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排序方式: 共有130条查询结果,搜索用时 15 毫秒
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Pauline M Snijder Madina Baratashvili Nicola A Grzeschik Henri G D Leuvenink Lucas Kuijpers Sippie Huitema Onno Schaap Ben N G Giepmans Jeroen Kuipers Jan Lj Miljkovic Aleksandra Mitrovic Eelke M Bos Csaba Szabó Harm H Kampinga Pascale F Dijkers Wilfred F A den Dunnen Milos R Filipovic Harry van Goor Ody C M Sibon 《Molecular medicine (Cambridge, Mass.)》2015,21(1):758-768
Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 (ATXN3) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a Drosophila model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of Drosophila cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies. 相似文献
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Ivana Nikolic Tatjana Kastratovic Aleksandar Zivanovic Marina Mitrovic 《Biochemical and biophysical research communications》2010,395(2):225-231
Proteins of the BCL-2 family are important regulators of apoptosis. The BCL-2 family includes three main subgroups: the anti-apoptotic group, such as BCL-2, BCL-XL, BCL-W, and MCL-1; multi-domain pro-apoptotic BAX, BAK; and pro-apoptotic “BH3-only” BIK, PUMA, NOXA, BID, BAD, and SPIKE. SPIKE, a rare pro-apoptotic protein, is highly conserved throughout the evolution, including Caenorhabditis elegans, whose expression is downregulated in certain tumors, including kidney, lung, and breast.In the literature, SPIKE was proposed to interact with BAP31 and prevent BCL-XL from binding to BAP31. Here, we utilized the Position Weight Matrix method to identify SPIKE to be a BH3-only pro-apoptotic protein mainly localized in the cytosol of all cancer cell lines tested. Overexpression of SPIKE weakly induced apoptosis in comparison to the known BH3-only pro-apoptotic protein BIK. SPIKE promoted mitochondrial cytochrome c release, the activation of caspase 3, and the caspase cleavage of caspase’s downstream substrates BAP31 and p130CAS. Although the informatics analysis of SPIKE implicates this protein as a member of the BH3-only BCL-2 subfamily, its role in apoptosis remains to be elucidated. 相似文献
35.
Douglas P. Westhorpe Simon M. Mitrovic David Ryan Tsuyoshi Kobayashi 《Hydrobiologia》2010,652(1):101-117
Flow regulation in lowland rivers has reduced the amount of allochthonous dissolved organic carbon (DOC) entering main channels
through less frequent wetting of benches, flood runners and floodplains. The hypothesis tested was that lowland riverine bacterioplankton
are DOC limited when flow events are absent and simulating an increase in assimilable DOC similar to that expected during
an environmental flow will lead to heterotrophic dominance. Experiments took place in the Namoi River, a highly regulated
lowland river in Australia. Specifically, in situ microcosms were used to examine the responses of bacterioplankton and phytoplankton
to various additions of DOC as glucose or leaf leachate, with and without additions of inorganic nutrients. The results indicated
that ambient DOC availability limited the bacterioplankton for the three seasons over which we conducted the experiments.
When DOC was added alone, dissolved oxygen concentrations decreased primarily because of increased bacterial respiration and
bacterioplankton growth generally increased relative to controls. Additions of DOC alone led to a pattern of decreased chlorophyll
a concentration relative to controls, except for willow leachate. Additions of inorganic nutrients alone increased chlorophyll
a concentrations above controls, indicating limitation of phytoplankton. These findings support our hypothesis. Based on the
present results, environmental flows should increase the duration of allochthonously driven heterotrophic dominance, thus
shifting regulated lowland rivers to more natural (pre-regulation) conditions for greater periods. 相似文献
36.
