全文获取类型
收费全文 | 2980篇 |
免费 | 251篇 |
国内免费 | 2篇 |
专业分类
3233篇 |
出版年
2023年 | 9篇 |
2022年 | 11篇 |
2021年 | 19篇 |
2020年 | 14篇 |
2019年 | 34篇 |
2018年 | 45篇 |
2017年 | 30篇 |
2016年 | 49篇 |
2015年 | 89篇 |
2014年 | 91篇 |
2013年 | 140篇 |
2012年 | 207篇 |
2011年 | 181篇 |
2010年 | 138篇 |
2009年 | 128篇 |
2008年 | 163篇 |
2007年 | 190篇 |
2006年 | 195篇 |
2005年 | 193篇 |
2004年 | 182篇 |
2003年 | 174篇 |
2002年 | 151篇 |
2001年 | 41篇 |
2000年 | 24篇 |
1999年 | 31篇 |
1998年 | 51篇 |
1997年 | 33篇 |
1996年 | 34篇 |
1995年 | 47篇 |
1994年 | 33篇 |
1993年 | 42篇 |
1992年 | 40篇 |
1991年 | 22篇 |
1990年 | 27篇 |
1989年 | 34篇 |
1988年 | 21篇 |
1987年 | 14篇 |
1986年 | 17篇 |
1985年 | 21篇 |
1984年 | 27篇 |
1983年 | 26篇 |
1982年 | 26篇 |
1981年 | 19篇 |
1980年 | 23篇 |
1979年 | 11篇 |
1978年 | 25篇 |
1977年 | 16篇 |
1976年 | 13篇 |
1974年 | 12篇 |
1973年 | 7篇 |
排序方式: 共有3233条查询结果,搜索用时 15 毫秒
31.
Many stage-structured density dependent populations with a continuum of stages can be naturally modeled using nonlinear integral projection models. In this paper, we study a trichotomy of global stability result for a class of density dependent systems which include a Platte thistle model. Specifically, we identify those systems parameters for which zero is globally asymptotically stable, parameters for which there is a positive asymptotically stable equilibrium, and parameters for which there is no asymptotically stable equilibrium. 相似文献
32.
Karelle Benardais Basem Kasem Alice Couegnas Brigitte Samama Sebastien Fernandez Christiane Schaeffer Maria-Cristina Antal Didier Job Annie Schweitzer Annie Andrieux Anne Giersch Astrid Nehlig Nelly Boehm 《PloS one》2010,5(9)
Background
STOP (Stable Tubulin-Only Polypeptide) null mice show behavioral deficits, impaired synaptic plasticity, decrease in synaptic vesicular pools and disturbances in dopaminergic transmission, and are considered a neurodevelopmental model of schizophrenia. Olfactory neurons highly express STOP protein and are continually generated throughout life. Experimentally-induced loss of olfactory neurons leads to epithelial regeneration within two months, providing a useful model to evaluate the role played by STOP protein in adult olfactory neurogenesis.Methodology/Principal Findings
Immunocytochemistry and electron microscopy were used to study the structure of the glomerulus in the main olfactory bulb and neurogenesis in the neurosensorial epithelia. In STOP null mice, olfactory neurons showed presynaptic swellings with tubulovesicular profiles and autophagic-like structures. In olfactory and vomeronasal epithelia, there was an increase in neurons turnover, as shown by the increase in number of proliferating, apoptotic and immature cells with no changes in the number of mature neurons. Similar alterations in peripheral olfactory neurogenesis have been previously described in schizophrenia patients. In STOP null mice, regeneration of the olfactory epithelium did not modify these anomalies; moreover, regeneration resulted in abnormal organisation of olfactory terminals within the olfactory glomeruli in STOP null mice.Conclusions/Significance
In conclusion, STOP protein seems to be involved in the establishment of synapses in the olfactory glomerulus. Our results indicate that the olfactory system of STOP null mice is a well-suited experimental model (1) for the study of the mechanism of action of STOP protein in synaptic function/plasticity and (2) for pathophysiological studies of the mechanisms of altered neuronal connections in schizophrenia. 相似文献33.
