全文获取类型
收费全文 | 15080篇 |
免费 | 1127篇 |
国内免费 | 825篇 |
专业分类
17032篇 |
出版年
2024年 | 32篇 |
2023年 | 194篇 |
2022年 | 495篇 |
2021年 | 768篇 |
2020年 | 461篇 |
2019年 | 591篇 |
2018年 | 568篇 |
2017年 | 408篇 |
2016年 | 570篇 |
2015年 | 854篇 |
2014年 | 960篇 |
2013年 | 1077篇 |
2012年 | 1304篇 |
2011年 | 1193篇 |
2010年 | 747篇 |
2009年 | 659篇 |
2008年 | 741篇 |
2007年 | 693篇 |
2006年 | 591篇 |
2005年 | 520篇 |
2004年 | 458篇 |
2003年 | 370篇 |
2002年 | 329篇 |
2001年 | 308篇 |
2000年 | 255篇 |
1999年 | 230篇 |
1998年 | 148篇 |
1997年 | 147篇 |
1996年 | 150篇 |
1995年 | 110篇 |
1994年 | 111篇 |
1993年 | 81篇 |
1992年 | 134篇 |
1991年 | 102篇 |
1990年 | 78篇 |
1989年 | 78篇 |
1988年 | 63篇 |
1987年 | 71篇 |
1986年 | 64篇 |
1985年 | 50篇 |
1984年 | 48篇 |
1983年 | 41篇 |
1982年 | 24篇 |
1981年 | 13篇 |
1980年 | 16篇 |
1979年 | 19篇 |
1977年 | 14篇 |
1976年 | 11篇 |
1973年 | 10篇 |
1972年 | 10篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
81.
Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts 总被引:14,自引:0,他引:14
Cohen AW Park DS Woodman SE Williams TM Chandra M Shirani J Pereira de Souza A Kitsis RN Russell RG Weiss LM Tang B Jelicks LA Factor SM Shtutin V Tanowitz HB Lisanti MP 《American journal of physiology. Cell physiology》2003,284(2):C457-C474
Recently, development ofa caveolin-1-deficient (Cav-1 null) mouse model has allowed thedetailed analysis of caveolin-1's function in the context of awhole animal. Interestingly, we now report that the hearts ofCav-1 null mice are markedly abnormal, despite the fact that caveolin-1is not expressed in cardiac myocytes. However, caveolin-1 is abundantlyexpressed in the nonmyocytic cells of the heart, i.e., cardiacfibroblasts and endothelia. Quantitative imaging studies of Cav-1 nullhearts demonstrate a significantly enlarged right ventricular cavityand a thickened left ventricular wall with decreased systolic function.Histological analysis reveals myocyte hypertrophy withinterstitial/perivascular fibrosis. Because caveolin-1 is thought toact as a negative regulator of the p42/44 MAP kinase cascade, weperformed Western blot analysis with phospho-specific antibodies thatonly recognize activated ERK1/2. As predicted, the p42/44 MAP kinasecascade is hyperactivated in Cav-1 null heart tissue (i.e.,interstitial fibrotic lesions) and isolated cardiac fibroblasts. Inaddition, endothelial and inducible nitric oxide synthase levels aredramatically upregulated. Thus loss of caveolin-1 expression drivesp42/44 MAP kinase activation and cardiac hypertrophy. 相似文献
82.
Zhimin Li Yushi Qiu David Personett Peng Huang Brandy Edenfield Jason Katz Darius Babusis Yang Tang Michael A. Shirely Mehran F. Moghaddam John A. Copland Han W. Tun 《PloS one》2013,8(8)
Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti-lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1-polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS lymphoma. POM should be further evaluated in clinical trials. 相似文献
83.
84.
