全文获取类型
收费全文 | 2274篇 |
免费 | 185篇 |
国内免费 | 2篇 |
专业分类
2461篇 |
出版年
2022年 | 12篇 |
2021年 | 32篇 |
2020年 | 13篇 |
2019年 | 21篇 |
2018年 | 27篇 |
2017年 | 25篇 |
2016年 | 62篇 |
2015年 | 99篇 |
2014年 | 82篇 |
2013年 | 117篇 |
2012年 | 147篇 |
2011年 | 148篇 |
2010年 | 112篇 |
2009年 | 79篇 |
2008年 | 142篇 |
2007年 | 137篇 |
2006年 | 108篇 |
2005年 | 108篇 |
2004年 | 126篇 |
2003年 | 126篇 |
2002年 | 122篇 |
2001年 | 22篇 |
2000年 | 20篇 |
1999年 | 28篇 |
1998年 | 46篇 |
1997年 | 31篇 |
1996年 | 29篇 |
1995年 | 28篇 |
1994年 | 31篇 |
1993年 | 31篇 |
1992年 | 31篇 |
1991年 | 29篇 |
1990年 | 18篇 |
1989年 | 22篇 |
1988年 | 25篇 |
1987年 | 13篇 |
1986年 | 16篇 |
1985年 | 15篇 |
1984年 | 20篇 |
1983年 | 13篇 |
1982年 | 12篇 |
1981年 | 19篇 |
1980年 | 15篇 |
1979年 | 13篇 |
1978年 | 13篇 |
1977年 | 13篇 |
1976年 | 16篇 |
1975年 | 7篇 |
1974年 | 11篇 |
1972年 | 6篇 |
排序方式: 共有2461条查询结果,搜索用时 0 毫秒
91.
Diverse functional outcomes of Plasmodium falciparum ligation of EPCR: potential implications for malarial pathogenesis 下载免费PDF全文
Mark R. Gillrie Marion Avril Andrew J. Brazier Shevaun P. Davis Monique F. Stins Joseph D. Smith May Ho 《Cellular microbiology》2015,17(12):1883-1899
Plasmodium falciparum‐infected erythrocytes (IRBC) expressing the domain cassettes (DC) 8 and 13 of the cytoadherent ligand P. falciparum erythrocyte membrane protein 1 adhere to the endothelial protein C receptor (EPCR). By interfering with EPCR anti‐coagulant and pro‐endothelial barrier functions, IRBC adhesion could promote coagulation and vascular permeability that contribute to the pathogenesis of cerebral malaria. In this study, we examined the adhesion of DC8‐ and DC13‐expressing parasite lines to endothelial cells from different microvasculature, and the consequences of EPCR engagement on endothelial cell function. We found that IRBC from IT4var19 (DC8) and IT4var07 (DC13) parasite lines adhered to human brain, lung and dermal endothelial cells under shear stress. However, the relative contribution of EPCR to parasite cytoadherence on different types of endothelial cell varied. We also observed divergent functional outcomes for DC8 cysteine‐rich interdomain region (CIDR)α1.1 and DC13 CIDRα1.4 domains. IT4var07 CIDRα1.4 inhibited generation of activated protein C (APC) on lung and dermal endothelial cells and blocked the APC–EPCR binding interaction on brain endothelial cells. IT4var19 CIDRα1.1 inhibited thrombin‐induced endothelial barrier dysfunction in lung endothelial cells, whereas IT4var07 CIDRα1.4 inhibited the protective effect of APC on thrombin‐induced permeability. Overall, these findings reveal a much greater complexity of how CIDRα1‐expressing parasites may modulate malaria pathogenesis through EPCR adhesion. 相似文献
92.
