17篇 |
2001年 | 3篇 |
2000年 | 4篇 |
1999年 | 6篇 |
1997年 | 5篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1990年 | 3篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1985年 | 1篇 |
1983年 | 2篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1971年 | 2篇 |
1969年 | 1篇 |
1968年 | 1篇 |
1962年 | 1篇 |
排序方式: 共有637条查询结果,搜索用时 41 毫秒
71.
Barrese AA Genis C Fisher SZ Orwenyo JN Kumara MT Dutta SK Phillips E Kiddle JJ Tu C Silverman DN Govindasamy L Agbandje-McKenna M McKenna R Tripp BC 《Biochemistry》2008,47(10):3174-3184
This paper examines the functional mechanism of thioxolone, a compound recently identified as a weak inhibitor of human carbonic anhydrase II by Iyer et al. (2006) J. Biomol. Screening 11, 782-791 . Thioxolone lacks sulfonamide, sulfamate, or hydroxamate functional groups that are typically found in therapeutic carbonic anhydrase (CA) inhibitors, such as acetazolamide. Analytical chemistry and biochemical methods were used to investigate the fate of thioxolone upon binding to CA II, including Michaelis-Menten kinetics of 4-nitrophenyl acetate esterase cleavage, liquid chromatography-mass spectrometry (LC-MS), oxygen-18 isotope exchange studies, and X-ray crystallography. Thioxolone is proposed to be a prodrug inhibitor that is cleaved via a CA II zinc-hydroxide mechanism known to catalyze the hydrolysis of esters. When thioxolone binds in the active site of CA II, it is cleaved and forms 4-mercaptobenzene-1,3-diol via the intermediate S-(2,4-thiophenyl)hydrogen thiocarbonate. The esterase cleavage product binds to the zinc active site via the thiol group and is therefore the active CA inhibitor, while the intermediate is located at the rim of the active-site cavity. The time-dependence of this inhibition reaction was investigated in detail. Because this type of prodrug inhibitor mechanism depends on cleavage of ester bonds, this class of inhibitors may have advantages over sulfonamides in determining isozyme specificity. A preliminary structure-activity relationship study with a series of structural analogues of thioxolone yielded similar estimates of inhibition constants for most compounds, although two compounds with bromine groups at the C1 carbon of thioxolone were not inhibitory, suggesting a possible steric effect. 相似文献
72.
Effect of the Environment on Genotypic Diversity of Actinomyces naeslundii and Streptococcus oralis in the Oral Biofilm 总被引:1,自引:0,他引:1 下载免费PDF全文
James S. Paddick Susan R. Brailsford Edwina A. M. Kidd Steven C. Gilbert Douglas T. Clark Sharmin Alam Zoe J. Killick David Beighton 《Applied microbiology》2003,69(11):6475-6480
The genotypic diversity of Actinomyces naeslundii genospecies 2 (424 isolates) and Streptococcus oralis (446 isolates) strains isolated from two sound approximal sites in all subjects who were either caries active (seven subjects) or caries free (seven subjects) was investigated by using the repetitive extragenic palindromic PCR. The plaque from the caries-active subjects harbored significantly greater proportions of mutans streptococci and lactobacilli and a smaller proportion of A. naeslundii organisms than the plaque sampled from the caries-free subjects. These data confirmed that the sites of the two groups of subjects were subjected to different environmental stresses, probably determined by the prevailing or fluctuating acidic pH values. We tested the hypothesis that the microfloras of the sites subjected to greater stresses (the plaque samples from the caries-active subjects) would exhibit reduced genotypic diversity since the sites would be less favorable. We found that the diversity of A. naeslundii strains did not change (χ2 = 0.68; P = 0.41) although the proportional representation of A. naeslundii was significantly reduced (P < 0.05). Conversely, the diversity of the S. oralis strains increased (χ2 = 11.71; P = 0.0006) and the proportional representation of S. oralis did not change. We propose that under these environmental conditions the diversity and number of niches within the oral biofilm that could be exploited by S. oralis increased, resulting in the increased genotypic diversity of this species. Apparently, A. naeslundii was not able to exploit the new niches since the prevailing conditions within the niches may have been deleterious and not supportive of its proliferation. These results suggest that environmental stress may modify a biofilm such that the diversity of the niches is increased and that these niches may be successfully exploited by some, but not necessarily all, members of the microbial community. 相似文献
73.
Michael E Clark Zoe Veneti Kostas Bourtzis Timothy L Karr 《Mechanisms of development》2002,111(1-2):3-15
Wolbachia is a cytoplasmically inherited alpha-proteobacterium found in a wide range of host arthropod and nematode taxa. Wolbachia infection in Drosophila is closely associated with the expression of a unique form of post-fertilization lethality termed cytoplasmic incompatibility (CI). This form of incompatibility is only expressed by infected males suggesting that Wolbachia exerts its effect during spermatogenesis. The growth and distribution of Wolbachia throughout sperm development in individual spermatocysts and elongating sperm bundles is described. Wolbachia growth within a developing cyst seems to begin during the pre-meiotic spermatocyte growth phase with the majority of bacteria accumulating during cyst elongation. Wolbachia are predominantly localized in the proximal end of the immature cyst, opposite the spermatid nuclei, and throughout development there appears little movement of Wolbachia between spermatids via the connecting cytoplasmic bridges. The overall number of new cysts infected as well as the number of spermatids/cysts infected seems to decrease with age and corresponds to the previously documented drop in CI with age. In contrast, in one CI expressing line of Drosophila melanogaster, fewer cysts are infected and a much greater degree of variation in numbers is observed between spermatids. Furthermore, the initiation and extent of the fastest period of Wolbachia growth in the D. melanogaster strain lags behind that of Drosophila simulans. The possible implications on the as yet unexplained mechanism of CI are discussed. 相似文献
74.