Plasmacytoid dendritic cells (pDCs) represent a unique and crucial immune cell population capable of producing large amounts
of type I interferons (IFNs) in response to viral infection. The function of pDCs as the professional type I IFN-producing
cells is linked to their selective expression of Toll-like receptor 7 (TLR7) and TLR9, which sense viral nucleic acids within
the endosomal compartments. Type I IFNs produced by pDCs not only directly inhibit viral replication but also play an essential
role in linking the innate and adaptive immune system. The aberrant activation of pDCs by self nucleic acids through TLR signaling
and the ongoing production of type I IFNs do occur in some autoimmune diseases. Therefore, pDC may serve as an attractive
target for therapeutic manipulations of the immune system to treat viral infectious diseases and autoimmune diseases. 相似文献
85.
Xiao Y Lan L Yin C Deng X Baker D Zhou JM Tang X 《Molecular plant-microbe interactions : MPMI》2007,20(3):223-234
The Pseudomonas syringae type III secretion system (T3SS) is induced during interaction with the plant or culture in minimal medium (MM). How the bacterium senses these environments to activate the T3SS is poorly understood. Here, we report the identification of a novel two-component system (TCS), RhpRS, that regulates the induction of P. syringae T3SS genes. The rhpR and rhpS genes are organized in an operon with rhpR encoding a putative TCS response regulator and rhpS encoding a putative biphasic sensor kinase. Transposon insertion in rhpS severely reduced the induction of P. syringae T3SS genes in the plant as well as in MM and significantly compromised the pathogenicity on host plants and hypersensitive response-inducing activity on nonhost plants. However, deletion of the rhpRS locus allowed the induction of T3SS genes to the same level as in the wild-type strain and the recovery of pathogenicity upon infiltration into plants. Overexpression of RhpR in the deltarhpRS deletion strain abolished the induction of T3SS genes. However, overexpression of RhpR in the wild-type strain or overexpression of RhpR(D70A), a mutant of the predicted phosphorylation site of RhpR, in the deltarhpRS deletion strain only slightly reduced the induction of T3SS genes. Based on these results, we propose that the phosphorylated RhpR represses the induction of T3SS genes and that RhpS reverses phosphorylation of RhpR under the T3SS-inducing conditions. Epistasis analysis indicated that rhpS and rhpR act upstream of hrpR to regulate T3SS genes. 相似文献
86.
87.
Simvastatin is an important cholesterol lowering compound and is currently synthesized from the natural product lovastatin via multistep chemical synthesis. We have previously reported the use of an Escherichia coli strain BL21(DE3)/pAW31 as the host for whole-cell biocatalytic conversion of monacolin J acid to simvastatin acid. During fermentation and bioconversion, unknown E. coli enzyme(s) hydrolyzed the membrane permeable thioester substrate dimethylbutyryl-S-methyl mercaptopropionate (DMB-S-MMP) to the free acid, significantly decreased the efficiencies of the whole-cell bioconversion and the downstream purification steps. Using the Keio K-12 Singe-Gene Knockout collection, we identified BioH as the sole enzyme responsible for the observed substrate hydrolysis. Purification and reconstitution of E. coli BioH activity in vitro confirmed its function. BioH catalyzed the rapid hydrolysis of DMB-S-MMP with kcat and Km values of 260+/-45 s(-1) and 229+/-26 microM, respectively. This is in agreement with previous reports that BioH can function as a carboxylesterase towards fatty acid esters. YT2, which is a delta bioH mutant of BL21(DE3), did not hydrolyze DMB-S-MMP during prolonged fermentation and was used as an alternative host for whole-cell biocatalysis. The rate of simvastatin acid synthesis in YT2 was significantly faster than in BL21(DE3) and 99% conversion of 15 mM simvastatin acid in less than 12 h was achieved. Furthermore, the engineered host required significantly less DMB-S-MMP to be added to accomplish complete conversion. Finally, simvastatin acid synthesized using YT2 can be readily purified from fermentation broth and no additional steps to remove the hydrolyzed dimethylbutyryl-S-mercaptopropionic acid is required. Together, the proteomic and metabolic engineering approaches render the whole-cell biocatalytic process more robust and economically attractive. 相似文献
88.
