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41.
The targeted removal of damaged proteins by proteolysis is crucial for cell survival. We have shown previously that the Lon protease selectively degrades oxidized mitochondrial proteins, thus preventing their aggregation and cross-linking. We now show that the Lon protease is a stress-responsive protein that is induced by multiple stressors, including heat shock, serum starvation, and oxidative stress. Lon induction, by pretreatment with low-level stress, protects against oxidative protein damage, diminished mitochondrial function, and loss of cell proliferation induced by toxic levels of hydrogen peroxide. Blocking Lon induction with Lon siRNA also blocks this induced protection. We propose that Lon is a generalized stress-protective enzyme whose decline may contribute to the increased levels of protein damage and mitochondrial dysfunction observed in aging and age-related diseases. 相似文献
42.
Lenore J. Launer Cora E. Lewis Pamela J. Schreiner Steve Sidney Harsha Battapady David R. Jacobs Kelvin O. Lim Mark D’Esposito Qian Zhang Jared Reis Christos Davatzikos R. Nick Bryan 《PloS one》2015,10(3)
Objective
To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF).Design
Cross-sectional brain Magnetic Resonance I (MRI) study.Setting
Community based cohort in three U.S. sites.Participants
A Caucasian and African-American sub-sample (n= 680; mean age 50.3 yrs) attending the 25 year follow-up exam of the Coronary Artery Risk Development in Young Adults Study.Primary and Secondary Outcomes
3T brain MR images processed for quantitative estimates of: total brain (TBV) and abnormal white matter (AWM) volume; white matter fractional anisotropy (WM-FA); and gray matter cerebral blood flow (GM-CBF). Total intracranial volume is TBV plus cerebral spinal fluid (TICV). A Global Cognitive Function (GCF) score was derived from tests of speed, memory and executive function.Results
Adjusting for TICV and demographic factors, current smoking was significantly associated with lower GM-CBF and TBV, and more AWM (all <0.05); SA with lower GM-CBF, WM-FA and TBV (p=0.01); increasing BMI with decreasing GM-CBF (p<0003); hypertension with lower GM-CBF, WM-FA, and TBV and higher AWM (all <0.05); and diabetes with lower TBV (p=0.007). The GCS was lower as TBV decreased, AWM increased, and WM-FA (all p<0.01).Conclusion
In middle age adults, CVRF are associated with brain health, reflected in MRI measures of structure and perfusion, and cognitive functioning. These findings suggest markers of mid-life cardiovascular and brain health should be considered as indication for early intervention and future risk of late-life cerebrovascular disease and dementia. 相似文献43.
Martin L. Decaris Claire L. Emson Kelvin Li Michelle Gatmaitan Flora Luo Jerome Cattin Corelle Nakamura William E. Holmes Thomas E. Angel Marion G. Peters Scott M. Turner Marc K. Hellerstein 《PloS one》2015,10(4)
Accumulation and degradation of scar tissue in fibrotic liver disease occur slowly, typically over many years. Direct measurement of fibrogenesis, the rate of scar tissue deposition, may provide valuable therapeutic and prognostic information. We describe here results from a pilot study utilizing in vivo metabolic labeling to measure the turnover rate of hepatic collagen and collagen-associated proteins in plasma for the first time in human subjects. Eight subjects with chronic liver disease were labeled with daily oral doses of 2H2O for up to 8 weeks prior to diagnostic liver biopsy and plasma collection. Tandem mass spectrometry was used to measure the abundance and fractional synthesis rate (FSR) of proteins in liver and blood. Relative protein abundance and FSR data in liver revealed marked differences among subjects. FSRs of hepatic type I and III collagen ranged from 0.2–0.6% per day (half-lives of 4 months to a year) and correlated significantly with worsening histologic fibrosis. Analysis of plasma protein turnover revealed two collagen-associated proteins, lumican and transforming growth factor beta-induced-protein (TGFBI), exhibiting FSRs that correlated significantly with FSRs of hepatic collagen. In summary, this is the first direct measurement of liver collagen turnover in vivo in humans and suggests a high rate of collagen remodeling in advanced fibrosis. In addition, the FSRs of collagen-associated proteins in plasma are measurable and may provide a novel strategy for monitoring hepatic fibrogenesis rates. 相似文献
44.
Phillip J. Blaen Li Jia Kelvin S.-H. Peh Rob H. Field Andrew Balmford Michael A. MacDonald Richard B. Bradbury 《PloS one》2015,10(4)
Despite growing recognition that mineral sites restored for nature conservation can enhance local biodiversity, the wider societal benefits provided by this type of restoration relative to alternative options are not well understood. This study addresses this research gap by quantifying differences in ecosystem services provision under two common mineral site after-uses: nature conservation and agriculture. Using a combination of site-specific primary field data, benefits transfer and modelling, we show that for our sites restoration for nature conservation provides a more diverse array of ecosystem services than would be delivered under an agricultural restoration scenario. We also explore the effects of addressing different conservation targets, which we find alter the provision of ecosystem services on a service-specific basis. Highly species-focused intervention areas are associated with increased carbon storage and livestock grazing provision, whereas non-intervention areas are important for carbon sequestration, fishing, recreation and flood risk mitigation. The results of this study highlight the wider societal importance of restored mineral sites and may help conservation managers and planners to develop future restoration strategies that provide benefits for both biodiversity and human well-being. 相似文献
45.
