全文获取类型
收费全文 | 428篇 |
免费 | 45篇 |
出版年
2022年 | 3篇 |
2021年 | 5篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 3篇 |
2017年 | 3篇 |
2016年 | 11篇 |
2015年 | 14篇 |
2014年 | 19篇 |
2013年 | 27篇 |
2012年 | 20篇 |
2011年 | 29篇 |
2010年 | 8篇 |
2009年 | 15篇 |
2008年 | 21篇 |
2007年 | 14篇 |
2006年 | 14篇 |
2005年 | 14篇 |
2004年 | 12篇 |
2003年 | 11篇 |
2002年 | 20篇 |
2001年 | 12篇 |
2000年 | 25篇 |
1999年 | 8篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 5篇 |
1995年 | 4篇 |
1994年 | 4篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 5篇 |
1990年 | 7篇 |
1989年 | 3篇 |
1988年 | 4篇 |
1986年 | 9篇 |
1985年 | 7篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1982年 | 3篇 |
1981年 | 4篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1973年 | 3篇 |
1970年 | 5篇 |
1969年 | 4篇 |
1967年 | 3篇 |
1966年 | 3篇 |
1903年 | 3篇 |
1901年 | 6篇 |
排序方式: 共有473条查询结果,搜索用时 156 毫秒
71.
72.
Increasing evidence suggests that oxidative damage is associated with normal aging and several neurodegenerative diseases. Mild cognitive impairment (MCI), the phase between normal aging and early dementia, is a common problem in the elderly with many subjects going on to develop Alzheimer's disease (AD). Although increased DNA oxidation is observed in the AD brain, it is unclear when the oxidative damage begins. To determine if DNA oxidation occurs in the brain of subjects with MCI, we quantified multiple oxidized bases in nuclear and mitochondrial DNA isolated from frontal, parietal and temporal lobes and cerebellum of short post-mortem interval autopsies of eight amnestic patients with MCI and six age-matched control subjects using gas chromatography/mass spectrometry with selective ion monitoring. We found statistically significant elevations (p < 0.05) of 8-hydroxyguanine, a widely studied biomarker of DNA damage, in MCI nuclear DNA from frontal and temporal lobe and in mitochondrial DNA from the temporal lobe compared with age-matched control subjects. Levels of 8-hydroxyadenine and 4,6-diamino-5-formamidopyrimidine were significantly elevated in nuclear DNA from all three neocortical regions in MCI. Statistically significant elevations of 4,6-diamino-5-formamidopyrimidine were also observed in mitochondrial DNA of MCI temporal, frontal and parietal lobes. These results suggest that oxidative damage to nuclear and mitochondrial DNA occurs in the earliest detectable phase of AD and may play a meaningful role in the pathogenesis of this disease. 相似文献
73.
In E. coli, MinD recruits MinE to the membrane, leading to a coupled oscillation required for spatial regulation of the cytokinetic Z ring. How these proteins interact, however, is not clear because the MinD-binding regions of MinE are sequestered within a six-stranded β sheet and masked by N-terminal helices. minE mutations that restore interaction between some MinD and MinE mutants were isolated. These mutations alter the MinE structure leading to release of the MinD-binding regions and the N-terminal helices that bind the membrane. Crystallization of MinD-MinE complexes revealed a four-stranded β sheet MinE dimer with the released β strands (MinD-binding regions) converted to α helices bound to MinD dimers. These results identify the MinD-dependent conformational changes in MinE that convert it from a latent to an active form and lead to a model of how MinE persists at the MinD-membrane surface. 相似文献
74.
Bromidge SM Clarke SE King FD Lovell PJ Newman H Riley G Routledge C Serafinowska HT Smith DR Thomas DR 《Bioorganic & medicinal chemistry letters》2002,12(10):1357-1360
The synthesis of novel 3-(octahydropyrido[1,2-a]pyrazin-2-yl)- and 3-(hexahydropyrrolo[1,2-a]pyrazin-2-yl)phenyl-2-benzo[b]thiophene sulphonamide derivatives 3, (S)-4 and (R)-4 is described. The compounds show high affinity for the 5-HT6 receptor, excellent selectivity against a range of other receptors and good brain penetration. 相似文献
75.
