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991.
In response to a DNA double-strand break (DSB), cells undergo a transient cell cycle arrest prior to mitosis until the break is repaired. In budding yeast (Saccharomyces cerevisiae), the DNA damage checkpoint is regulated by a signaling cascade of protein kinases, including Mec1 and Rad53. When DSB repair is complete, cells resume cell cycle progression (a process called "recovery") by turning off the checkpoint. Recovery involves two members of the protein phosphatase 2C (PP2C) family, Ptc2 and Ptc3, as well as the protein phosphatase 4 (PP4) enzyme, Pph3. Here, we demonstrate a new function of these three phosphatases in DSB repair. Cells lacking all three phosphatases Pph3, Ptc2, and Ptc3 exhibit synergistic sensitivities to the DNA-damaging agents camptothecin and methyl methanesulfonate, as well as hydroxyurea but not to UV light. Moreover, the simultaneous absence of Pph3, Ptc2, and Ptc3 results in defects in completing DSB repair, whereas neither single nor double deletion of the phosphatases causes a repair defect. Specifically, cells lacking all three phosphatases are defective in the repair-mediated DNA synthesis. Interestingly, the repair defect caused by the triple deletion of Pph3, Ptc2, and Ptc3 is most prominent when a DSB is slowly repaired and the DNA damage checkpoint is fully activated. 相似文献
992.
Hwee DT Gomes AV Bodine SC 《American journal of physiology. Endocrinology and metabolism》2011,301(5):E967-E977
Muscle ring finger-1 (MuRF1) is a muscle-specific E3 ubiquitin ligase that has been implicated in the regulation of cardiac mass through its control of the ubiquitin proteasome system. While it has been suggested that MuRF1 is required for cardiac atrophy, a resting cardiac phenotype has not been reported in mice with a null deletion [knockout (KO)] of MuRF1. Here, we report that MuRF1 KO mice have significantly larger hearts than age-matched wild-type (WT) littermates at ≥ 6 mo of age and that loss of cardiac mass can occur in the absence of MuRF1. The objective of this study was to determine whether changes in proteasome activity were responsible for the cardiac phenotypes observed in MuRF1 KO mice. Cardiac function, architecture, and proteasome activity were analyzed at rest and following 28 days of dexamethasone (Dex) treatment in 6-mo-old WT and MuRF1 KO mice. Echocardiography demonstrated normal cardiac function in the enlarged hearts in MURF1 KO mice. At rest, heart mass and cardiomyocyte diameter were significantly greater in MuRF1 KO than in WT mice. The increase in cardiac size in MuRF1 KO mice was related to a decrease in proteasome activity and an increase in Akt signaling relative to WT mice. Dex treatment induced a significant loss of cardiac mass in MuRF1 KO, but not WT, mice. Furthermore, Dex treatment resulted in an increase in proteasome activity in KO, but a decrease in WT, mice. In contrast, Akt/mammalian target of rapamycin signaling decreased in MuRF1 KO mice and increased in WT mice in response to Dex treatment. These findings demonstrate that MuRF1 plays an important role in regulating cardiac size through alterations in protein turnover and that MuRF1 is not required to induce cardiac atrophy. 相似文献
993.
Brendan Fisher Richard B. Bradbury Julian E. Andrews Malcolm Ausden Stephanie Bentham-Green Sue M. White Jennifer A. Gill 《Biodiversity and Conservation》2011,20(11):2461-2481
Biodiversity conservation organisations have recently begun to consider a wider ecosystem services context for their activities.
While the literature suggests the potential of ‘win–win’ situations where biodiversity conservation and the delivery of ecosystem
services overlap, empirical evidence is wanting. Here we explore the role that species-led management for the benefit of biodiversity
in cultural landscapes can play in the delivery of wider ecosystem services. We use UK lowland wetlands as a case study and
show how successful delivery of species-led conservation through management interventions relies on practices that can affect
greenhouse gas fluxes, water quality and regulation, and cultural benefits. In these wetlands, livestock grazing has potentially
large effects on water and greenhouse gas related services, but there is little scope to alter management without compromising
species objectives. Likewise, there is little potential to alter reedbed management without compromising conservation objectives.
There is some potential to alter woodland and scrub management, but this would likely have limited influence due to the relatively
small area over which such management is practiced. The management of water levels potentially has large effects on provision
of several services and there does appear to be some scope to align this objective with biodiversity objectives. A comprehensive
understanding of the net costs and benefits to society of these interventions will require fine-grained research integrating ecological, economic
and social science research. However, a less analytic understanding of the potential costs and benefits can highlight ways
by which land management principally to achieve biodiversity conservation objectives might be modified to enhance delivery
of other ecosystem services. 相似文献
994.
Jin-Su Park Jun-Hyuk Han Sue Jung Lee Kwang-Soon Shin Yon-Suk Kim Ju-Hui Kang Se-Bin Lee Tae-Bong Kang Kwang-Ho Lee 《化学与生物多样性》2021,18(5):e2100031
Macrophages play a major role in innate immune responses by producing a variety of immune mediators and cytokines. The stimulation of macrophages by natural products may lead to an enhanced innate immune system. This study evaluated the immunostimulatory effects of a polysaccharide-rich crude fraction of Celosia cristata L. flowers (CCP) on murine macrophages. CCP treatment induced the production of inducible nitric oxide synthase, cyclooxygenase-2, and cytokines by macrophages. Mechanistically, the activation of mitogen-activated protein kinases, NF-κB and toll-like receptor 4 were found to be associated with the stimulatory functions of CCP. CCP was found to be primarily composed of galacturonic acid and glucose in addition to small amounts of arabinose and galactose. This study demonstrated that CCP may enhance the innate immune responses and potentially improve the immune functions in the body. 相似文献
995.
