全文获取类型
收费全文 | 563篇 |
免费 | 41篇 |
出版年
2022年 | 7篇 |
2021年 | 7篇 |
2018年 | 6篇 |
2017年 | 5篇 |
2016年 | 9篇 |
2015年 | 19篇 |
2014年 | 19篇 |
2013年 | 21篇 |
2012年 | 20篇 |
2011年 | 18篇 |
2010年 | 13篇 |
2009年 | 10篇 |
2008年 | 22篇 |
2007年 | 15篇 |
2006年 | 17篇 |
2005年 | 12篇 |
2004年 | 16篇 |
2003年 | 16篇 |
2002年 | 17篇 |
2001年 | 8篇 |
2000年 | 5篇 |
1999年 | 10篇 |
1998年 | 5篇 |
1994年 | 9篇 |
1990年 | 6篇 |
1979年 | 6篇 |
1977年 | 9篇 |
1973年 | 8篇 |
1972年 | 5篇 |
1971年 | 5篇 |
1970年 | 7篇 |
1969年 | 12篇 |
1968年 | 11篇 |
1967年 | 10篇 |
1966年 | 6篇 |
1965年 | 12篇 |
1964年 | 7篇 |
1963年 | 9篇 |
1961年 | 7篇 |
1960年 | 8篇 |
1959年 | 15篇 |
1958年 | 10篇 |
1957年 | 6篇 |
1956年 | 8篇 |
1955年 | 8篇 |
1954年 | 4篇 |
1953年 | 12篇 |
1951年 | 7篇 |
1950年 | 6篇 |
1949年 | 5篇 |
排序方式: 共有604条查询结果,搜索用时 15 毫秒
501.
Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice 下载免费PDF全文
Kirsty Foote Johannes Reinhold Emma P. K. Yu Nichola L. Figg Alison Finigan Michael P. Murphy Martin R. Bennett 《Aging cell》2018,17(4)
Aging is the largest risk factor for cardiovascular disease, yet the molecular mechanisms underlying vascular aging remain unclear. Mitochondrial DNA (mtDNA) damage is linked to aging, but whether mtDNA damage or mitochondrial dysfunction is present and directly promotes vascular aging is unknown. Furthermore, mechanistic studies in mice are severely hampered by long study times and lack of sensitive, repeatable and reproducible parameters of arterial aging at standardized early time points. We examined the time course of multiple invasive and noninvasive arterial physiological parameters and structural changes of arterial aging in mice, how aging affects vessel mitochondrial function, and the effects of gain or loss of mitochondrial function on vascular aging. Vascular aging was first detected by 44 weeks (wk) of age, with reduced carotid compliance and distensibility, increased β‐stiffness index and increased aortic pulse wave velocity (PWV). Aortic collagen content and elastin breaks also increased at 44 wk. Arterial mtDNA copy number (mtCN) and the mtCN‐regulatory proteins TFAM, PGC1α and Twinkle were reduced by 44 wk, associated with reduced mitochondrial respiration. Overexpression of the mitochondrial helicase Twinkle (Tw+) increased mtCN and improved mitochondrial respiration in arteries, and delayed physiological and structural aging in all parameters studied. Conversely, mice with defective mitochondrial polymerase‐gamma (PolG) and reduced mtDNA integrity demonstrated accelerated vascular aging. Our study identifies multiple early and reproducible parameters for assessing vascular aging in mice. Arterial mitochondrial respiration reduces markedly with age, and reduced mtDNA integrity and mitochondrial function directly promote vascular aging. 相似文献
502.
Stephanie?M. Cope Sandip Shinde Robert?B. Best Giovanna Ghirlanda Sara?M. Vaiana 《Biophysical journal》2013,105(7):1661-1669
We report for the first time, to our knowledge, that the N-terminal loop (N_loop) of amylin (islet amyloid polypeptide (IAPP) residues 1–8) forms extremely long and stable non-β-sheet fibers in solution under the same conditions in which human amylin (hIAPP) forms amyloid fibers. This observation applies to the cyclic, oxidized form of the N_loop but not to the linear, reduced form, which does not form fibers. Our findings indicate a potential role of direct N_loop-N_loop interactions in hIAPP aggregation, which has not been previously explored, with important implications for the mechanism of hIAPP amyloid fiber formation, the inhibitory action of IAPP variants, and the competition between ordered and disordered aggregation in peptides of the calcitonin peptide family. 相似文献
503.
504.
The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells 总被引:1,自引:0,他引:1
Jones S Horwood N Cope A Dazzi F 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(5):2824-2831
Although it has been widely demonstrated that human mesenchymal stem cells exert potent immunosuppressive effects, there is little information as to whether more mature mesenchymal stromal cells (SC) share the same property. Accordingly, we set out to test the ability of SC from different human tissues to inhibit the proliferation of PBMC following polyclonal stimuli. Chondrocytes, as well as fibroblasts from synovial joints, lung, and skin, were used as a source of SC. Irrespective of their differentiation potential and/or content of progenitor cells, SC from all tissues exhibited antiproliferative functions. This was in marked contrast to parenchymal cells. Although SC did not interfere with early T lymphocyte activation, they arrested stimulated T cells in the G(0)/G(1) phase of the cell cycle and rescued them from apoptosis. In addition, IFN-gamma and TNF-alpha production were reduced. We observed that the inhibitory effect is ultimately mediated by soluble factors, the production of which requires SC to be licensed in an inflammatory environment by cell contact. We conclude that the immunosuppressive effect of mesenchymal cells is not confined to multipotent stem cells, but is a fundamental characteristic of all stroma. Our data suggest that SC, appropriately licensed, regulate T cell homeostasis. 相似文献
505.