Peter V Lovell Morgan Wirthlin Larry Wilhelm Patrick Minx Nathan H Lazar Lucia Carbone Wesley C Warren Claudio V Mello 《Genome biology》2014,15(12)
Background
Birds are one of the most highly successful and diverse groups of vertebrates, having evolved a number of distinct characteristics, including feathers and wings, a sturdy lightweight skeleton and unique respiratory and urinary/excretion systems. However, the genetic basis of these traits is poorly understood.Results
Using comparative genomics based on extensive searches of 60 avian genomes, we have found that birds lack approximately 274 protein coding genes that are present in the genomes of most vertebrate lineages and are for the most part organized in conserved syntenic clusters in non-avian sauropsids and in humans. These genes are located in regions associated with chromosomal rearrangements, and are largely present in crocodiles, suggesting that their loss occurred subsequent to the split of dinosaurs/birds from crocodilians. Many of these genes are associated with lethality in rodents, human genetic disorders, or biological functions targeting various tissues. Functional enrichment analysis combined with orthogroup analysis and paralog searches revealed enrichments that were shared by non-avian species, present only in birds, or shared between all species.Conclusions
Together these results provide a clearer definition of the genetic background of extant birds, extend the findings of previous studies on missing avian genes, and provide clues about molecular events that shaped avian evolution. They also have implications for fields that largely benefit from avian studies, including development, immune system, oncogenesis, and brain function and cognition. With regards to the missing genes, birds can be considered ‘natural knockouts’ that may become invaluable model organisms for several human diseases.Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0565-1) contains supplementary material, which is available to authorized users. 相似文献76.
Sarah E. Knowles Gill Toms Caroline Sanders Penny Bee Karina Lovell Stefan Rennick-Egglestone David Coyle Catriona M. Kennedy Elizabeth Littlewood David Kessler Simon Gilbody Peter Bower 《PloS one》2014,9(1)
Objective
Computerised therapies play an integral role in efforts to improve access to psychological treatment for patients with depression and anxiety. However, despite recognised problems with uptake, there has been a lack of investigation into the barriers and facilitators of engagement. We aimed to systematically review and synthesise findings from qualitative studies of computerised therapies, in order to identify factors impacting on engagement.Method
Systematic review and meta-synthesis of qualitative studies of user experiences of computer delivered therapy for depression and/or anxiety.Results
8 studies were included in the review. All except one were of desktop based cognitive behavioural treatments. Black and minority ethnic and older participants were underrepresented, and only one study addressed users with a co-morbid physical health problem. Through synthesis, we identified two key overarching concepts, regarding the need for treatments to be sensitive to the individual, and the dialectal nature of user experience, with different degrees of support and anonymity experienced as both positive and negative. We propose that these factors can be conceptually understood as the ‘non-specific’ or ‘common’ factors of computerised therapy, analogous to but distinct from the common factors of traditional face-to-face therapies.Conclusion
Experience of computerised therapy could be improved through personalisation and sensitisation of content to individual users, recognising the need for users to experience a sense of ‘self’ in the treatment which is currently absent. Exploiting the common factors of computerised therapy, through enhancing perceived connection and collaboration, could offer a way of reconciling tensions due to the dialectal nature of user experience. Future research should explore whether the findings are generalisable to other patient groups, to other delivery formats (such as mobile technology) and other treatment modalities beyond cognitive behaviour therapy. The proposed model could aid the development of enhancements to current packages to improve uptake and support engagement. 相似文献77.
Colin Green David A. Richards Jacqueline J. Hill Linda Gask Karina Lovell Carolyn Chew-Graham Peter Bower John Cape Stephen Pilling Ricardo Araya David Kessler J. Martin Bland Simon Gilbody Glyn Lewis Chris Manning Adwoa Hughes-Morley Michael Barkham 《PloS one》2014,9(8)
Background
Collaborative care is an effective treatment for the management of depression but evidence on its cost-effectiveness in the UK is lacking.Aims
To assess the cost-effectiveness of collaborative care in a UK primary care setting.Methods
An economic evaluation alongside a multi-centre cluster randomised controlled trial comparing collaborative care with usual primary care for adults with depression (n = 581). Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER) were calculated over a 12-month follow-up, from the perspective of the UK National Health Service and Personal Social Services (i.e. Third Party Payer). Sensitivity analyses are reported, and uncertainty is presented using the cost-effectiveness acceptability curve (CEAC) and the cost-effectiveness plane.Results
The collaborative care intervention had a mean cost of £272.50 per participant. Health and social care service use, excluding collaborative care, indicated a similar profile of resource use between collaborative care and usual care participants. Collaborative care offered a mean incremental gain of 0.02 (95% CI: –0.02, 0.06) quality-adjusted life-years over 12 months, at a mean incremental cost of £270.72 (95% CI: –202.98, 886.04), and resulted in an estimated mean cost per QALY of £14,248. Where costs associated with informal care are considered in sensitivity analyses collaborative care is expected to be less costly and more effective, thereby dominating treatment as usual.Conclusion
Collaborative care offers health gains at a relatively low cost, and is cost-effective compared with usual care against a decision-maker willingness to pay threshold of £20,000 per QALY gained. Results here support the commissioning of collaborative care in a UK primary care setting. 相似文献78.
