全文获取类型
收费全文 | 2962篇 |
免费 | 192篇 |
专业分类
3154篇 |
出版年
2023年 | 5篇 |
2022年 | 27篇 |
2021年 | 60篇 |
2020年 | 35篇 |
2019年 | 55篇 |
2018年 | 78篇 |
2017年 | 51篇 |
2016年 | 65篇 |
2015年 | 128篇 |
2014年 | 183篇 |
2013年 | 218篇 |
2012年 | 290篇 |
2011年 | 245篇 |
2010年 | 148篇 |
2009年 | 138篇 |
2008年 | 214篇 |
2007年 | 175篇 |
2006年 | 153篇 |
2005年 | 152篇 |
2004年 | 150篇 |
2003年 | 123篇 |
2002年 | 104篇 |
2001年 | 25篇 |
2000年 | 21篇 |
1999年 | 25篇 |
1998年 | 40篇 |
1997年 | 25篇 |
1996年 | 16篇 |
1995年 | 11篇 |
1994年 | 15篇 |
1993年 | 12篇 |
1992年 | 10篇 |
1991年 | 11篇 |
1990年 | 14篇 |
1989年 | 12篇 |
1988年 | 13篇 |
1987年 | 4篇 |
1986年 | 8篇 |
1985年 | 8篇 |
1984年 | 7篇 |
1983年 | 12篇 |
1981年 | 9篇 |
1980年 | 5篇 |
1979年 | 7篇 |
1978年 | 9篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1972年 | 4篇 |
1969年 | 3篇 |
1960年 | 3篇 |
排序方式: 共有3154条查询结果,搜索用时 8 毫秒
71.
72.
73.
Flavia Biamonte Fabiana Zolea Andrea Bisognin Maddalena Di Sanzo Claudia Saccoman Domenica Scumaci Ilenia Aversa Mariafranca Panebianco Maria Concetta Faniello Stefania Bortoluzzi Giovanni Cuda Francesco Costanzo 《PloS one》2015,10(3)
In a previous study, we showed that the silencing of the heavy subunit (FHC) offerritin, the central iron storage molecule in the cell, is accompanied by a modification in global gene expression. In this work, we explored whether different FHC amounts might modulate miRNA expression levels in K562 cells and studied the impact of miRNAs in gene expression profile modifications. To this aim, we performed a miRNA-mRNA integrative analysis in K562 silenced for FHC (K562shFHC) comparing it with K562 transduced with scrambled RNA (K562shRNA). Four miRNAs, namely hsa-let-7g, hsa-let-7f, hsa-let-7i and hsa-miR-125b, were significantly up-regulated in silenced cells. The remarkable down-regulation of these miRNAs, following FHC expression rescue, supports a specific relation between FHC silencing and miRNA-modulation. The integration of target predictions with miRNA and gene expression profiles led to the identification of a regulatory network which includes the miRNAs up-regulated by FHC silencing, as well as91 down-regulated putative target genes. These genes were further classified in 9 networks; the highest scoring network, “Cell Death and Survival, Hematological System Development and Function, Hematopoiesis”, is composed by 18 focus molecules including RAF1 and ERK1/2. We confirmed that, following FHC silencing, ERK1/2 phosphorylation is severely impaired and that RAF1 mRNA is significantly down-regulated. Taken all together, our data indicate that, in our experimental model, FHC silencing may affect RAF1/pERK1/2 levels through the modulation of a specific set of miRNAs and add new insights in to the relationship among iron homeostasis and miRNAs. 相似文献
74.
Structure of internalin,a major invasion protein of Listeria monocytogenes,in complex with its human receptor E-cadherin 总被引:13,自引:0,他引:13
Schubert WD Urbanke C Ziehm T Beier V Machner MP Domann E Wehland J Chakraborty T Heinz DW 《Cell》2002,111(6):825-836
Listeria monocytogenes, a food-borne bacterial pathogen, enters mammalian cells by inducing its own phagocytosis. The listerial protein internalin (InlA) mediates bacterial adhesion and invasion of epithelial cells in the human intestine through specific interaction with its host cell receptor E-cadherin. We present the crystal structures of the functional domain of InlA alone and in a complex with the extracellular, N-terminal domain of human E-cadherin (hEC1). The leucine rich repeat (LRR) domain of InlA surrounds and specifically recognizes hEC1. Individual interactions were probed by mutagenesis and analytical ultracentrifugation. These include Pro16 of hEC1, a major determinant for human susceptibility to L. monocytogenes infection that is essential for intermolecular recognition. Our studies reveal the structural basis for host tro-pism of this bacterium and the molecular deception L. monocytogenes employs to exploit the E-cadherin system. 相似文献
75.
Graziella Bellone Stefania Silvestri Elisa Artusio Daniela Tibaudi Anna Turletti Massimo Geuna Claudia Giachino Guido Valente Giorgio Emanuelli Ulrich Rodeck 《Journal of cellular physiology》1997,172(1):1-11
Activation of the receptor tyrosine kinase c-kit by the kit-ligand, also known as stem cell factor (SCF), is essential to melanocyte and germ cell development and during the early stages of hematopoiesis. Deregulated expression of c-kit has been reported in malignancies affecting these lineages, i.e., myeloid leukemias, melanomas, and germ cell tumors. In addition, c-kit and SCF are coexpressed in some breast and colorectal cancer (CRC) cells, raising the question of whether c-kit serves an autocrine role in normal or malignant epithelial tissues. In this study, we demonstrate that human colorectal carcinomas, but not normal colorectal mucosa cells, coexpress SCF and c-kit in situ. Expression of c-kit was also observed in mucosa adjacent to colorectal tumor tissue. Consistent with a growth-regulatory role of SCF in CRC cells, exogenous SCF stimulated anchorage-dependent and anchorage-independent growth in four out of five CRC cell lines. Exogenous transforming growth factor (TGF)-β1 added at nanomolar concentrations to HT-29 CRC cells, which express the type I, II, and III TGF-β receptors, downregulated c-kit expression to background levels and inhibited c-kit–dependent proliferation. Similarly, TGF-β1 inhibited SCF-dependent proliferation of three first-passage CRC cell lines. In summary, expression of the potential autocrine SCF/c-kit axis is a tumor-associated phenomenon in colorectal cancer that can be suppressed by TGF-β1 in TGF-β–responsive CRC cells. J. Cell. Physiol. 172:1–11, 1997. © 1997 Wiley-Liss, Inc. 相似文献
76.