Seth D Seegobin Margaret HY Ma Chanaka Dahanayake Andrew P Cope David L Scott Cathryn M Lewis Ian C Scott 《Arthritis research & therapy》2014,16(1):R13
Introduction
UK guidelines recommend that all early active rheumatoid arthritis (RA) patients are offered combination disease-modifying antirheumatic drugs (DMARDs) and short-term corticosteroids. Anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA may differ in their treatment responses. We used data from a randomized controlled trial - the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trial - to examine whether responses to intensive combination treatments in early RA differ by ACPA status.Methods
The CARDERA trial randomized 467 early active RA patients to receive: (1) methotrexate, (2) methotrexate/ciclosporin, (3) methotrexate/prednisolone or (4) methotrexate/ciclosporin/prednisolone in a factorial-design. Patients were assessed every six months for two years. In this analysis we evaluated 431 patients with available ACPA status. To minimize multiple testing we used a mixed-effects repeated measures ANOVA model to test for an interaction between ACPA and treatment on mean changes from baseline for each outcome (Larsen, disease activity scores on a 28-joint count (DAS28), Health Assessment Questionnaire (HAQ), EuroQol, SF-36 physical component summary (PCS) and mental component summary (MCS) scores). When a significant interaction was present, mean changes in outcomes were compared by treatment group at each time point using t-tests stratified by ACPA status. Odds ratios (ORs) for the onset of new erosions with treatment were calculated stratified by ACPA.Results
ACPA status influenced the need for combination treatments to reduce radiological progression. ACPA-positive patients had significant reductions in Larsen score progression with all treatments. ACPA-positive patients receiving triple therapy had the greatest benefits: two-year mean Larsen score increases comprised 3.66 (95% confidence interval (CI) 2.27 to 5.05) with triple therapy and 9.58 (95% CI 6.76 to 12.39) with monotherapy; OR for new erosions with triple therapy versus monotherapy was 0.32 (95% CI 0.14 to 0.72; P = 0.003). ACPA-negative patients had minimal radiological progression irrespective of treatment. Corticosteroid’s impact on improving DAS28/PCS scores was confined to ACPA-positive RA.Conclusions
ACPA status influences the need for combination DMARDs and high-dose tapering corticosteroids in early RA. In CARDERA, combination therapy was only required to prevent radiological progression in ACPA-positive patients; corticosteroids only provided significant disease activity and physical health improvements in ACPA-positive disease. This suggests ACPA is an important biomarker for guiding treatment decisions in early RA.Trial registration
Current Controlled Trials ISRCTN32484878 相似文献506.
Leslie M. Cope Mary Jo Fackler Zoila Lopez-Bujanda Antonio C. Wolff Kala Visvanathan Joe W. Gray Saraswati Sukumar Christopher B. Umbricht 《PloS one》2014,9(8)
It is well documented that tumor cells undergo dramatic genetic and epigenetic changes during initial establishment as cell lines and in subsequent serial passaging, and that the resultant cell lines may have evolved significantly from the primary tumors from which they were derived. This has potential implications due to their widespread use in drug response experiments and studies of genomic function. One approach to optimizing the design of such cell line studies is to identify and use the cell lines that faithfully recapitulate critical features of primary tumors. To evaluate the epigenetic fidelity of breast cancer cell lines in the context of primary tumors, we performed methylation profiling of 55 well-characterized breast cancer cell lines on the Illumina HumanMethylation27 BeadChip platform, and compared them to publicly available methylation profiles of primary breast tumors. We found that the DNA methylation profiles of breast cancer cell lines largely retain the features that characterize primary tumors, although there are crucial differences as well. We describe these similarities and differences between primary tumors and breast cancer cell lines in detail, and develop a quantitative measure of similarity that is used to score each cell line with respect to how faithfully its methylation profile mirrors that of primary tumors. 相似文献
507.
508.
Select human cancer mutants of NRMT1 alter its catalytic activity and decrease N‐terminal trimethylation 下载免费PDF全文
509.
Jonathan G. Pattrick Tom Shepherd Will Hoppitt Nichola S. Plowman Pat Willmer 《Arthropod-Plant Interactions》2017,11(5):623-627
Ant-repellent floral volatiles offer one method through which plants can mediate the detrimental effects of ants on flowers. Although the repellence itself is well documented, the volatiles involved are less well explored. Here, we investigated the floral bouquet of ant-repellent male flowers of Petasites fragrans, identifying 4-methoxybenzaldehyde as the main component. 4-methoxybenzaldehyde significantly repelled ants when presented in isolation in an olfactometer and thus is the likely source of the repellent effect. As 4-methoxybenzaldehyde has previously been shown to attract pollinators, it may therefore have a dual function in P. fragrans, pollinator-attractant and ant-repellent. Additionally, 4-methoxybenzaldehyde is particularly interesting as an ant-repellent as it has been observed in the bouquets of other plant species with specific ant interactions. 相似文献
510.
W R Whalley J Lipiec W E Finch-Savage R E Cope L J Clark H R Rowse 《Journal of experimental botany》2001,52(358):1129-1133
The effect of water stress on the early seedling growth of onions was studied by placing newly-germinated seedlings in vermiculite equilibrated at different water potentials. Roots and shoots elongated more at -0.29 than at -0.64 MPa, but did not elongate at -1.66 MPa. However, roots and shoots of seedlings that had been incubated in vermiculite at -1.66 MPa for up to 35 d resumed elongation when subsequently placed on wet filter boards. This suggests that water stress can induce quiescence in newly-germinated seedlings. 相似文献