全文获取类型
收费全文 | 429篇 |
免费 | 44篇 |
国内免费 | 32篇 |
专业分类
505篇 |
出版年
2022年 | 3篇 |
2021年 | 5篇 |
2020年 | 7篇 |
2019年 | 6篇 |
2018年 | 12篇 |
2017年 | 6篇 |
2016年 | 11篇 |
2015年 | 12篇 |
2014年 | 14篇 |
2013年 | 19篇 |
2012年 | 28篇 |
2011年 | 27篇 |
2010年 | 34篇 |
2009年 | 24篇 |
2008年 | 18篇 |
2007年 | 17篇 |
2006年 | 29篇 |
2005年 | 21篇 |
2004年 | 14篇 |
2003年 | 13篇 |
2002年 | 11篇 |
2001年 | 10篇 |
2000年 | 3篇 |
1999年 | 9篇 |
1998年 | 15篇 |
1997年 | 9篇 |
1996年 | 9篇 |
1995年 | 4篇 |
1994年 | 10篇 |
1992年 | 7篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 6篇 |
1988年 | 7篇 |
1987年 | 7篇 |
1985年 | 2篇 |
1983年 | 2篇 |
1982年 | 6篇 |
1981年 | 8篇 |
1980年 | 6篇 |
1978年 | 2篇 |
1977年 | 6篇 |
1971年 | 4篇 |
1963年 | 2篇 |
1959年 | 2篇 |
1958年 | 3篇 |
1957年 | 2篇 |
1955年 | 3篇 |
1949年 | 5篇 |
1948年 | 2篇 |
排序方式: 共有505条查询结果,搜索用时 15 毫秒
31.
Kekenes-Huskey PM Muegge I von Rauch M Gust R Knapp EW 《Bioorganic & medicinal chemistry》2004,12(24):794-6537
Numerous selective estrogen receptor modulators (SERMs) have been synthesized and assayed in recent years. The focus of this study is to apply coarse-grain molecular docking procedures coupled with fine-grain all-atom force field optimization strategies to shed light on the binding mechanisms of currently available estrogen receptor-active compounds. Although the mechanics of ligand binding in estrogen receptors is generally well understood, there is room for surprises. In this paper computational evidence corroborating the experimentally observed type I agonistic binding mode for estradiol (E2) and diethylstilbesterol (DES) and the type II antagonistic binding mode for 4-hydroxytamoxifen and raloxifen is presented. Included in this type I agonistic mode are the DES derivatives, transstilbene and 1,2-diaryldiaminoethane. In addition, a novel ‘type II agonistic’ binding mode for 2,3-diarylimidazolines, 4,5-diarylimidazoles, 2,3-diarylpiperazines is introduced. This mode is stabilized by suggesting alternative hydrogen bond anchor points in the ligand binding domain as potential leads for future drug design. 相似文献
32.
High rate of DNA loss in the Drosophila melanogaster and Drosophila virilis species groups 总被引:6,自引:3,他引:3
We recently proposed that patterns of evolution of non-LTR
retrotransposable elements can be used to study patterns of spontaneous
mutation. Transposition of non-LTR retrotransposable elements commonly
results in creation of 5' truncated, "dead-on-arrival" copies. These
inactive copies are effectively pseudogenes and, according to the neutral
theory, their molecular evolution ought to reflect rates and patterns of
spontaneous mutation. Maximum parsimony can be used to separate the
evolution of active lineages of a non-LTR element from the fate of the
"dead-on-arrival" insertions and to directly assess the relative
frequencies of different types of spontaneous mutations. We applied this
approach using a non-LTR element, Helena, in the Drosophila virilis group
and have demonstrated a surprisingly high incidence of large deletions and
the virtual absence of insertions. Based on these results, we suggested
that Drosophila in general may exhibit a high rate of spontaneous large
deletions and have hypothesized that such a high rate of DNA loss may help
to explain the puzzling dearth of bona fide pseudogenes in Drosophila. We
also speculated that variation in the rate of spontaneous deletion may
contribute to the divergence of genome size in different taxa by affecting
the amount of superfluous "junk" DNA such as, for example, pseudogenes or
long introns. In this paper, we extend our analysis to the D. melanogaster
subgroup, which last shared a common ancestor with the D. virilis group
approximately 40 MYA. In a different region of the same transposable
element, Helena, we demonstrate that inactive copies accumulate deletions
in species of the D. melanogaster subgroup at a rate very similar to that
of the D. virilis group. These results strongly suggest that the high rate
of DNA loss is a general feature of Drosophila and not a peculiar property
of a particular stretch of DNA in a particular species group.
相似文献
33.
34.
