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71.
Wang G Dinkins M He Q Zhu G Poirier C Campbell A Mayer-Proschel M Bieberich E 《The Journal of biological chemistry》2012,287(25):21384-21395
Amyloid protein is well known to induce neuronal cell death, whereas only little is known about its effect on astrocytes. We found that amyloid peptides activated caspase 3 and induced apoptosis in primary cultured astrocytes, which was prevented by caspase 3 inhibition. Apoptosis was also prevented by shRNA-mediated down-regulation of PAR-4, a protein sensitizing cells to the sphingolipid ceramide. Consistent with a potentially proapoptotic effect of PAR-4 and ceramide, astrocytes surrounding amyloid plaques in brain sections of the 5xFAD mouse (and Alzheimer disease patient brain) showed caspase 3 activation and were apoptotic when co-expressing PAR-4 and ceramide. Apoptosis was not observed in astrocytes with deficient neutral sphingomyelinase 2 (nSMase2), indicating that ceramide generated by nSMase2 is critical for amyloid-induced apoptosis. Antibodies against PAR-4 and ceramide prevented amyloid-induced apoptosis in vitro and in vivo, suggesting that apoptosis was mediated by exogenous PAR-4 and ceramide, potentially associated with secreted lipid vesicles. This was confirmed by the analysis of lipid vesicles from conditioned medium showing that amyloid peptide induced the secretion of PAR-4 and C18 ceramide-enriched exosomes. Exosomes were not secreted by nSMase2-deficient astrocytes, indicating that ceramide generated by nSMase2 is critical for exosome secretion. Consistent with the ceramide composition in amyloid-induced exosomes, exogenously added C18 ceramide restored PAR-4-containing exosome secretion in nSMase2-deficient astrocytes. Moreover, isolated PAR-4/ceramide-enriched exosomes were taken up by astrocytes and induced apoptosis in the absence of amyloid peptide. Taken together, we report a novel mechanism of apoptosis induction by PAR-4/ceramide-enriched exosomes, which may critically contribute to Alzheimer disease. 相似文献
72.
The development of neuron-microelectrode interfaces (neurochips) is highly desirable for the non-invasive recording of the cellular response to neuroactive drugs as well as the electrical stimulation of nervous tissue by implantable electrodes. A prerequisite for neuron-to-electrode signal transmission (NEST) is the formation of synapse-like contacts between the neuronal cell and the conductive surface of a microelectrode array. We attempted synapse formation by neuronal differentiation of rat pheochromocytoma cells (PC12) and blastocyst-derived murine embryonic stem cells (ES-J1) on interdigitated microelectrode arrays that were made of gold (Au), platinum (Pt), or indium tin oxide (ITO). PC12 or ES cells were in vitro differentiated by incubation with nerve growth factor (NGF) and forskolin, or by serum deprivation and treatment with basic fibroblast growth factor (FGF-2), respectively. On top of ITO electrodes, the neuronal cells extended extremely long processes that terminated in pili-like contact structures, which is typical for growth cone formation. ES cells differentiated into neurons as verified by immunofluorescence staining of MAP-2 and developed synapse-like junctions with the ITO electrode surface as indicated by synaptophysin staining. Differentiated PC12 and ES cells showed bona fide morphological characteristics of synaptic growth cones that were unprecedented in tissue culture. Cones formed by PC12 cells could be stimulated with KCI and carbachol as shown by uptake of FM1-43, a fluorescent marker for synaptic vesicle formation. In contrast to Electrical Cell Impedance Spectroscopy (ECIS) recordings, AC impedance spectrometry with differentiated PC12 cells settled on interdigitated microelectrode arrays revealed lower AC impedance than that with undifferentiated cells, indicating that the complex impedance is dependent on ion fluxes at the neuron-to-electrode contact surface. 相似文献
73.
74.
We examined the effects of Pandinus imperator scorpion venom on voltage-gated potassium channels in cultured clonal rat anterior pituitary cells (GH3 cells) using the gigohm-seal voltage-clamp method in the whole-cell configuration. We found that Pandinus venom blocks the voltage-gated potassium channels of GH3 cells in a voltage-dependent and dose-dependent manner. Crude venom in concentrations of 50-500 micrograms/ml produced 50-70% block of potassium currents measured at -20 mV, compared with 25-60% block measured at +50 mV. The venom both decreased the peak potassium current and shifted the voltage dependence of potassium current activation to more positive potentials. Pandinus venom affected potassium channel kinetics by slowing channel opening, speeding deactivation slightly, and increasing inactivation rates. Potassium currents in cells exposed to Pandinus venom did not recover control amplitudes or kinetics even after 20-40 min of washing with venom-free solution. The concentration dependence of crude venom block indicates that the toxins it contains are effective in the nanomolar range of concentrations. The effects of Pandinus venom were mimicked by zinc at concentrations less than or equal to 0.2 mM. Block of potassium current by zinc was voltage dependent and resembled Pandinus venom block, except that block by zinc was rapidly reversible. Since zinc is found in crude Pandinus venom, it could be important in the interaction of the venom with the potassium channel. We conclude that Pandinus venom contains toxins that bind tightly to voltage-dependent potassium channels in GH3 cells. Because of its high affinity for voltage-gated potassium channels and its irreversibility, Pandinus venom may be useful in the isolation, mapping, and characterization of voltage-gated potassium channels. 相似文献
75.
