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131.
TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway 总被引:16,自引:0,他引:16
Dumitru CD Ceci JD Tsatsanis C Kontoyiannis D Stamatakis K Lin JH Patriotis C Jenkins NA Copeland NG Kollias G Tsichlis PN 《Cell》2000,103(7):1071-1083
Tpl2 knockout mice produce low levels of TNF-alpha when exposed to lipopolysaccharide (LPS) and they are resistant to LPS/D-Galactosamine-induced pathology. LPS stimulation of peritoneal macrophages from these mice did not activate MEK1, ERK1, and ERK2 but did activate JNK, p38 MAPK, and NF-kappaB. The block in ERK1 and ERK2 activation was causally linked to the defect in TNF-alpha induction by experiments showing that normal murine macrophages treated with the MEK inhibitor PD98059 exhibit a similar defect. Deletion of the AU-rich motif in the TNF-alpha mRNA minimized the effect of Tpl2 inactivation on the induction of TNF-alpha. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport of TNF-alpha mRNA from the nucleus to the cytoplasm. 相似文献
132.
We describe a two-dimensional stochastic model of intercellular Ca(2+) wave (ICW) spread in glia that includes contributions of external stimuli, ionotropic and metabotropic P2 receptors, exo- and ecto-nucleotidases, second messengers, and gap junctions. In this model, an initial stimulus evokes ATP and UTP release from a single cell. Agonists diffuse and are degraded both in bulk solution and at cell surfaces. Ca(2+) elevation in individual cells is determined by bound agonist concentrations s and by number and features of P2 receptors summed with that generated by IP(3) diffusing through gap junction channels. Variability of ICWs is provided by randomly distributing a predetermined density of cells in a rectangular grid and by randomly selecting within intervals values characterizing the extracellular compartment, individual cells, and interconnections with neighboring cells. Variability intervals were obtained from experiments on astrocytoma cells transfected to express individual P2 receptors and/or the gap junction protein connexin43. The simulation program (available as Supplementary Material) permits individual alteration of ICW components, allowing comparison of simulations with data from cells expressing connexin43 and/or various P2 receptor subtypes. Such modeling is expected to be useful for testing phenomenological hypotheses and in understanding consequences of alteration of system components under experimental or pathological conditions. 相似文献
133.
Claudia Alexandra Dumitru Stephan Dreschers Erich Gulbins 《Cellular physiology and biochemistry》2006,17(3-4):159-166
Rhinoviral infections belong to the most frequent human infections characterized by common cold, chronic bronchitis, exacerbations of asthma, otitis media and sinusitis. Here, we define molecular mechanisms that mediate infections of human epithelial cells with human rhinovirus strain 14 (RV14). We demonstrate that RV14 activates p38-MAPKinase (p38-K) in a biphasic time course. Early stimulation of p38-K by RV14 was observed a few minutes after initiation of the infection, while the late increase of p38-K activity occurred 7-12 hrs upon infection. The stimulation of p38-K was mediated by the small G-protein RhoA,which was activated by RV14. Transfection of a genetic construct preventing RhoA activation blocked RV14-induced p38-K activation. Further, integrity of cholesterol and sphingolipid-enriched membrane domains was required for RV14-mediated p38-K activation, which was inhibited by destruction of membrane rafts. The data indicate that RV employs a signaling cascade from membrane rafts via the small G-protein RhoA to p38-K to infect human cells. 相似文献
134.
Speranta Dumitru 《Ethnic and racial studies》2018,41(15):2790-2808
The paper analyses migration flows from the Philippines in two gendered occupations: domestic helpers and computer programmers. The international division of labour theory claims that foreign investment determines migration from developing countries, especially of women, towards low-skilled gendered occupations in developed countries. This paper shows that the division of labour is neither gendered nor international in the predicted sense. For instance, data from Philippines Overseas Employment Agency shows that the theory is Eurocentric as Northern America and Europe are destinations for only 3 per cent of domestic workers’ flows. The paper argues that neo-Marxism creates bias in gender and migration research and hinders understanding of important gendered effects concerning migrants. Two examples of such gendered effects are highlighted here: the higher vulnerability to legislative change of migrant men employed as domestic workers in Italy and the higher penetration of women into computer programming in the migrant flows to the U.S. 相似文献
135.