Kelvin K.W. Hui Nicole Liadis Jennifer Robertson Anish Kanungo Jeffrey T. Henderson 《Journal of cellular and molecular medicine》2010,14(3):671-686
The immunosuppressive agents cyclosporin A (CsA) and FK‐506 have previously been shown to exhibit neurotrophic and neuroprotective properties in vivo. Given that significant clinical expertise exists for both drugs, they represent an attractive starting point for treatment of acute neural injuries. One putative mechanism for neuroprotection by these drugs relates to inhibition of calcineurin activity. However each drug–immunophilin complex can potentially influence additional signal transduction pathways. Furthermore, several non‐immunosuppressive immunophilin ligands have been described as possessing neuroprotective properties, suggesting that neuroprotection may be separable from calcineurin inhibition. In the present study, we examined the mechanism of this neuroprotection in facial motor neurons following axotomy‐induced injury. Similar to previous studies in rats, CsA and FK‐506 enhanced motor neuron survival in mice following acute injury. To examine the mechanism responsible for neuroprotection by these agents, pharmacologic inhibitors of several potential alternate signalling pathways (17‐(allylamino)‐17‐demethoxygeldanamycin, rapamycin, cypermethrin) were evaluated with respect to neuroprotection. Of these, only cypermethrin, a direct calcineurin inhibitor not previously associated with neuronal survival properties, was observed to significantly enhance motor neuron survival following injury. The results demonstrate for the first time that direct inhibition of calcineurin is neuroprotective in vivo. These data support a model in which calcineurin inhibition promotes neuronal survival, distinct from effects upon neurite outgrowth. 相似文献
46.
47.
Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome 总被引:2,自引:2,他引:0
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Cameron MJ Ran L Xu L Danesh A Bermejo-Martin JF Cameron CM Muller MP Gold WL Richardson SE Poutanen SM Willey BM DeVries ME Fang Y Seneviratne C Bosinger SE Persad D Wilkinson P Greller LD Somogyi R Humar A Keshavjee S Louie M Loeb MB Brunton J McGeer AJ;Canadian SARS Research Network Kelvin DJ 《Journal of virology》2007,81(16):8692-8706
It is not understood how immune inflammation influences the pathogenesis of severe acute respiratory syndrome (SARS). One area of strong controversy is the role of interferon (IFN) responses in the natural history of SARS. The fact that the majority of SARS patients recover after relatively moderate illness suggests that the prevailing notion of deficient type I IFN-mediated immunity, with hypercytokinemia driving a poor clinical course, is oversimplified. We used proteomic and genomic technology to systematically analyze host innate and adaptive immune responses of 40 clinically well-described patients with SARS during discrete phases of illness from the onset of symptoms to discharge or a fatal outcome. A novel signature of high IFN-alpha, IFN-gamma, and IFN-stimulated chemokine levels, plus robust antiviral IFN-stimulated gene (ISG) expression, accompanied early SARS sequelae. As acute illness progressed, SARS patients entered a crisis phase linked to oxygen saturation profiles. The majority of SARS patients resolved IFN responses at crisis and expressed adaptive immune genes. In contrast, patients with poor outcomes showed deviated ISG and immunoglobulin gene expression levels, persistent chemokine levels, and deficient anti-SARS spike antibody production. We contend that unregulated IFN responses during acute-phase SARS may culminate in a malfunction of the switch from innate immunity to adaptive immunity. The potential for the use of the gene signatures we describe in this study to better assess the immunopathology and clinical management of severe viral infections, such as SARS and avian influenza (H5N1), is therefore worth careful examination. 相似文献
48.
With the development of cell-based assays and therapies, the purity of reagents used to grow and maintain cells has become
much more important. In particular, the use of fetal calf serum for culturing cells presents a direct path for potential contamination
of cell cultures. In recent years, much research has focused on the development of serum-free culturing systems, not only
to alleviate difficulties due to availability and cost of fetal calf serum but also to prevent the transmission of potentially
fatal diseases to human patients. Additionally, methods need to be developed for long-term storage of cell stocks that also
reduce the risk of exposure to harmful diseases. As most methods employ fetal calf serum in their freezing formulations, solutions
that avoid the use of fetal calf serum while providing equivalent or better recovery of cells upon thawing would be ideal.
In this study, two vascular cell lines have been cryopreserved as adherent cell populations in two widely used cryoprotectants,
dimethyl sulfoxide and 1,2-propanediol, and two vehicle solutions, Euro-Collins and Unisol-cryoprotectant vehicle specifically
formulated for the maintenance of cell homeostasis at temperatures below 37° C. The addition of serum to these formulations
was also evaluated to determine if its presence provided any additional benefit to the cells during cryopreservation. The
results demonstrated that using vehicle solutions designed for lower temperatures produced viable cells that retained cell
population viability values up to 75% of unfrozen controls. These results also demonstrated that including serum in the formulation
provided no additional benefit to the cells and in some cases actually produced lower cell viability after cryopreservation.
In conclusion, the development of solutions designed for low-temperature storage of cells provides a viable alternative to
more conventional cryopreservation protocols and eliminates the necessity of including serum in these formulations. 相似文献
49.
Neurochemical Research - The bidirectional communication between the brain and peripheral organs have been widely documented, but the impact of visceral adipose tissue (VAT) dysfunction and its... 相似文献
50.