全文获取类型
收费全文 | 466篇 |
免费 | 38篇 |
出版年
2022年 | 5篇 |
2021年 | 13篇 |
2020年 | 5篇 |
2019年 | 4篇 |
2018年 | 12篇 |
2017年 | 7篇 |
2016年 | 17篇 |
2015年 | 18篇 |
2014年 | 20篇 |
2013年 | 24篇 |
2012年 | 22篇 |
2011年 | 13篇 |
2010年 | 11篇 |
2009年 | 9篇 |
2008年 | 19篇 |
2007年 | 17篇 |
2006年 | 16篇 |
2005年 | 14篇 |
2004年 | 18篇 |
2003年 | 16篇 |
2002年 | 22篇 |
2001年 | 7篇 |
2000年 | 12篇 |
1999年 | 19篇 |
1998年 | 6篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 10篇 |
1992年 | 7篇 |
1991年 | 10篇 |
1990年 | 10篇 |
1989年 | 6篇 |
1988年 | 6篇 |
1987年 | 8篇 |
1986年 | 10篇 |
1985年 | 8篇 |
1984年 | 4篇 |
1983年 | 8篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1979年 | 7篇 |
1978年 | 3篇 |
1977年 | 4篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1971年 | 2篇 |
1970年 | 2篇 |
1968年 | 5篇 |
1967年 | 3篇 |
排序方式: 共有504条查询结果,搜索用时 46 毫秒
81.
Dong Zhang Marios S. Markoulides Dmitrijs Stepanovs Anna M. Rydzik Ahmed El-Hussein Corentin Bon Jos J.A.G. Kamps Klaus-Daniel Umland Patrick M. Collins Samuel T. Cahill David Y. Wang Frank von Delft Jürgen Brem Michael A. McDonough Christopher J. Schofield 《Bioorganic & medicinal chemistry》2018,26(11):2928-2936
Metallo-β-lactamases (MBLs) enable bacterial resistance to almost all classes of β-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging ‘hydrolytic’ water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products. 相似文献
82.
Hannah J. Winfield Michael M. Cahill Kevin D. OShea Larry T. Pierce Thomas Robert Sandrine Ruchaud Stéphane Bach Pascal Marchand Florence O. McCarthy 《Bioorganic & medicinal chemistry》2018,26(14):4209-4224
Synthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates. 相似文献
83.
84.
85.
86.
Genetic differentiation and reduced genetic diversity at the northern range edge of two species with different dispersal modes
下载免费PDF全文
![点击此处可从《Molecular ecology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Theory predicts that genetic variation should be reduced at range margins, but empirical support is equivocal. Here, we used genotyping‐by‐sequencing technology to investigate genetic variation in central and marginal populations of two species in the marine gastropod genus Crepidula. These two species have different development and dispersal types and might therefore show different spatial patterns of genetic variation. Both allelic richness and the proportion of private alleles were highest in the most central populations of both species, and lower at the margin. The species with low dispersal, Crepidula convexa, showed high degrees of structure throughout the range that conform to the pattern found in previous studies using other molecular markers. The northernmost populations of the high‐dispersing species, Crepidula fornicata, are distinct from more central populations, although this species has been previously observed to have little genetic structure over much of its range. Although genetic diversity was significantly lower at the range margin, the absolute reduction in diversity observed with these genomewide markers was slight, and it is not yet known whether there are functional consequences for the marginal populations. 相似文献
87.
W Shi C M Li P C Tyler R H Furneaux S M Cahill M E Girvin C Grubmeyer V L Schramm S C Almo 《Biochemistry》1999,38(31):9872-9880
Malaria is a leading cause of worldwide mortality from infectious disease. Plasmodium falciparum proliferation in human erythrocytes requires purine salvage by hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase). The enzyme is a target for the development of novel antimalarials. Design and synthesis of transition-state analogue inhibitors permitted cocrystallization with the malarial enzyme and refinement of the complex to 2.0 A resolution. Catalytic site contacts in the malarial enzyme are similar to those of human hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) despite distinct substrate specificity. The crystal structure of malarial HGXPRTase with bound inhibitor, pyrophosphate, and two Mg(2+) ions reveals features unique to the transition-state analogue complex. Substrate-assisted catalysis occurs by ribooxocarbenium stabilization from the O5' lone pair and a pyrophosphate oxygen. A dissociative reaction coordinate path is implicated in which the primary reaction coordinate motion is the ribosyl C1' in motion between relatively immobile purine base and (Mg)(2)-pyrophosphate. Several short hydrogen bonds form in the complex of the enzyme and inhibitor. The proton NMR spectrum of the transition-state analogue complex of malarial HGXPRTase contains two downfield signals at 14.3 and 15.3 ppm. Despite the structural similarity to the human enzyme, the NMR spectra of the complexes reveal differences in hydrogen bonding between the transition-state analogue complexes of the human and malarial HG(X)PRTases. The X-ray crystal structures and NMR spectra reveal chemical and structural features that suggest a strategy for the design of malaria-specific transition-state inhibitors. 相似文献
88.
89.
Abigail E. Cahill Christopher J. Breen Irene CoronaAvila Cesar A. Cortes Rosemary Hernandez Saige Jost Breh L. K. Ruger Rachel M. H. Stander Bach V. Tran 《Ecology and evolution》2021,11(21):14351
Inland salt marshes are rare habitats in the Great Lakes region of North America, formed on salt deposits from the Silurian period. These patchy habitats are abiotically stressful for the freshwater invertebrates that live there, and provide an opportunity to study the relationship between stress and diversity. We used morphological and COI metabarcoding data to assess changes in diversity and composition across both space (a transect from the salt seep to an adjacent freshwater area) and time (three sampling seasons). Richness was significantly lower at the seep site with both datatypes, while metabarcoding data additionally showed reduced richness at the freshwater transect end, consistent with a pattern where intermediate levels of stress show higher diversity. We found complementary, rather than redundant, patterns of community composition using the two datatypes: not all taxa were equally sequenced with the metabarcoding protocol. We identified taxa that are abundant at the salt seep of the marsh, including biting midges (Culicoides) and ostracods (Heterocypris). We conclude that (as found in other studies) molecular and morphological work should be used in tandem to identify the biodiversity in this rare habitat. Additionally, salinity may be a driver of community membership in this system, though further ecological research is needed to rule out alternate hypotheses. 相似文献
90.
Omar JM Hamza Mecky IN Matee Mainen J Moshi Elison NM Simon Ferdinand Mugusi Frans HM Mikx Wim H van Palenstein Helderman Antonius JMM Rijs André JAM van der Ven Paul E Verweij 《BMC microbiology》2008,8(1):135