An immunoaffinity chromatographic procedure with monoclonal antibodies (MA) has been developed for purification of the uncultivable, bacterium-like organism associated with greening disease of citrus. The greening organism (GO) was partially purified from leaf midribs of infected periwinkle plants by differential centrifugation. The GO present in such preparations was retained on an affinity matrix consisting of CNBr-activated Sepharose 4B on which GO-specific MA had been covalently linked. The unbound plant material was washed from the matrix, and the GOs were eluted with 0.1M glycine (pH 11.5). Purified GOs were compared with organisms observed in the initial plant preparation by both immunofluorescence and electron microscopic techniques. The morphology and serological characteristics of the GO were retained following purification procedures. 相似文献
93.
Stacey L. Tannenbaum Monique Hernandez D. Dandan Zheng Daniel A. Sussman David J. Lee 《PloS one》2014,9(8)
Purpose
We examined individual-level and neighborhood-level predictors of mortality in CRC patients diagnosed in Florida to identify high-risk groups for targeted interventions.Methods
Demographic and clinical data from the Florida Cancer Data System registry (2007–2011) were linked with Agency for Health Care Administration and US Census data (n = 47,872). Cox hazard regression models were fitted with candidate predictors of CRC survival and stratified by age group (18–49, 50–64, 65+).Results
Stratified by age group, higher mortality risk per comorbidity was found among youngest (21%), followed by middle (19%), and then oldest (14%) age groups. The two younger age groups had higher mortality risk with proximal compared to those with distal cancer. Compared with private insurance, those in the middle age group were at higher death risk if not insured (HR = 1.35), or received healthcare through Medicare (HR = 1.44), Medicaid (HR = 1.53), or the Veteran’s Administration (HR = 1.26). Only Medicaid in the youngest (52% higher risk) and those not insured in the oldest group (24% lower risk) were significantly different from their privately insured counterparts. Among 18–49 and 50–64 age groups there was a higher mortality risk among the lowest SES (1.17- and 1.23-fold higher in the middle age and 1.12- and 1.17-fold higher in the older age group, respectively) compared to highest SES. Married patients were significantly better off than divorced/separated (HR = 1.22), single (HR = 1.29), or widowed (HR = 1.19) patients.Conclusion
Factors associated with increased risk for mortality among individuals with CRC included being older, uninsured, unmarried, more comorbidities, living in lower SES neighborhoods, and diagnosed at later disease stage. Higher risk among younger patients was attributed to proximal cancer site, Medicaid, and distant disease; however, lower SES and being unmarried were not risk factors in this age group. Targeted interventions to improve survivorship and greater social support while considering age classification may assist these high-risk groups. 相似文献94.
Intrusive memories are a hallmark symptom of posttraumatic stress disorder (PTSD). They reflect excessive and uncontrolled retrieval of the traumatic memory. Acute elevations of cortisol are known to impair the retrieval of already stored memory information. Thus, continuous cortisol administration might help in reducing intrusive memories in PTSD. Strong perceptual priming for neutral stimuli associated with a “traumatic” context has been shown to be one important learning mechanism that leads to intrusive memories. However, the memory modulating effects of cortisol have only been shown for explicit declarative memory processes. Thus, in our double blind, placebo controlled study we aimed to investigate whether cortisol influences perceptual priming of neutral stimuli that appeared in a “traumatic” context. Two groups of healthy volunteers (N = 160) watched either neutral or “traumatic” picture stories on a computer screen. Neutral objects were presented in between the pictures. Memory for these neutral objects was tested after 24 hours with a perceptual priming task and an explicit memory task. Prior to memory testing half of the participants in each group received 25 mg of cortisol, the other half received placebo. In the placebo group participants in the “traumatic” stories condition showed more perceptual priming for the neutral objects than participants in the neutral stories condition, indicating a strong perceptual priming effect for neutral stimuli presented in a “traumatic” context. In the cortisol group this effect was not present: Participants in the neutral stories and participants in the “traumatic” stories condition in the cortisol group showed comparable priming effects for the neutral objects. Our findings show that cortisol inhibits perceptual priming for neutral stimuli that appeared in a “traumatic” context. These findings indicate that cortisol influences PTSD-relevant memory processes and thus further support the idea that administration of cortisol might be an effective treatment strategy in reducing intrusive reexperiencing. 相似文献
95.