Brigitte Marazzi Elena Conti Michael J. Sanderson Michelle M. McMahon Judith L. Bronstein 《Annals of botany》2013,111(6):1263-1275
Background and Aims
Plants display a wide range of traits that allow them to use animals for vital tasks. To attract and reward aggressive ants that protect developing leaves and flowers from consumers, many plants bear extrafloral nectaries (EFNs). EFNs are exceptionally diverse in morphology and locations on a plant. In this study the evolution of EFN diversity is explored by focusing on the legume genus Senna, in which EFNs underwent remarkable morphological diversification and occur in over 80 % of the approx. 350 species.Methods
EFN diversity in location, morphology and plant ontogeny was characterized in wild and cultivated plants, using scanning electron microscopy and microtome sectioning. From these data EFN evolution was reconstructed in a phylogenetic framework comprising 83 Senna species.Key Results
Two distinct kinds of EFNs exist in two unrelated clades within Senna. ‘Individualized’ EFNs (iEFNs), located on the compound leaves and sometimes at the base of pedicels, display a conspicuous, gland-like nectary structure, are highly diverse in shape and characterize the species-rich EFN clade. Previously overlooked ‘non-individualized’ EFNs (non-iEFNs) embedded within stipules, bracts, and sepals are cryptic and may represent a new synapomorphy for clade II. Leaves bear EFNs consistently throughout plant ontogeny. In one species, however, early seedlings develop iEFNs between the first pair of leaflets, but later leaves produce them at the leaf base. This ontogenetic shift reflects our inferred diversification history of iEFN location: ancestral leaves bore EFNs between the first pair of leaflets, while leaves derived from them bore EFNs either between multiple pairs of leaflets or at the leaf base.Conclusions
EFNs are more diverse than previously thought. EFN-bearing plant parts provide different opportunities for EFN presentation (i.e. location) and individualization (i.e. morphology), with implications for EFN morphological evolution, EFN–ant protective mutualisms and the evolutionary role of EFNs in plant diversification. 相似文献34.
Fran?oise Vilaine Pavel Kerchev Gilles Clément Brigitte Batailler Thibaud Cayla Laurence Bill Lionel Gissot Sylvie Dinant 《The Plant cell》2013,25(5):1689-1708
The complex process of phloem sugar transport involves symplasmic and apoplasmic events. We characterized Arabidopsis thaliana lines ectopically expressing a phloem-specific gene encoding NDR1/HIN1-like26 (NHL26), a putative membrane protein. NHL26 overexpressor plants grew more slowly than wild-type plants, accumulated high levels of carbohydrates in mature leaves, and had a higher shoot biomass, contrasting with slower root growth and a lower seed yield. Similar effects were observed when NHL26 was overexpressed in companion cells, under the control of a companion cell–specific promoter. The soluble sugar content of the phloem sap and sink organs was lower than that in the wild type, providing evidence of a sugar export defect. This was confirmed in a phloem-export assay with the symplastic tracer carboxyfluorescein diacetate. Leaf sugar accumulation was accompanied by higher organic acid, amino acid, and protein contents, whereas analysis of the metabolite profile of phloem sap exudate revealed no change in amino acid or organic acid content, indicating a specific effect on sugar export. NHL26 was found to be located in the phloem plasmodesmata and the endoplasmic reticulum. These findings reveal that NHL26 accumulation affects either the permeability of plasmodesmata or sugar signaling in companion cells, with a specific effect on sugar export. 相似文献
35.
Nathaniel Edward Bennett Saidu Imad Abu Asali Brigitte Czepukojc Berthold Seitz Claus Jacob Mathias Montenarh 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Diallyl mono- and polysulfanes from garlic are known to induce an adaptive cell response and the formation of antioxidants in cancer cells. In the case of a severe ER stress and a failure in the response, cancer cells eventually go into apoptosis. Only little is known about the response of normal cells upon treatment.Methods
Normal ARPE-19 cells were treated with diallyl tetrasulfide to study their cellular response and the results were compared with those of HCT116 cancer cells. Cell viability was checked by an MTT assay and cytofluorimetry. The formation of superoxide radicals, H2O2 and thiols were determined and proteins involved in the ER stress response were also detected by Western blot analysis.Results
We found that diallyl tetrasulfide induced reactive oxygen species (ROS) in normal cells similar to cancer cells in a time (0 to 60 min) and dose dependent manner (0 to 50 μM). The level of heme oxigenase-1 (HO-1) was up-regulated in both cell types. Initially, we found a decrease in the total thiol level in both cell types but in contrast to cancer cells, normal cells recovered from the decrease in the total thiol concentration within 60 min of treatment.Conclusions
The recovery of the thiol concentration in normal cells treated with diallyl tetrasulfide seems to be responsible for the failure to induce the ER stress signalling pathway and finally apoptosis in normal cells.General Significance
The difference in the recovery of the thiol status might be an explanation for the anti-carcinogenic effects of garlic compounds. 相似文献36.
