全文获取类型
收费全文 | 194篇 |
免费 | 45篇 |
专业分类
239篇 |
出版年
2021年 | 1篇 |
2020年 | 1篇 |
2019年 | 3篇 |
2018年 | 11篇 |
2017年 | 7篇 |
2016年 | 3篇 |
2015年 | 4篇 |
2014年 | 5篇 |
2013年 | 9篇 |
2012年 | 5篇 |
2011年 | 6篇 |
2010年 | 2篇 |
2009年 | 4篇 |
2008年 | 6篇 |
2007年 | 7篇 |
2006年 | 6篇 |
2005年 | 8篇 |
2004年 | 4篇 |
2003年 | 9篇 |
2002年 | 11篇 |
2001年 | 11篇 |
2000年 | 10篇 |
1999年 | 11篇 |
1997年 | 3篇 |
1996年 | 7篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1991年 | 5篇 |
1990年 | 4篇 |
1989年 | 6篇 |
1988年 | 6篇 |
1987年 | 4篇 |
1986年 | 8篇 |
1985年 | 3篇 |
1984年 | 6篇 |
1983年 | 3篇 |
1982年 | 6篇 |
1981年 | 4篇 |
1980年 | 1篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1972年 | 1篇 |
1968年 | 1篇 |
1952年 | 1篇 |
1922年 | 1篇 |
排序方式: 共有239条查询结果,搜索用时 15 毫秒
51.
52.
Stopping cancer before it colonizes 总被引:2,自引:0,他引:2
53.
Andrew T. Treweeke Benjamin H. Maskrey Kirsty Hickson John H. Miller Stephen J. Leslie Ian L. Megson 《PloS one》2016,11(1)
Background
There is no consensus and a limited evidence base for choice of contrast agents (CA) in angiography. This study evaluated the impact of iohexol and iodixanol CA on fibrinolytic factors (tissue plasminogen activator [t-PA] and plasminogen activator inhibitor-1 [PAI-1]), as well as platelet-monocyte conjugates in cardiac patients undergoing elective angiography in a double-blind, randomised parallel group study.Methods
Patients (men, 50–70 years old; n = 12) were randomised to receive either iohexol (Omnipaque; n = 6) or iodixanol (Visipaque; n = 6) during elective angiography at Raigmore Hospital, Inverness, UK. Arterial and venous blood samples were drawn prior to CA delivery and following angiography. Assessment of platelet-monocyte conjugation, t-PA and PAI-1 antigen and activity was conducted in samples pre- and post-angiography.Outcome
Plasma t-PA antigen was depressed equally in the study groups after angiography, but there was a greater reduction in PAI-1 antigen in the group receiving iodixanol. These findings corresponded to a substantial reduction in t-PA activity in patients receiving iohexol, with no change in those receiving iodixanol (P = 0.023 between the CA groups). Both CAs caused a reduction in platelet-monocyte conjugation, with no difference between the groups. No adverse events were reported during the trial.Conclusion
Avoiding reduced plasma t-PA activity might be an important consideration in choosing iodixanol over iohexol in patients at risk of thrombosis following angiography. The trial is registered on the ISRCTN register (ISRCTN51509735) and funded by the Coronary Thrombosis Trust and National Health Service (Highland) R&D Endowments. The funders had no influence over study design or reporting.Trial Registration
Controlled-Trials.com ISRCTN51509735 相似文献54.
William?N.?SetzerEmail authorView authors OrcID profile 《Journal of molecular modeling》2018,24(3):74
Frankincense oleoresin has been used in traditional medicine for more than 5000 years. The phytochemistry of frankincense (Boswellia spp.) resins includes triterpenoids (including boswellic acids and their derivatives), diterpenoids (cembrenoids and cneorubenoids), and essential oils. The macrocyclic cembrene diterpenoids may play a part in the biological activities of frankincense resin, but neither the biological targets nor the modes of interaction with the targets are currently known. How these macrocycles interact with biological macromolecules likely depends on what conformation(s) are energetically available to them. In this work, a conformational analysis of 15 Boswellia cembrene diterpenoids and 1 verticillane diterpenoid was carried out at the B3LYP/6-31G* and M06-2X/6-31G* levels of theory, including the SM8 aqueous solvation model. The lowest-energy conformations of boscartin B and incensole oxide were the same as the previously reported X-ray crystal structures, while the lowest-energy conformations of boscartins A and C were very similar to the crystal structures. Boscartins D-H and isoincensole oxide showed only one low-energy conformation for each compound and are predicted to be conformationally locked. Incensole, isoincensolol, and serratol are predicted to be conformationally mobile with several low-energy forms. The conformational mobility of Boswellia cembrenoid diterpenoids depends largely on the degree of epoxidation, either oxirane or tetrahydrofuran rings. 相似文献
55.
Jitka Simandlova Jennifer Zagelbaum Miranda J. Payne Wai Kit Chu Igor Shevelev Katsuhiro Hanada Sujoy Chatterjee Dylan A. Reid Ying Liu Pavel Janscak Eli Rothenberg Ian D. Hickson 《The Journal of biological chemistry》2013,288(47):34168-34180
Efficient repair of DNA double strand breaks and interstrand cross-links requires the homologous recombination (HR) pathway, a potentially error-free process that utilizes a homologous sequence as a repair template. A key player in HR is RAD51, the eukaryotic ortholog of bacterial RecA protein. RAD51 can polymerize on DNA to form a nucleoprotein filament that facilitates both the search for the homologous DNA sequences and the subsequent DNA strand invasion required to initiate HR. Because of its pivotal role in HR, RAD51 is subject to numerous positive and negative regulatory influences. Using a combination of molecular genetic, biochemical, and single-molecule biophysical techniques, we provide mechanistic insight into the mode of action of the FBH1 helicase as a regulator of RAD51-dependent HR in mammalian cells. We show that FBH1 binds directly to RAD51 and is able to disrupt RAD51 filaments on DNA through its ssDNA translocase function. Consistent with this, a mutant mouse embryonic stem cell line with a deletion in the FBH1 helicase domain fails to limit RAD51 chromatin association and shows hyper-recombination. Our data are consistent with FBH1 restraining RAD51 DNA binding under unperturbed growth conditions to prevent unwanted or unscheduled DNA recombination. 相似文献
56.