De Paepe ME Mao Q Chao Y Powell JL Rubin LP Sharma S 《American journal of physiology. Lung cellular and molecular physiology》2005,289(4):L647-L659
Alveolar epithelial apoptosis is an important feature of hyperoxia-induced lung injury in vivo and has been described in the early stages of bronchopulmonary dysplasia (chronic lung disease of preterm newborn). Molecular regulation of hyperoxia-induced alveolar epithelial cell death remains incompletely understood. In view of functional involvement of Fas/FasL system in physiological postcanalicular type II cell apoptosis, we speculated this system may also be a critical regulator of hyperoxia-induced apoptosis. The aim of this study was to investigate the effects of hyperoxia on apoptosis and apoptotic gene expression in alveolar epithelial cells. Apoptosis was studied by TUNEL, electron microscopy, DNA size analysis, and caspase assays. Fas/FasL expression was determined by Western blot analysis and RPA. We determined that in MLE-12 cells exposed to hyperoxia, caspase-mediated apoptosis was the first morphologically and biochemically recognizable mode of cell death, followed by necrosis of residual adherent cells. The apoptotic stage was associated with a threefold upregulation of Fas mRNA and protein expression and increased susceptibility to direct Fas receptor activation, concomitant with a threefold increase of FasL protein levels. Fas gene silencing by siRNAs significantly reduced hyperoxia-induced apoptosis. In murine fetal type II cells, hyperoxia similarly induced markedly increased Fas/FasL protein expression, confirming validity of results obtained in transformed MLE-12 cells. Our findings implicate the Fas/FasL system as an important regulator of hyperoxia-induced type II cell apoptosis. Elucidation of regulation of hyperoxia-induced lung apoptosis may lead to alternative therapeutic strategies for perinatal or adult pulmonary diseases characterized by dysregulated type II cell apoptosis. 相似文献
96.
Ana O. Fagundes Maira R. Aguiar Claudia S. Aguiar Giselli Scaini Monique U. Sachet Nayara M. Bernhardt Gislaine T. Rezin Samira S. Valvassori João Quevedo Emilio L. Streck 《Neurochemical research》2010,35(11):1675-1680
Methylphenidate is commonly used for the treatment of attention deficit/hyperactivity disorder. There are still few works
regarding the effects of methylphenidate on brain energy metabolism. Thus, in the present study we evaluated the effect of
chronic administration of methylphenidate on the activities of mitochondrial respiratory chain complexes I and III in the
brain of young rats. The effect of acute administration of methylphenidate on mitochondrial respiratory chain complexes I,
II, III and IV in the brain of young rats was also investigated. For acute administration, a single injection of methylphenidate
was given to rats on postnatal day 25. For chronic administration, methylphenidate injections were given starting at postnatal
day 25 once daily for 28 days. Our results showed that complexes I and III were not affected by chronic administration of
methylphenidate. Moreover, the acute administration of methylphenidate decreased complex I activity in cerebellum and prefrontal
cortex, whereas complexes II, III and IV were not altered. 相似文献
97.
Activities of the matrix metalloproteinase stromelysin-2 (MMP-10) in matrix degradation and keratinocyte organization in wounded skin 下载免费PDF全文
Krampert M Bloch W Sasaki T Bugnon P Rülicke T Wolf E Aumailley M Parks WC Werner S 《Molecular biology of the cell》2004,15(12):5242-5254
The matrix metalloproteinase stromelysin-2 is expressed in keratinocytes of the epithelial tongue of skin wounds, suggesting a role in keratinocyte migration. Here, we show that stromelysin-2 enhances migration of cultured keratinocytes. To gain insight into the in vivo activities of stromelysin-2 in epithelial repair, we generated transgenic mice expressing a constitutively active stromelysin-2 mutant in keratinocytes. These animals had no alterations in skin architecture, and the healing rate of skin wounds was normal. Histologically, however, we found abnormalities in the organization of the wound epithelium. Keratinocytes at the migrating epidermal tip were scattered in most sections of mice with high expression level, and there was a reduced deposition of new matrix. In particular, the staining pattern of laminin-5 at the wound site was altered. This may be due to proteolytic processing of laminin-5 by stromelysin-2, because degradation of laminin-5 by this enzyme was observed in vitro. The inappropriate matrix contact of keratinocytes was accompanied by aberrant localization of beta1-integrins and phosphorylated focal adhesion kinase, as well as by increased apoptosis of wound keratinocytes. These results suggest that a tightly regulated expression level of stromelysin-2 is required for limited matrix degradation at the wound site, thereby controlling keratinocyte migration. 相似文献
98.