Florian M. Gebhardt Ann D. Mitrovic Daniel F. Gilbert Robert J. Vandenberg Joseph W. Lynch Peter R. Dodd 《The Journal of biological chemistry》2010,285(41):31313-31324
The glial transporter excitatory amino acid transporter-2 (EAAT2) is the main mediator of glutamate clearance in brain. The wild-type transporter (EAAT2wt) forms trimeric membrane complexes in which each protomer functions autonomously. Several EAAT2 variants are found in control and Alzheimer-diseased human brains; their expression increases with pathological severity. These variants might alter EAAT2wt-mediated transport by abrogating membrane trafficking, or by changing the configuration or functionality of the assembled transporter complex. HEK293 cells were transfected with EAAT2wt; EAAT2b, a C-terminal variant; or either of two exon-skipping variants: alone or in combination. Surface biotinylation studies showed that only the exon-7 deletion variant was not trafficked to the membrane when transfected alone, and that all variants could reach the membrane when co-transfected with EAAT2wt. Fluorescence resonance energy transfer (FRET) studies showed that co-transfected EAAT2wt and EAAT2 splice variants were expressed in close proximity. Glutamate transporter function was measured using a whole cell patch clamp technique, or by changes in membrane potential indexed by a voltage-sensitive fluorescent dye (FMP assay): the two methods gave comparable results. Cells transfected with EAAT2wt or EAAT2b showed glutamate-dependent membrane potential changes consistent with functional expression. Cells transfected with EAAT2 exon-skipping variants alone gave no response to glutamate. Co-transfection of EAAT2wt (or EAAT2b) and splice variants in various ratios significantly raised glutamate EC50 and decreased Hill coefficients. We conclude that exon-skipping variants form heteromeric complexes with EAAT2wt or EAAT2b that traffic to the membrane but show reduced glutamate-dependent activity. This could allow glutamate to accumulate extracellularly and promote excitotoxicity. 相似文献
37.
Excitatory amino acid transporters (EAATs) regulate glutamate concentrations in the brain to maintain normal excitatory synaptic transmission. A widely accepted view of transporters is that they consist of a pore with alternating access to the intracellular and extracellular solutions, which serves to couple ion movement to the movement of substrate. However, recent observations that EAATs, and also a number of other neurotransmitter transporters, can also function as ligand-gated chloride channels have blurred the distinctions between transporters and ion channels. Here we show that mutations in the second transmembrane domain (TM2) of EAAT1 alter anion permeation properties without affecting glutamate transport and that a number of TM2 residues are accessible to the external aqueous solution. Furthermore, we demonstrate that the extracellular edge of TM2 is in close proximity to a membrane-associated domain that influences glutamate transport. This study will provide the foundation for beginning to understand how transporters can function as both transporters and ion channels. 相似文献
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D. Mitrovic L. Lippiello F. Gruson F. Aprile H.J. Mankin 《Prostaglandins & other lipid mediators》1981,22(3):499-511
The dose-dependent effects of 9 prostanoids (PGA1, PGA2, PGE1, PGE2, PGF1α, PGF2α, PGD2, PGI2, 6 keto- PGF1α) on metabolism of cultured bovine articular chrondrocytes were investigated. Most prostanoids dose-dependently inhibited 35SO4= and 3H-glycine incorporation. At 25 μg/ml, the inhibitory sequence was A2D2>E2 = E1 = A1>6 keto-F1α>F1>F2, but sensivity (lowest dose eliciting inhibition) followed the sequence E2 > 6 keto-F1α = F1 > A2 = D2>E1>A1. At 25 μg/ml PGA2 also inhibited incorporation of 3H-cytidine and #H-thymidine, but had no significant effect on 3H-glucose or 14C-xylose incorporation. The inhibitory effect of PGA2 was apparent after 30 minutes exposure for 35SO4= and after 60 minutesd for 3H-cytidine, and was still present up to 72 hours following incubation in fresh non-PG-containing medium. PGI2 had no significant effect of 35SO4= incorporation but at concentrations below 10 μg/ml enhanced uptake of 3H-glycine.The PG-induced inhibitory effect was apparently not due to cell damage as indicated by measurement of 3H-glucose metabolism and lactate production. 相似文献