57.
Taxonomic and ecological studies of freshwater harpacticoid copepods are limited globally by the ability to easily and accurately identify specimens. Here, we test the use of the mitochondrial cytochrome c oxidase subunit I (COI) gene locus as a tool for assessing the diversity of freshwater Harpacticoida. We obtained sequences from New Zealand harpacticoid copepods, representing two families, five genera and nine species, including the non-indigenous Elaphoidella sewelli. All species were delineated by the COI gene. However, high intraspecific diversity was evident among populations of Elaphoidella bidens (>12%), and between North and South Island populations of Bryocamptus pygmaeus (>18%), potentially indicating the presence of morphologically cryptic taxa. We suggest that mitochondrial DNA (COI) sequences can provide a useful tool for the routine identification of freshwater harpacticoid copepods. Applications of these data will include assessing species diversity and biogeography as well as assisting with the detection of non-indigenous species. 相似文献
58.
Direct association of Bloom’s syndrome gene product with the human mismatch repair protein MLH1 下载免费PDF全文
Graziella Pedrazzi Claudia Perrera Heiko Blaser Patrick Kuster Giancarlo Marra Sally L. Davies Gi-Hyuck Ryu Raimundo Freire Ian D. Hickson Josef Jiricny Igor Stagljar 《Nucleic acids research》2001,29(21):4378-4386
Bloom’s syndrome (BS) is a rare genetic disorder characterised by genomic instability and cancer susceptibility. BLM, the gene mutated in BS, encodes a member of the RecQ family of DNA helicases. Here, we identify hMLH1, which is involved in mismatch repair (MMR) and recombination, as a protein that directly interacts with BLM both in vivo and in vitro, and that the two proteins co-localise to discrete nuclear foci. The interaction between BLM and hMLH1 appears to have been evolutionarily conserved, as Sgs1p, the Saccharomyces cerevisiae homologue of BLM, interacts with yeast Mlh1p. However, cell extracts derived from BS patients show no obvious defects in MMR compared to wild-type- and BLM-complemented BS cell extracts. We conclude that the hMLH1–BLM interaction is not essential for post-replicative MMR, but, more likely, is required for some aspect of genetic recombination. 相似文献
59.
Wu L Davies SL North PS Goulaouic H Riou JF Turley H Gatter KC Hickson ID 《The Journal of biological chemistry》2000,275(13):9636-9644
Bloom's syndrome is a rare genetic disorder associated with loss of genomic integrity and a large increase in the incidence of many types of cancer at an early age. The Bloom's syndrome gene product, BLM, belongs to the RecQ family of DNA helicases, which also includes the human Werner's and Rothmund-Thomson syndrome gene products and the Sgs1 protein of Saccharomyces cerevisiae. This family shows strong evolutionary conservation of protein structure and function. Previous studies have shown that Sgs1p interacts both physically and genetically with topoisomerase III. Here, we have investigated whether this interaction has been conserved in human cells. We show that BLM and hTOPO IIIalpha, one of two human topoisomerase III homologues, co-localize in the nucleus of human cells and can be co-immunoprecipitated from human cell extracts. Moreover, the purified BLM and hTOPO IIIalpha proteins are able to bind specifically to each other in vitro, indicating that the interaction is direct. We have mapped two independent domains on BLM that are important for mediating the interaction with hTOPO IIIalpha. Furthermore, through characterizing a genetic interaction between BLM and TOP3 in S. cerevisiae, we have identified a functional role for the hTOPO IIIalpha interaction domains in BLM. 相似文献
60.
Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha 下载免费PDF全文
Freire R d'Adda Di Fagagna F Wu L Pedrazzi G Stagljar I Hickson ID Jackson SP 《Nucleic acids research》2001,29(15):3172-3180
In higher eukaryotes, the integration of signals triggered in response to certain types of stress can result in programmed cell death. Central to these events is the sequential activation of a cascade of proteinases known as caspases. The final activated effector caspases of this cascade digest a number of cellular proteins, in some cases increasing their enzymatic activity, in others destroying their function. Of the proteins shown to be targets for caspase-mediated proteolysis, a surprisingly large proportion are proteins involved in the signalling or repair of DNA damage. Here we investigate whether BLM, the product of the gene mutated in Bloom’s syndrome, a human autosomal disease characterised by cancer predisposition and sunlight sensitivity, is cleaved during apoptosis. BLM interacts with topoisomerase IIIα and has been proposed to play an important role in maintaining genomic integrity through its roles in DNA repair and replication. We show that BLM is cleaved during apoptosis by caspase-3 and reveal that the main cleavage site is located at the junction between the N-terminal and central helicase domains of BLM. Proteolytic cleavage by caspase-3 produces a 120 kDa fragment, which contains the intact helicase domain and three smaller fragments, the relative amounts of which depend on time of incubation with caspase-3. The 120 kDa fragment retains the helicase activity of the intact BLM protein. However, its interaction with topoisomerase IIIα is severely impaired. Since the BLM–topoisomerase interaction is believed to be necessary for many of the replication and recombination functions of BLM, we suggest that caspase-3 cleavage of BLM could alter the localisation and/or function of BLM and that these changes may be important in the process of apoptosis. 相似文献