Sylvie Rodrigues-Ferreira Anne Di Tommaso Ariane Dimitrov Sylvie Cazaubon Nadège Gruel Hélène Colasson André Nicolas Nathalie Chaverot Vincent Molinié Fabien Reyal Brigitte Sigal-Zafrani Benoit Terris Olivier Delattre Fran?ois Radvanyi Franck Perez Anne Vincent-Salomon Clara Nahmias 《PloS one》2009,4(10)
Background
Breast cancer is a heterogeneous disease that is not totally eradicated by current therapies. The classification of breast tumors into distinct molecular subtypes by gene profiling and immunodetection of surrogate markers has proven useful for tumor prognosis and prediction of effective targeted treatments. The challenge now is to identify molecular biomarkers that may be of functional relevance for personalized therapy of breast tumors with poor outcome that do not respond to available treatments. The Mitochondrial Tumor Suppressor (MTUS1) gene is an interesting candidate whose expression is reduced in colon, pancreas, ovary and oral cancers. The present study investigates the expression and functional effects of MTUS1 gene products in breast cancer.Methods and Findings
By means of gene array analysis, real-time RT-PCR and immunohistochemistry, we show here that MTUS1/ATIP3 is significantly down-regulated in a series of 151 infiltrating breast cancer carcinomas as compared to normal breast tissue. Low levels of ATIP3 correlate with high grade of the tumor and the occurrence of distant metastasis. ATIP3 levels are also significantly reduced in triple negative (ER- PR- HER2-) breast carcinomas, a subgroup of highly proliferative tumors with poor outcome and no available targeted therapy. Functional studies indicate that silencing ATIP3 expression by siRNA increases breast cancer cell proliferation. Conversely, restoring endogenous levels of ATIP3 expression leads to reduced cancer cell proliferation, clonogenicity, anchorage-independent growth, and reduces the incidence and size of xenografts grown in vivo. We provide evidence that ATIP3 associates with the microtubule cytoskeleton and localizes at the centrosomes, mitotic spindle and intercellular bridge during cell division. Accordingly, live cell imaging indicates that ATIP3 expression alters the progression of cell division by promoting prolonged metaphase, thereby leading to a reduced number of cells ungergoing active mitosis.Conclusions
Our results identify for the first time ATIP3 as a novel microtubule-associated protein whose expression is significantly reduced in highly proliferative breast carcinomas of poor clinical outcome. ATIP3 re-expression limits tumor cell proliferation in vitro and in vivo, suggesting that this protein may represent a novel useful biomarker and an interesting candidate for future targeted therapies of aggressive breast cancer. 相似文献37.
Tsai CH Singh P Chen CW Thomas J Weber J Mauch-Mani B Zimmerli L 《The Plant journal : for cell and molecular biology》2011,65(3):469-479
The priming agent β-aminobutyric acid (BABA) is known to enhance Arabidopsis resistance to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst) DC3000 by potentiating salicylic acid (SA) defence signalling, notably PR1 expression. The molecular mechanisms underlying this phenomenon remain unknown. A genome-wide microarray analysis of BABA priming during Pst DC3000 infection revealed direct and primed up-regulation of genes that are responsive to SA, the SA analogue benzothiadiazole and pathogens. In addition, BABA was found to inhibit the Arabidopsis response to the bacterial effector coronatine (COR). COR is known to promote bacterial virulence by inducing the jasmonic acid (JA) response to antagonize SA signalling activation. BABA specifically repressed the JA response induced by COR without affecting other plant JA responses. This repression was largely SA-independent, suggesting that it is not caused by negative cross-talk between SA and JA signalling cascades. Treatment with relatively high concentrations of purified COR counteracted BABA inhibition. Under these conditions, BABA failed to protect Arabidopsis against Pst DC3000. BABA did not induce priming and resistance in plants inoculated with a COR-deficient strain of Pst DC3000 or in the COR-insensitive mutant coi1-16. In addition, BABA blocked the COR-dependent re-opening of stomata during Pst DC3000 infection. Our data suggest that BABA primes for enhanced resistance to Pst DC3000 by interfering with the bacterial suppression of Arabidopsis SA-dependent defences. This study also suggests the existence of a signalling node that distinguishes COR from other JA responses. 相似文献
38.
The role of abscisic acid in plant-pathogen interactions 总被引:15,自引:0,他引:15
The effect of the abiotic stress hormone abscisic acid on plant disease resistance is a neglected field of research. With few exceptions, abscisic acid has been considered a negative regulator of disease resistance. This negative effect appears to be due to the interference of abscisic acid with biotic stress signaling that is regulated by salicylic acid, jasmonic acid and ethylene, and to an additional effect of ABA on shared components of stress signaling. However, recent research shows that abscisic acid can also be implicated in increasing the resistance of plants towards pathogens via its positive effect on callose deposition. 相似文献
39.
40.
Lena Hess Verena Moos Arnel A. Lauber Wolfgang Reiter Michael Schuster Natascha Hartl Daniel Lackner Thorina Boenke Anna Koren Paloma M. Guzzardo Brigitte Gundacker Anna Riegler Petra Vician Claudia Miccolo Susanna Leiter Mahesh B. Chandrasekharan Terezia Vcelkova Andrea Tanzer Jun Qi Jun James Bradner Gerald Brosch Markus Hartl Christoph Bock Tilmann Bürckstümmer Stefan Kubicek Susanna Chiocca Srividya Bhaskara Christian Seiser 《PLoS genetics》2022,18(8)
The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention. 相似文献