99.
Dietary myristic acid at physiologically relevant levels increases the tissue content of C20:5 n-3 and C20:3 n-6 in the rat 总被引:1,自引:0,他引:1
This study was designed to investigate the effect of myristic acid on the biosynthesis and metabolism of highly unsaturated fatty acids, when it is supplied in a narrow physiological range in the diet of the rat (0.2-1.2% of total dietary energy). Three experimental diets were designed, containing 22% of total dietary energy as lipids and increasing doses of myristic acid (0.71, 3.00 and 5.57% of total fatty acids). Saturated fat did not exceed 31% of total fat and the C18:3 n-3 amount in each diet was strictly equal (1.6% of total fatty acids). After 7 weeks, the diets had no effect on plasma cholesterol level but greatly modified the liver, plasma and adipose tissue saturated, monounsaturated and polyunsaturated fatty acid profiles. Firstly, daily intakes of myristic acid resulted in a dose-dependent tissue accumulation of myristic acid itself. Palmitic acid was significantly increased in the tissues of the rats fed the higher dose of myristic acid. A dose-response accumulation of tissue C16:1 n-7 as a function of dietary C14:0 was also shown. Secondly, a main finding was that, among n-3 and n-6 polyunsaturated fatty acids, a dose-response accumulation of liver and plasma C20:5 n-3 and C20:3 n-6 (two precursors of eicosanoids) as a function of dietary C14:0 was shown. This result suggests that dietary myristic acid may participate in the regulation of highly unsaturated fatty acid biosynthesis and metabolism. 相似文献
100.
Christian W. Keller Monica Loi Svenja Ewert Isaak Quast Romina Theiler Monique Gannagé 《Autophagy》2017,13(6):1025-1036
Invariant natural killer T (iNKT) cells are innate T cells with powerful immune regulatory functions that recognize glycolipid antigens presented by the CD1D protein. While iNKT cell-activating glycolipids are currently being explored for their efficacy to improve immunotherapy against infectious diseases and cancer, little is known about the mechanisms that control CD1D antigen presentation and iNKT cell activation in vivo. CD1D molecules survey endocytic pathways to bind lipid antigens in MHC class II-containing compartments (MIICs) before recycling to the plasma membrane. Autophagosomes intersect with MIICs and autophagy-related proteins are known to support antigen loading for increased CD4+ T cell immunity. Here, we report that mice with dendritic cell (DC)-specific deletion of the essential autophagy gene Atg5 showed better CD1D1-restricted glycolipid presentation in vivo. These effects led to enhanced iNKT cell cytokine production upon antigen recognition and lower bacterial loads during Sphingomonas paucimobilis infection. Enhanced iNKT cell activation was independent of receptor-mediated glycolipid uptake or costimulatory signals. Instead, loss of Atg5 in DCs impaired clathrin-dependent internalization of CD1D1 molecules via the adaptor protein complex 2 (AP2) and, thus, increased surface expression of stimulatory CD1D1-glycolipid complexes. These findings indicate that the autophagic machinery assists in the recruitment of AP2 to CD1D1 molecules resulting in attenuated iNKT cell activation, in contrast to the supporting role of macroautophagy in CD4+ T cell stimulation. 相似文献