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101.
102.
Markus Mandler Radmila Santic Petra Gruber Yeliz Cinar Dagmar Pichler Susanne Aileen Funke Dieter Willbold Achim Schneeberger Walter Schmidt Frank Mattner 《PloS one》2015,10(1)
Recent evidence suggests Alzheimer-Disease (AD) to be driven by aggregated Aß. Capitalizing on the mechanism of molecular mimicry and applying several selection layers, we screened peptide libraries for moieties inducing antibodies selectively reacting with Aß-aggregates. The technology identified a pool of peptide candidates; two, AFFITOPES AD01 and AD02, were assessed as vaccination antigens and compared to Aβ1-6, the targeted epitope. When conjugated to Keyhole Limpet Hemocyanin (KLH) and adjuvanted with aluminum, all three peptides induced Aß-targeting antibodies (Abs). In contrast to Aß1-6, AD01- or AD02-induced Abs were characterized by selectivity for aggregated forms of Aß and absence of reactivity with related molecules such as Amyloid Precursor Protein (APP)/ secreted APP-alpha (sAPPa). Administration of AFFITOPE-vaccines to APP-transgenic mice was found to reduce their cerebral amyloid burden, the associated neuropathological alterations and to improve their cognitive functions. Thus, the AFFITOME-technology delivers vaccines capable of inducing a distinct Ab response. Their features may be beneficial to AD-patients, a hypothesis currently tested within a phase-II-study. 相似文献
103.
Silvia Bolognin Federica Pasqualetto Carla Mucignat-Caretta Janez Scancar Radmila Milacic Pamela Zambenedetti Bruno Cozzi Paolo Zatta 《PloS one》2012,7(10)
Copper dyshomeostasis has been suggested as an aetiological risk factor for some neurodegenerative diseases, such as Alzheimer’s disease. However, the precise mechanism at the base of this involvement is still obscure. In this work, we show the effects of a copper-deficient diet in aged CD1 mice and the influence of such a diet on: a) the concentration of various metal ions (aluminium, copper, iron, calcium, zinc) in the main organs and in different brain areas; b) the alteration of metallothioneins I-II and tyrosine hydroxylase immunopositivity in the brain; c) behavioural tests (open field, pole, predatory aggression, and habituation/dishabituation smell tests). Our data suggested that the copper-deficiency was able to produce a sort of “domino effect” which altered the concentration of the other tested metal ions in the main organs as well as in the brain, without, however, significantly affecting the animal behaviour. 相似文献
104.
Mirjana Hranisavljević-Jakovljević Jelena Miljković-Stojanović Radmila Dimitrijević Vukic Mićović 《Carbohydrate research》1975,39(1):115-123
A water-soluble glucan, [α]2D +217° (water), and an alkali-soluble glucan, +152° (sodium hydroxide), have been isolated from the oak lichen Evernia prunastri (L.) Ach. On the basis of methylation analysis, periodate oxidation, and partial acid hydrolysis, the water-soluble polysaccharide has been shown to be a neutral, slightly branched glucan with a main chain composed of (1→3)- and (1→4)- linked glucopyranose residues in the ratio 1?:1. Branching occurs most probably at position 2 of (1→4)-linked glucopyranose residues. On the basis of optical rotation and i.r. spectral data, and enzymic hydrolysis, the α-D configuration has been assigned to the glycosidic linkages. Likewise, the alkali-soluble polysaccharide was shown to be a neutral, branched glucan with a main chain composed of (1→3)- and (1→4)-linked α-D-glucopyranose residues in the ratio 6:1. Each of the (1→4)-linked units was a branch point involving position 6. The presence of some β-D linkages is not excluded since hydrolysis with β-D-glucosidase occurred to a small extent. 相似文献
105.
Mirjana Hranisavljević-Jakovljević Jelena Miljković-Stojanović Radmila Dimitrijević Vukić M. Mićović 《Carbohydrate research》1980,80(2):291-295
An alkali-soluble polysaccharide, [α] +43° (M sodium hydroxide), containing d-glucose and d-glucuronic acid has been isolated from the oak lichen Cetraria islandica (L.) Ach. On the basis of methylation, periodate oxidation, and partial hydrolysis studies, the polysaccharide has been shown to contain (1→3)-linked glucopyranose and glucuronic acid residues and (1→4)- and/or (1→6)-linked gluco-pyranose residues as the main structural features of the basic chain. A preponderance of β linkages, indicated by the low optical rotation and the i.r. spectrum, was corro-borated by the formation of laminaribiose, cellobiose, and gentiobiose on partial hydrolysis. 相似文献
106.
We studied the occurrence of (TTAGG)
n
telomere repeats in 12 species of beetles, representing main lineages of the Coleoptera phylogenetic tree, by Southern hybridization and fluorescence in situ hybridization (FISH). In contrast to other insect orders, beetles were heterogeneous with respect to the occurrence of TTAGG repeats. In addition, the presence or absence of (TTAGG)
n
motif was irrespective of phylogenetic relationships. In the suborder Polyphaga, six species displayed positive hybridization signals. These were Silpha obscura, Agrilus viridis, Ampedus sanguineus, Stegobium paniceum, Oryzaephilus surinamensis, and Leptinotarsa decemlineata. Whereas negative signals were obtained in three polyphagan species, Geotrupes stercorarius, Thanasimus formicarius, and Sitophilus granarius. In the suborder Adephaga, the TTAGG sequence was present in one species, Graphoderus cinereus, and absent in two species, Orectochilus villosus and Pterostichus oblongopunctatus. We concluded that the telomerase-dependent (TTAGG)
n
motif had been repeatedly lost in different phylogenetic branches of Coleoptera and probably replaced with another mechanism of telomere elongation. This had to happen at least 5–6 times. The results suggest a predisposition or a backup mechanism of telomere maintenance in the genome of beetles that enabled them to make frequent evolutionary changes in the telomere composition. 相似文献
107.