Ingo Ott Konrad Kowalski Ronald Gust Jörg Maurer Philipp Mücke Rainer F. Winter 《Bioorganic & medicinal chemistry letters》2010,20(3):866-869
Two ethylene linked binuclear mixed ferrocene/ruthenium complexes were biologically investigated in comparison to structurally related mononuclear ferrocene or ruthenium species with styryl substituents or ligands. Results indicated that the electron distribution (but not the redox potential), cellular uptake and (to some minor extent) anti-estrogenic effects were the key contributors to antiproliferative effects observed in tumor cell lines. 相似文献
35.
Intensified antineoplastic effect by combining an HDAC‐inhibitor,an mTOR‐inhibitor and low dosed interferon alpha in prostate cancer cells 下载免费PDF全文
Igor Tsaur Lukasz Hudak Jasmina Makarević Eva Juengel Jens Mani Hendrik Borgmann Kilian M. Gust David Schilling Georg Bartsch Karen Nelson Roman A. Blaheta 《Journal of cellular and molecular medicine》2015,19(8):1795-1804
A significant proportion of men diagnosed with prostate cancer (PCa) eventually develop metastatic disease, which progresses to castration resistance, despite initial response to androgen deprivation. As anticancer therapy has become increasingly effective, acquired drug resistance has emerged, limiting efficacy. Combination treatment, utilizing different drug classes, exemplifies a possible strategy to foil resistance development. The effects of the triple application of the histone deacetylase (HDAC) inhibitor valproic acid (VPA), the mammalian target of rapamycin inhibitor everolimus and low dosed interferon alpha (IFNα) on PCa cell growth and dissemination capacity were investigated. For that purpose, the human PCa cell lines, PC‐3, DU‐145 and LNCaP were treated with the combined regimen or separate single agents. Cell growth was investigated by the MTT dye reduction assay. Flow cytometry served to analyse cell cycle progression. Adhesion to vascular endothelium or immobilized collagen, fibronectin and laminin was quantified. Migration and invasion characteristics were determined by the modified Boyden chamber assay. Integrin α and β subtypes were investigated by flow cytometry, western blotting and RT‐PCR. Integrin related signalling, Epidermal Growth Factor Receptor (EGFr), Akt, p70S6kinase and extracellular signal‐regulated kinases (ERK)1/2 activation were also assessed. The triple application of VPA, everolimus and low dosed IFNα blocked tumour cell growth and dissemination significantly better than any agent alone. Antitumour effects were associated with pronounced alteration in the cell cycle machinery, intracellular signalling and integrin expression profile. Combining VPA, everolimus and low dosed IFNα might be a promising option to counteract resistance development and improve outcome in PCa patients. 相似文献
36.
Stefan Vallo Martin Michaelis Florian Rothweiler Georg Bartsch Kilian M. Gust Dominik M. Limbart Franz R?del Felix Wezel Axel Haferkamp Jindrich Cinatl Jr. 《Translational oncology》2015,8(3):210-216
Combination chemotherapy with gemcitabine and cisplatin in patients with metastatic urothelial cancer of the bladder frequently results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance could help to identify candidate treatments for an efficient second-line therapy. Six cisplatin- and six gemcitabine-resistant cell lines were established. Cell viability assays were performed to evaluate the sensitivity to 16 different chemotherapeutic substances. The activity of the drug transporter ATP-binding cassette transporter, subfamily B, member 1 (ABCB1, a critical mediator of multidrug resistance in cancer) was evaluated using fluorescent ABCB1 substrates. For functional assessment, cells overexpressing ABCB1 were generated by transduction with a lentiviral vector encoding for ABCB1, while zosuquidar was used for selective inhibition. In this study, 8 of 12 gemcitabine- or cisplatin-resistant cell lines were cross-resistant to carboplatin, 5 to pemetrexed, 4 to methotrexate, 3 to oxaliplatin, 5-fluorouracil, and paclitaxel, and 2 to cabazitaxel, larotaxel, docetaxel, topotecan, doxorubicin, and mitomycin c, and 1 of 12 cell lines was cross-resistant to vinflunine and vinblastine. In one cell line with acquired resistance to gemcitabine (TCC-SUPrGEMCI20), cross-resistance seemed to be mediated by ABCB1 expression. Our model identified the vinca alkaloids vinblastine and vinflunine, in Europe an already approved second-line therapeutic for metastatic bladder cancer, as the most effective compounds in urothelial cancer cells with acquired resistance to gemcitabine or cisplatin. These results demonstrate that this in vitro model can reproduce clinically relevant results and may be suitable to identify novel substances for the treatment of metastatic bladder cancer. 相似文献
37.
Béatris Mastelic Sohail Ahmed William M. Egan Giuseppe Del Giudice Hana Golding Ian Gust Pieter Neels Steven G. Reed Rebecca L. Sheets Claire-Anne Siegrist Paul-Henri Lambert 《Biologicals》2010,38(5):594-601
For decades, the search for new vaccine adjuvants has been largely empirical. A series of new adjuvants and related formulations are now emerging that are acting through identified immunological mechanisms. Understanding adjuvant mechanism of action is crucial for vaccine design, since this allows for directing immune responses towards efficacious disease-specific effector mechanisms and appropriate memory. It is also of great importance to build new paradigms for assessing adjuvant safety at development stages and at regulatory level. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference, organized by the International Association for Biologicals (IABS), on the mode of action of adjuvants on 29–30 April 2010 in Bethesda, Maryland, USA, particularly focusing on how understanding adjuvants mode of action can impact on the assessment of vaccine safety and help to develop target-specific vaccines. More information on the conference output can be found on the IABS website, http://www.iabs.org/. 相似文献
38.