75.
Unconventional Sequence Requirement for Viral Late Gene Core Promoters of Murine Gammaherpesvirus 68
Elaine Wong-Ho Ting-Ting Wu Zoe H. Davis Bingqing Zhang Jian Huang Hao Gong Hongyu Deng Fenyong Liu Britt Glaunsinger Ren Sun 《Journal of virology》2014,88(6):3411-3422
Infection with the human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi''s sarcoma-associated herpesvirus (KSHV), is associated with several cancers. During lytic replication of herpesviruses, viral genes are expressed in an ordered cascade. However, the mechanism by which late gene expression is regulated has not been well characterized in gammaherpesviruses. In this study, we have investigated the cis element that mediates late gene expression during de novo lytic infection with murine gammaherpesvirus 68 (MHV-68). A reporter system was established and used to assess the activity of viral late gene promoters upon infection with MHV-68. It was found that the viral origin of lytic replication, orilyt, must be on the reporter plasmid to support activation of the late gene promoter. Furthermore, the DNA sequence required for the activation of late gene promoters was mapped to a core element containing a distinct TATT box and its neighboring sequences. The critical nucleotides of the TATT box region were determined by systematic mutagenesis in the reporter system, and the significance of these nucleotides was confirmed in the context of the viral genome. In addition, EBV and KSHV late gene core promoters could be activated by MHV-68 lytic replication, indicating that the mechanisms controlling late gene expression are conserved among gammaherpesviruses. Therefore, our results on MHV-68 establish a solid foundation for mechanistic studies of late gene regulation. 相似文献
76.
77.
Gradients of disturbance and environmental conditions shape coral community structure for south‐eastern Indian Ocean reefs 下载免费PDF全文
Jens Zinke James P. Gilmour Rebecca Fisher Marji Puotinen Joseph Maina Emily Darling Michael Stat Zoe T. Richards Timothy R. McClanahan Maria Beger Cordelia Moore Nicholas A. J. Graham Ming Feng Jean‐Paul A. Hobbs Scott N. Evans Stuart Field George Shedrawi Russ C. Babcock Shaun K. Wilson 《Diversity & distributions》2018,24(5):605-620
78.
Maria J. Gomez-Lamarca Julia Falo-Sanjuan Robert Stojnic Sohaib Abdul Rehman Leila Muresan Matthew L. Jones Zoe Pillidge Gustavo Cerda-Moya Zhenyu Yuan Sarah Baloul Phillippe Valenti Kerstin Bystricky Francois Payre Kevin OHolleran Rhett Kovall Sarah J. Bray 《Developmental cell》2018,44(5):611-623.e7
79.
Antonio Murgia Christine Hinz Sonia Liggi Jùlìa Denes Zoe Hall James West Maria Laura Santoru Cristina Piras Cristina Manis Paolo Usai Luigi Atzori Julian L. Griffin Pierluigi Caboni 《Metabolomics : Official journal of the Metabolomic Society》2018,14(10):140
Background
Inflammatory bowel disease is a group of pathologies characterised by chronic inflammation of the intestine and an unclear aetiology. Its main manifestations are Crohn’s disease and ulcerative colitis. Currently, biopsies are the most used diagnostic tests for these diseases and metabolomics could represent a less invasive approach to identify biomarkers of disease presence and progression.Objectives
The lipid and the polar metabolite profile of plasma samples of patients affected by inflammatory bowel disease have been compared with healthy individuals with the aim to find their metabolomic differences. Also, a selected sub-set of samples was analysed following solid phase extraction to further characterise differences between pathological samples.Methods
A total of 200 plasma samples were analysed using drift tube ion mobility coupled with time of flight mass spectrometry and liquid chromatography for the lipid metabolite profile analysis, while liquid chromatography coupled with triple quadrupole mass spectrometry was used for the polar metabolite profile analysis.Results
Variations in the lipid profile between inflammatory bowel disease and healthy individuals were highlighted. Phosphatidylcholines, lyso-phosphatidylcholines and fatty acids were significantly changed among pathological samples suggesting changes in phospholipase A2 and arachidonic acid metabolic pathways. Variations in the levels of cholesteryl esters and glycerophospholipids were also found. Furthermore, a decrease in amino acids levels suggests mucosal damage in inflammatory bowel disease.Conclusions
Given good statistical results and predictive power of the model produced in our study, metabolomics can be considered as a valid tool to investigate inflammatory bowel disease.80.
Linsen Li Antony Okumu Sheri Dellos-Nolan Zoe Li Soumendrakrishna Karmahapatra Anthony English Jack C. Yalowich Daniel J. Wozniak Mark J. Mitton-Fry 《Bioorganic & medicinal chemistry letters》2018,28(14):2477-2480
Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. We report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compound 9 demonstrated MICs ≤1?μg/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs. 相似文献