High nucleotide sequence variation in a region of low recombination in Drosophila simulans is consistent with the background selection model 总被引:2,自引:0,他引:2
We surveyed nucleotide sequence variation at glucose dehydrogenase (Gld),
in a region of low recombination on chromosome 3R, from a population sample
of Drosophila simulans. The levels of nucleotide variation were
surprisingly high. There was no departure from the expectation of a neutral
model for the level of polymorphism, indicating no evidence of a selective
sweep in this region. There was a significant deficiency of singleton
polymorphisms according to the Fu and Li test, although Tajima and Hudson,
Kreitman, and Aguade (HKA) tests do not provide evidence of a significant
elevation of variation due to balancing selection. Genetic map data for the
D. simulans third chromosome were used to calculate expected values of pi
for Gld under a current model of background selection, varying the values
for the parameter sh (selection coefficient against deleterious mutations).
We show that the recombinational landscape of D. simulans is sufficiently
different from that of D. melanogaster that we expect higher variation
under the background selection model, even when effective population sizes
are assumed to be equal. The data for Gld were tested against the
predictions using computer simulations of the distribution of the number of
segregating sites conditioned on pi. Background selection alone can explain
our observations as long as sh is larger than 0.005 and species-level
effective population size is assumed to be several- fold larger than in D.
melanogaster. Alternatively, the deleterious mutation rate may be smaller
in D. simulans, or balancing selection may be acting nearby, thereby
reducing the effect of background selection.
相似文献
76.
Ali Ebrahim Eivind Almaas Eugen Bauer Aarash Bordbar Anthony P Burgard Roger L Chang Andreas Dräger Iman Famili Adam M Feist Ronan MT Fleming Stephen S Fong Vassily Hatzimanikatis Markus J Herrgård Allen Holder Michael Hucka Daniel Hyduke Neema Jamshidi Sang Yup Lee Nicolas Le Novère Joshua A Lerman Nathan E Lewis Ding Ma Radhakrishnan Mahadevan Costas Maranas Harish Nagarajan Ali Navid Jens Nielsen Lars K Nielsen Juan Nogales Alberto Noronha Csaba Pal Bernhard O Palsson Jason A Papin Kiran R Patil Nathan D Price Jennifer L Reed Michael Saunders Ryan S Senger Nikolaus Sonnenschein Yuekai Sun Ines Thiele 《Molecular systems biology》2015,11(10)
77.
78.
79.
Raheleh Toughiri Xiang Li Quansheng Du Charles J. Bieberich 《Journal of cellular biochemistry》2013,114(4):823-830
Aurora‐A is a serine/threonine kinase that has oncogenic properties in vivo. The expression and kinase activity of Aurora‐A are up‐regulated in multiple malignancies. Aurora‐A is a key regulator of mitosis that localizes to the centrosome from the G2 phase through mitotic exit and regulates mitotic spindle formation as well as centrosome separation. Overexpression of Aurora‐A in multiple malignancies has been linked to higher tumor grade and poor prognosis through mechanisms that remain to be defined. Using an unbiased proteomics approach, we identified the protein nuclear mitotic apparatus (NuMA) as a robust substrate of Aurora‐A kinase. Using a small molecule Aurora‐A inhibitor in conjunction with a reverse in‐gel kinase assay (RIKA), we demonstrate that NuMA becomes hypo‐phosphorylated in vivo upon Aurora‐A inhibition. Using an alanine substitution strategy, we identified multiple Aurora‐A phospho‐acceptor sites in the C‐terminal tail of NuMA. Functional analyses demonstrate that mutation of three of these phospho‐acceptor sites significantly diminished cell proliferation. In addition, alanine mutation at these sites significantly increased the rate of apoptosis. Using confocal immunofluorescence microscopy, we show that the NuMA T1804A mutant mis‐localizes to the cytoplasm in interphase nuclei in a punctate pattern. The identification of Aurora‐A phosphorylation sites in NuMA that are important for cell cycle progression and apoptosis provides new insights into Aurora‐A function. J. Cell. Biochem. 114: 823–830, 2013. © 2012 Wiley Periodicals, Inc. 相似文献
80.
Comparative evolutionary analysis of rDNA ITS regions in Drosophila 总被引:15,自引:2,他引:15
Schlotterer C; Hauser MT; von Haeseler A; Tautz D 《Molecular biology and evolution》1994,11(3):513-522
The internal transcribed spacer (ITS) of the ribosomal DNA is generally
considered to be under low functional constraint, and it is therefore often
treated as a typical nonfunctional spacer sequence. We have analyzed the
ITS regions of five species from the Drosophila melanogaster subgroup, two
Drosophila species from outside this group (D. pseudoobscura and D.
virilis), as well as from the more distantly related dipteran fly Musca
domestica. The sequence comparisons show a distinctive
conservation/divergence pattern, indicating that some regions are more
conserved than others. Moreover, secondary-structure calculations indicate
several conserved structural elements within the ITS regions. On the other
hand, a statistical test that allows us to estimate the fraction of sites
that are not under selective constraint suggests that more than half of the
spacer is apparently free to diverge and evolves with a rate that is close
to the neutral rate of sequence evolution in Drosophila. The ITS sequences
can be used to derive a molecular phylogeny for the species under study. We
find that the ITS tree is largely in line with the so-far-known phylogeny
of this group of species, with one difference. The species most distant
within the D. melanogaster subgroup is D. yakuba, rather than D. orena, as
is normally assumed.
相似文献