Jamal Elkharaz Aslihan Ugun-Klusek Dumitru Constantin-Teodosiu Karen Lawler R John Mayer Ellen Billett James Lowe Lynn Bedford 《生物化学与生物物理学报:疾病的分子基础》2013,1832(12):1930-1938
Neurodegenerative diseases are characterized by progressive degeneration of selective neurones in the nervous system, but the underlying mechanisms involved in neuroprotection and neurodegeneration remain unclear. Dysfunction of the ubiquitin proteasome system is one of the proposed hypotheses for the cause and progression of neuronal loss. We have performed quantitative two-dimensional fluorescence difference in-gel electrophoresis combined with peptide mass fingerprinting to reveal proteome changes associated with neurodegeneration following 26S proteasomal depletion in mouse forebrain neurones. Differentially expressed proteins were validated by Western blotting, biochemical assays and immunohistochemistry. Of significance was increased expression of the antioxidant enzyme peroxiredoxin 6 (PRDX6) in astrocytes, associated with oxidative stress. Interestingly, PRDX6 is a bifunctional enzyme with antioxidant peroxidase and phospholipase A2 (PLA2) activities. The PLA2 activity of PRDX6 was also increased following 26S proteasomal depletion and may be involved in neuroprotective or neurodegenerative mechanisms. This is the first in vivo report of oxidative stress caused directly by neuronal proteasome dysfunction in the mammalian brain. The results contribute to understanding neuronal–glial interactions in disease pathogenesis, provide an in vivo link between prominent disease hypotheses and importantly, are of relevance to a heterogeneous spectrum of neurodegenerative diseases. 相似文献
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138.
Grindberg RV Ishoey T Brinza D Esquenazi E Coates RC Liu WT Gerwick L Dorrestein PC Pevzner P Lasken R Gerwick WH 《PloS one》2011,6(4):e18565
Filamentous marine cyanobacteria are extraordinarily rich sources of structurally novel, biomedically relevant natural products. To understand their biosynthetic origins as well as produce increased supplies and analog molecules, access to the clustered biosynthetic genes that encode for the assembly enzymes is necessary. Complicating these efforts is the universal presence of heterotrophic bacteria in the cell wall and sheath material of cyanobacteria obtained from the environment and those grown in uni-cyanobacterial culture. Moreover, the high similarity in genetic elements across disparate secondary metabolite biosynthetic pathways renders imprecise current gene cluster targeting strategies and contributes sequence complexity resulting in partial genome coverage. Thus, it was necessary to use a dual-method approach of single-cell genomic sequencing based on multiple displacement amplification (MDA) and metagenomic library screening. Here, we report the identification of the putative apratoxin. A biosynthetic gene cluster, a potent cancer cell cytotoxin with promise for medicinal applications. The roughly 58 kb biosynthetic gene cluster is composed of 12 open reading frames and has a type I modular mixed polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) organization and features loading and off-loading domain architecture never previously described. Moreover, this work represents the first successful isolation of a complete biosynthetic gene cluster from Lyngbya bouillonii, a tropical marine cyanobacterium renowned for its production of diverse bioactive secondary metabolites. 相似文献
139.
Our study was designed to examine how components of complex mixtures can
inhibit the binding of other components to receptor sites in the olfactory
system of the spiny lobster Panulirus argus. Biochemical binding assays
were used to study how two- to six-component mixtures inhibit binding of
the radiolabeled odorants taurine, L-glutamate and
adenosine-5'-monophosphate to a tissue fraction rich in dendritic membrane
of olfactory receptor neurons. Our results indicate that binding inhibition
by mixtures can be large and is dependent on the nature of the odorant
ligand and on the concentration and composition of the mixture. The binding
inhibition by mixtures of structurally related components was generally
predicted using a competitive binding model and binding inhibition data for
the individual components. This was not the case for binding inhibition by
most mixtures of structurally unrelated odorants. The binding inhibition
for these mixtures was generally smaller than that for one or more of their
components, indicating that complex binding interactions between components
can reduce their ability to inhibit binding. The magnitude of binding
inhibition was influenced more by the mixture's precise composition than by
the number of components in it, since mixtures with few components were
sometimes more inhibitory than mixtures with more components. These
findings raise the possibility that complex binding interactions between
components of a mixture and their receptors may shape the output of
olfactory receptor neurons to complex mixtures.
相似文献
140.