77.
Blanda Di Luccia Nicola Manzo Loredana Baccigalupi Viola Calabrò Elvira Crescenzi Ezio Ricca Alessandra Pollice 《PloS one》2013,8(7)
It is now commonly accepted that the intestinal microbiota plays a crucial role in the gut physiology and homeostasis, and that both qualitative and quantitative alterations in the compositions of the gut flora exert profound effects on the host’s intestinal cells. In spite of this, the details of the interaction between commensal bacteria and intestinal cells are still largely unknown and only in few cases the molecular mechanisms have been elucidated. Here we analyze the effects of molecules produced and secreted by Lactobacillus gasseri SF1183 on human intestinal HCT116 cells. L. gasseri is a well known species of lactic acid bacteria, commonly associated to the human intestine and SF1183 is a human strain previously isolated from an ileal biopsy of an healthy volunteer. SF1183 produces and secretes, in a growth phase-dependent way, molecule(s) able to drastically interfere with HCT116 cell proliferation. Although several attempts to purify and identify the bioactive molecule(s) have been so far unsuccessful, a partial characterization has indicated that it is smaller than 3 kDa, thermostable and of proteinaceous nature. L. gasseri molecule(s) stimulate a G1-phase arrest of the cell cycle by up-regulation of p21WAF1 rendering cells protected from intrinsic and extrinsic apoptosis. A L. gasseri-mediated reduction of apoptosis and of cell proliferation could be relevant in protecting epithelial barrier integrity and helping in reconstituting tissutal homeostasis. 相似文献
78.
Capone S Zampaglione I Vitelli A Pezzanera M Kierstead L Burns J Ruggeri L Arcuri M Cappelletti M Meola A Ercole BB Tafi R Santini C Luzzago A Fu TM Colloca S Ciliberto G Cortese R Nicosia A Fattori E Folgori A 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(10):7462-7471
Induction of multispecific, functional CD4+ and CD8+ T cells is the immunological hallmark of acute self-limiting hepatitis C virus (HCV) infection in humans. In the present study, we showed that gene electrotransfer (GET) of a novel candidate DNA vaccine encoding an optimized version of the nonstructural region of HCV (from NS3 to NS5B) induced substantially more potent, broad, and long-lasting CD4+ and CD8+ cellular immunity than naked DNA injection in mice and in rhesus macaques as measured by a combination of assays, including IFN-gamma ELISPOT, intracellular cytokine staining, and cytotoxic T cell assays. A protocol based on three injections of DNA with GET induced a substantially higher CD4+ T cell response than an adenovirus 6-based viral vector encoding the same Ag. To better evaluate the immunological potency and probability of success of this vaccine, we have immunized two chimpanzees and have compared vaccine-induced cell-mediated immunity to that measured in acute self-limiting infection in humans. GET of the candidate HCV vaccine led to vigorous, multispecific IFN-gamma+CD8+ and CD4+ T lymphocyte responses in chimpanzees, which were comparable to those measured in five individuals that cleared spontaneously HCV infection. These data support the hypothesis that T cell responses elicited by the present strategy could be beneficial in prophylactic vaccine approaches against HCV. 相似文献
79.
80.
A minor component of chromatin, the phospholipid fraction, changes during cell cycle as result of the activation of intranuclear lipid metabolism enzymes including phosphatidylcholine-dependent phospholipase C activity. It is known that this enzyme may be activated by phosphatidylcholine plasmalogen (Plg). Until now, there has been little evidences for the presence of Plgs inside the nucleus. The aim of our study is to ascertain if they are present in the nucleus and are responsible of the activation of phosphatidylcholine-dependent phospholipase C during cell proliferation and apoptosis. Therefore, we have analysed the Plg composition of the whole homogenate, cytosol, nuclei and chromatin of hepatocytes. The phosphatidylcholine-dependent phospholipase C activity was assayed using both phosphatidylcholine and plasmalogenyl-phosphatidylcholine as substrates. Our results show, for the first time, that Plgs are present in chromatin and the plasmalogenyl-phosphatidylcholine stimulates the phosphatidylcholine-dependent phospholipase C activity more than phosphatidylcholine. Finally, in order to verify the possible role of these molecules during cell proliferation and apoptosis, we used liver of rats fed with ciprofibrate which stimulates hepatocytes proliferation during the treatment and, after withdrawal, apoptosis. After 3 days of ciprofibrate treatment, the chromatin plasmalogenyl-phosphatidylcholine increases as well as the phosphatidylcholine-dependent phospholipase C activity. After drug withdrawal, when the hepatocytes undergo to apoptosis, the plasmalogenyl-phosphatidylcholine content together with phosphatidylcholine-dependent phospholipase C activity decreases. Therefore, it can be concluded that plamalogens are present in the chromatin, and probably may have a function both in regulating phosphatidylcholine dependent phospholipase C and cell cycle. 相似文献