996.
Gail F. Forrest Karen Hutchinson Douglas J. Lorenz Jeffrey J. Buehner Leslie R. VanHiel Sue Ann Sisto D. Michele Basso 《PloS one》2014,9(5)
Objective
To evaluate the relationship and redundancy between gait speeds measured by the 10 Meter Walk Test (10MWT) and 6 Minute Walk Test (6MWT) after motor incomplete spinal cord injury (iSCI). To identify gait speed thresholds supporting functional ambulation as measured with the Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI).Design
Prospective observational cohort.Setting
Seven outpatient rehabilitation centers from the Christopher and Dana Reeve Foundation NeuroRecovery Network (NRN).Participants
249 NRN patients with American Spinal Injury Association Impairment Scale (AIS) level C (n = 20), D (n = 179) and (n = 50) iSCI not AIS evaluated, from February 2008 through April 2011.Interventions
Locomotor training using body weight support and walking on a treadmill, overground and home/community practice.Main Outcome Measure(s)
10MWT and 6MWT collected at enrollment, approximately every 20 sessions, and upon discharge.Results
The 10MWT and 6MWT speeds were highly correlated and the 10MWT speeds were generally faster. However, the predicted 6MWT gait speed from the 10MWT, revealed increasing error with increased gait speed. Regression lines remained significantly different from lines of agreement, when the group was divided into fast (≥0.44 m/s) and slow walkers (<0.44 m/s). Significant differences between 6MWT and 10MWT gait speeds were observed across SCI-FAI walking mobility categories (Wilcoxon sign rank test p<.001), and mean speed thresholds for limited community ambulation differed for each measure. The smallest real difference for the 6MWT and 10MWT, as well as the minimally clinically important difference (MCID) values, were also distinct for the two tests.Conclusions
While the speeds were correlated between the 6MWT and 10MWT, redundancy in the tests using predictive modeling was not observed. Different speed thresholds and separate MCIDs were defined for community ambulation for each test. 相似文献997.
Sue Sha Damayanthi Devineni Atalanta Ghosh David Polidori Marcus Hompesch Sabine Arnolds Linda Morrow Heike Spitzer Keith Demarest Paul Rothenberg 《PloS one》2014,9(8)
Introduction
This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.Methods
Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days –1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations.Results
Canagliflozin increased UGE dose-dependently (∼80–120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4–5 mM (72–90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values.Conclusions
Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes.Trial Registration
ClinicalTrials.gov NCT00963768相似文献998.
Aron S. Buchman Sue E. Leurgans Aner Weiss Veronique VanderHorst Anat Mirelman Robert Dawe Lisa L. Barnes Robert S. Wilson Jeffrey M. Hausdorff David A. Bennett 《PloS one》2014,9(1)
Objective
To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait.Methods
During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a) walking, b) transition from sit to stand, c) transition from stand to sit, d) turning and e) standing posture. Parkinsonian gait and other mild parkinsonian signs were assessed with a modified version of the original Unified Parkinson’s Disease Rating Scale (mUPDRS).Results
In a series of separate regression models which adjusted for age and sex, all 5 mobility subtask measures were associated with parkinsonian gait and accounted for 2% to 32% of its variance. When all 5 subtask measures were considered in a single model, backward elimination showed that measures of walking sit to stand and turning showed independent associations with parkinsonian gait and together accounted for more than 35% of its variance. Cross-validation using data from a 2nd group of 258 older adults showed similar results. In similar analyses, only walking was associated with bradykinesia and sway with tremor.Interpretation
Quantitative mobility subtask measures vary in their associations with parkinsonian gait scores and other parkinsonian signs in older adults. Quantifying the different facets of mobility has the potential to facilitate the clinical characterization and understanding the biologic basis for impaired mobility in older adults. 相似文献999.
Background
Children''s exposure to secondhand smoke (SHS) has been causally linked to a number of childhood morbidities and mortalities. Over 50% of UK children whose parents are smokers are regularly exposed to SHS at home. No previous review has identified the factors associated with children''s SHS exposure in the home.Aim
To identify by systematic review, the factors which are associated with children''s SHS exposure in the home, determined by parent or child reports and/or biochemically validated measures including cotinine, carbon monoxide or home air particulate matter.Methods
Electronic searches of MEDLINE, EMBASE, PsychINFO, CINAHL and Web of Knowledge to July 2014, and hand searches of reference lists from publications included in the review were conducted.Findings
Forty one studies were included in the review. Parental smoking, low socioeconomic status and being less educated were all frequently and consistently found to be independently associated with children''s SHS exposure in the home. Children whose parents held more negative attitudes towards SHS were less likely to be exposed. Associations were strongest for parental cigarette smoking status; compared to children of non-smokers, those whose mothers or both parents smoked were between two and 13 times more likely to be exposed to SHS.Conclusion
Multiple factors are associated with child SHS exposure in the home; the best way to reduce child SHS exposure in the home is for smoking parents to quit. If parents are unable or unwilling to stop smoking, they should instigate smoke-free homes. Interventions targeted towards the socially disadvantaged parents aiming to change attitudes to smoking in the presence of children and providing practical support to help parents smoke outside the home may be beneficial. 相似文献1000.
Adams C Aldous DJ Amendola S Bamborough P Bright C Crowe S Eastwood P Fenton G Foster M Harrison TK King S Lai J Lawrence C Letallec JP McCarthy C Moorcroft N Page K Rao S Redford J Sadiq S Smith K Souness JE Thurairatnam S Vine M Wyman B 《Bioorganic & medicinal chemistry letters》2003,13(18):3105-3110
The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed. 相似文献