M. Gust E. Vulliet B. Giroud F. Garnier S. Couturier J. Garric T. Buronfosse 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(19):1487-1492
The role of vertebrate-like sex-steroids (testosterone, T, progesterone, P, and 17β-estradiol, E2) in molluscs is still debated, but they could represent potential biomarkers of endocrine disruption. A radioimmunoassay (RIA) and a liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) methods have been developed and compared to measure their levels in a gastropod snail Potamopyrgus antipodarum. Both methods showed a good reproducibility despite the complex matrix and the very low levels of vertebrate-like sex-steroids. Only T and P were detected using the LC–MS/MS method, while the RIA method reached lower detection limits and enabled the detection of all three steroids. Results indicated that T and P were mainly present as unconjugated forms. Both methods were compared in the analysis of snails exposed to waste water treatment plant effluents and led to the same conclusions concerning the modulation of steroids levels. Moreover, they both were in agreement concerning T measurements. On the other hand, LC–MS/MS appeared to be more suitable when analyzing P levels due to a low sensitivity of the RIA method. As E2 was not measured using the LC–MS/MS method because of a higher detection limit compared to the other steroids, the results obtained with the RIA method should be interpreted with caution. LC–MS/MS remains the gold standard for sex-steroid determinations, however a relevant and alternative method based on RIA was developed, requiring fewer organisms. RIA seems a promising method as a screening tool for experimental use, allowing comparison of sex-steroid levels in the mudsnail both in laboratory and in field experiments. 相似文献
39.
LEANDRO AMBRÓSIO CAMPOS HÉLIO RICARDO DA SILVA ANTONIO SEBBEN 《Biological journal of the Linnean Society. Linnean Society of London》2010,99(4):752-767
We describe the extra bony elements, plates, and osteoderms present in species of the genus Brachycephalus. Samples of eight species of Brachycephalus, including seven populations of Brachycephalus ephippium, were examined. The large additional elements associated with the skull (parotic plate) and vertebrae (vertebral and paravertebral plates) all comprise intramembranous bone, similar to that of the frontoparietal or nasal bones of the skull of most of frogs. Additionally, in the dermis of one unnamed species, we discovered and described true osteoderms. We discuss the morphological nature and diversity of theses elements and their importance as evidence of phylogenetic relationship within Brachycephalus. In summary, three distinct conditions of extra bony elements occur in the genus Brachycephalus: (1) bony plates may be present or absent in species of the genus; (2) a few, small bony plates may be developed and these may be represented by (a) paravertebral plates small and restricted to the distal ends of the transverse processes of the presacral IV, (b) parotic plates small and not covering the tops of the squamosals, and (c) ornamented spinal plates on all vertebrae; and (3) well‐developed bony plates may be present as (a) paravertebral plates forming a ‘bone‐shield’ on the dorsal surface of the trunk, ornamented, and visible through the integument, (b) parotic plates covering the tops of the squamosals, and (c) spinal plates associated with all vertebrae, and ornamented on vertebrate I–VI. Although the phenomenon of miniaturization may be associated with the appearance of new elements in at least some of the species in the genus, the traditional rule may not be universally applicable. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2010, 99 , 752–767. 相似文献
40.
PATRICIA FERNANDES NERES VERÔNICA GOMES DA FONSECA‐GENEVOIS RODRIGO AUGUSTO TORRES MARIANA DA FONSECA CAVALCANTI FRANCISCO JOSÉ VICTOR DE CASTRO NEYVAN RENATO RODRIGUES DA SILVA TANIA TASSINARI RIEGER WILFRIDA DECRAEMER 《Zoological Journal of the Linnean Society》2010,158(1):1-15
A new species of Daptonema is described based upon morphological characters and 18S rRNA sequence. Daptonema matrona sp. nov. was collected in Pina Basin (north‐eastern Brazil). It differs from all other species of the genus by the presence of reduced cephalic setae and straight spicules. These features require an adaptation of the generic diagnosis. Moreover, the females are characterized by intra‐uterine development of the offspring, considered herein as their major autapomorphic feature. Molecular systematic analyses supported Daptonema matrona sp. nov. as a distinct genetic and evolutionary lineage. The data also indicate hypotheses of taxonomic synonymies amongst some related taxa from Xyalidae as well as the paraphyly of Daptonema. © 2010 The Linnean Society of London, Zoological Journal of the Linnean Society, 2010, 158 , 1–15. 相似文献