Huo X Qi X Tang F Zu R Li L Wu B Qin Y Ji H Fu J Wang S Tian H Hu Z Yang H Zhou M Wang H Zhu F 《PloS one》2011,6(3):e17995
Background
We investigated the seropositive rates and persistence of antibody against pandemic (H1N1) 2009 virus (pH1N1) in pregnant women and voluntary blood donors after the second wave of the pandemic in Nanjing, China.Methodology/Principal Findings
Serum samples of unvaccinated pregnant women (n = 720) and voluntary blood donors (n = 320) were collected after the second wave of 2009 pandemic in Nanjing. All samples were tested against pH1N1 strain (A/California/7/2009) with hemagglutination inhibition assay. A significant decline in seropositive rates, from above 50% to about 20%, was observed in pregnant women and voluntary blood donors fifteen weeks after the second wave of the pandemic. A quarter of the samples were tested against a seasonal H1N1 strain (A/Brisbane/59/2007). The antibody titers against pH1N1 strain were found to correlate positively with those against seasonal H1N1 strain. The correlation was modest but statistically significant.Conclusions and Significance
The high seropositive rates in both pregnant women and voluntary blood donors suggested that the pH1N1 virus had widely spread in these two populations. Immunity derived from natural infection seemed not to be persistent well. 相似文献89.
利用分离的叶绿体作实验材料,发现华山松(Pinus armandi Franch.)南方种源的4阶导数吸收光谱在680nm处峰值较大,在670nm处峰值较小,而北方种源中出现了在680nm处峰值较在670nm峰值小的类群,推断北方种群反应中心活力有下降趋势。南、北种源之间的低温(77K)荧光发射光谱有明显差异,PSⅠ、PSⅡ发射峰位置出现地理变动。低温荧光激发光谱分析表明,地理变异主要发生在叶绿素a的分子状态上。研究还表明,完整的针叶因为有角质层、松脂等物质干扰,检测不出光谱的差异,不是理想的实验材料。 相似文献
90.
Using gamma distribution and spatial autocorrelation, it was demonstrated that plant biomass per unit area of a pasture grazed by cattle exhibited two kinds of spatial heterogeneity: small-scale heterogeneity caused by grazing and large-scale heterogeneity caused by topography, land aspect, etc. For each of the 10 measurement times from May to August, 100 quadrats 50cm × 50cm were arranged along a straight line 50m long in a pasture, and the plants within the quadrats were harvested at the height of 3cm above the ground surface to measure the dry weight. The data were aggregated into frequency distributions, and gamma distribution and the parameter values were estimated. This analysis showed that with the progression of grazing the amount of biomass decreased and the degree of spatial heterogeneity in biomass, measured per 0.25m2, increased, and due to plant regrowth the trends were reversed. By rearranging the 100 biomass data in order of weight, it was suggested that plots with an extremely large biomass were not grazed by cattle and remained in the pasture. For the same data, variations of biomass along the straight line were divided into two parts based on the moving average: the spatial trend and the residuals which cannot be explained by the trend. In this analysis, 48–75% of the total spatial variation was explained by the trend along the straight line. Analysis using spatial autocorrelation for the actual biomass changes showed that the biomass changes within a range of about 10m on the straight line gave a positive correlation, which indicates a topographical trend in biomass. Spatial autocorrelation for residuals suggested that the spatial changes in biomass along the straight line followed a wave-like or checker-board pattern. Small-scale spatial heterogeneity in plant biomass may be caused by the uneven deposition of excreta by grazing animals, uneven use of the grassland by grazing animals, and uneven dispersal of plant seeds through faeces over the grassland. The possibility that such unevenness might accelerate energy flow in the grassland ecosystem and contribute to grassland sustainability is discussed. 相似文献