Michael L. Barta Keisha Thomas Hongling Yuan Scott Lovell Kevin P. Battaile Vern L. Schramm P. Scott Hefty 《The Journal of biological chemistry》2014,289(46):32214-32229
The obligate intracellular human pathogen Chlamydia trachomatis is the etiological agent of blinding trachoma and sexually transmitted disease. Genomic sequencing of Chlamydia indicated this medically important bacterium was not exclusively dependent on the host cell for energy. In order for the electron transport chain to function, electron shuttling between membrane-embedded complexes requires lipid-soluble quinones (e.g. menaquionone or ubiquinone). The sources or biosynthetic pathways required to obtain these electron carriers within C. trachomatis are poorly understood. The 1.58Å crystal structure of C. trachomatis hypothetical protein CT263 presented here supports a role in quinone biosynthesis. Although CT263 lacks sequence-based functional annotation, the crystal structure of CT263 displays striking structural similarity to 5′-methylthioadenosine nucleosidase (MTAN) enzymes. Although CT263 lacks the active site-associated dimer interface found in prototypical MTANs, co-crystal structures with product (adenine) or substrate (5′-methylthioadenosine) indicate that the canonical active site residues are conserved. Enzymatic characterization of CT263 indicates that the futalosine pathway intermediate 6-amino-6-deoxyfutalosine (kcat/Km = 1.8 × 103
m−1 s−1), but not the prototypical MTAN substrates (e.g. S-adenosylhomocysteine and 5′-methylthioadenosine), is hydrolyzed. Bioinformatic analyses of the chlamydial proteome also support the futalosine pathway toward the synthesis of menaquinone in Chlamydiaceae. This report provides the first experimental support for quinone synthesis in Chlamydia. Menaquinone synthesis provides another target for agents to combat C. trachomatis infection. 相似文献
79.
Gennadiy Tenin Christopher Clowes Kathryn Wolton Eliska Krejci Jayne A. Wright Simon C. Lovell David Sedmera Kathryn E. Hentges 《PloS one》2014,9(9)
The heart is the first organ required to function during embryonic development and is absolutely necessary for embryo survival. Cardiac activity is dependent on both the sinoatrial node (SAN), which is the pacemaker of heart''s electrical activity, and the cardiac conduction system which transduces the electrical signal though the heart tissue, leading to heart muscle contractions. Defects in the development of cardiac electrical function may lead to severe heart disorders. The Erbb2 (Epidermal Growth Factor Receptor 2) gene encodes a member of the EGF receptor family of receptor tyrosine kinases. The Erbb2 receptor lacks ligand-binding activity but forms heterodimers with other EGF receptors, stabilising their ligand binding and enhancing kinase-mediated activation of downstream signalling pathways. Erbb2 is absolutely necessary in normal embryonic development and homozygous mouse knock-out Erbb2 embryos die at embryonic day (E)10.5 due to severe cardiac defects. We have isolated a mouse line, l11Jus8, from a random chemical mutagenesis screen, which carries a hypomorphic missense mutation in the Erbb2 gene. Homozygous mutant embryos exhibit embryonic lethality by E12.5-13. The l11Jus8 mutants display cardiac haemorrhage and a failure of atrial function due to defects in atrial electrical signal propagation, leading to an atrial-specific conduction block, which does not affect ventricular conduction. The l11Jus8 mutant phenotype is distinct from those reported for Erbb2 knockout mouse mutants. Thus, the l11Jus8 mouse reveals a novel function of Erbb2 during atrial conduction system development, which when disrupted causes death at mid-gestation. 相似文献
80.
Amy Woods Laura A. Garvican-Lewis Philo U. Saunders Greg Lovell David Hughes Ruth Fazakerley Bev Anderson Christopher J. Gore Kevin G. Thompson 《PloS one》2014,9(9)