Modulation of SR Ca release by luminal Ca and calsequestrin in cardiac myocytes: effects of CASQ2 mutations linked to sudden cardiac death 下载免费PDF全文
Terentyev D Kubalova Z Valle G Nori A Vedamoorthyrao S Terentyeva R Viatchenko-Karpinski S Bers DM Williams SC Volpe P Gyorke S 《Biophysical journal》2008,95(4):2037-2048
Cardiac calsequestrin (CASQ2) is an intrasarcoplasmic reticulum (SR) low-affinity Ca-binding protein, with mutations that are associated with catecholamine-induced polymorphic ventricular tachycardia (CPVT). To better understand how CASQ2 mutants cause CPVT, we expressed two CPVT-linked CASQ2 mutants, a truncated protein (at G112+5X, CASQ2DEL) or CASQ2 containing a point mutation (CASQ2R33Q), in canine ventricular myocytes and assessed their effects on Ca handling. We also measured CASQ2-CASQ2 variant interactions using fluorescence resonance transfer in a heterologous expression system, and evaluated CASQ2 interaction with triadin. We found that expression of CASQ2DEL or CASQ2R33Q altered myocyte Ca signaling through two different mechanisms. Overexpressing CASQ2DEL disrupted the CASQ2 polymerization required for high capacity Ca binding, whereas CASQ2R33Q compromised the ability of CASQ2 to control ryanodine receptor (RyR2) channel activity. Despite profound differences in SR Ca buffering strengths, local Ca release terminated at the same free luminal [Ca] in control cells, cells overexpressing wild-type CASQ2 and CASQ2DEL-expressing myocytes, suggesting that a decline in [Ca]SR is a signal for RyR2 closure. Importantly, disrupting interactions between the RyR2 channel and CASQ2 by expressing CASQ2R33Q markedly lowered the [Ca]SR threshold for Ca release termination. We conclude that CASQ2 in the SR determines the magnitude and duration of Ca release from each SR terminal by providing both a local source of releasable Ca and by effects on luminal Ca-dependent RyR2 gating. Furthermore, two CPVT-inducing CASQ2 mutations, which cause mechanistically different defects in CASQ2 and RyR2 function, lead to increased diastolic SR Ca release events and exhibit a similar CPVT disease phenotype. 相似文献
108.
Sridhar A Nishijima Y Terentyev D Terentyeva R Uelmen R Kukielka M Bonilla IM Robertson GA Györke S Billman GE Carnes CA 《American journal of physiology. Regulatory, integrative and comparative physiology》2008,295(5):R1463-R1472
Ventricular tachyarrhythmias are the most common cause of sudden cardiac death (SCD); a healed myocardial infarction increases the risk of SCD. We determined the contribution of specific repolarization abnormalities to ventricular tachyarrhythmias in a postinfarction model of SCD. For our methods, we used a postinfarction canine model of SCD, where an exercise and ischemia test was used to stratify animals as either susceptible (VF(+)) or resistant (VF(-)) to sustained ventricular tachyarrhythmias. Our results show no changes in global left ventricular contractility or volumes occurred after infarction. At 8-10 wk postmyocardial infarction, myocytes were isolated from the left ventricular midmyocardial wall and studied. In the VF(+) animals, myocyte action potential (AP) prolongation occurred at 50 and 90% repolarization (P < 0.05) and was associated with increased variability of AP duration and afterdepolarizations. Multiple repolarizing K(+) currents (I(Kr), I(to)) and inward I(K1) were also reduced (P < 0.05) in myocytes from VF(+) animals compared with control, noninfarcted dogs. In contrast, only I(to) was reduced in VF(-) myocytes compared with controls (P < 0.05). While afterdepolarizations were not elicited at baseline in myocytes from VF(-) animals, afterdepolarizations were consistently elicited after the addition of an I(Kr) blocker. In conclusion, the loss of repolarization reserve via reductions in multiple repolarizing currents in the VF(+) myocytes leads to AP prolongation, repolarization instability, and afterdepolarizations in myocytes from animals susceptible to SCD. These abnormalities may provide a substrate for initiation of postmyocardial infarction ventricular tachyarrhythmias. 相似文献
109.
Drago D Bettella M Bolognin S Cendron L Scancar J Milacic R Ricchelli F Casini A Messori L Tognon G Zatta P 《The international journal of biochemistry & cell biology》2008,40(4):731-746
The etiopathogenesis of Alzheimer's disease is far from being clearly understood. However, the involvement of metal ions as a potential key factor towards conformational modifications and aggregation of amyloid is widely recognized. The aim of the present study is to shed some light on the relationship between metal ions, amyloid conformation/aggregation, and their potential relationship with the conformational aspects of AD. We compare the effects of beta-amyloid(1-42) and its various metal complexes (beta-amyloid-Al, beta-amyloid-Zn, beta-amyloid-Cu, beta-amyloid-Fe) in human neuroblastoma cells in terms of cell viability, membrane structure properties, and cell morphology. No significant toxic effects were observed in neuroblastoma cells after 24h treatment both with beta-amyloid and beta-amyloid-metals (beta-amyloid-Zn, beta-amyloid-Cu, beta-amyloid-Fe); on the other hand, there was a marked reduction of cellular viability after treatment with beta-amyloid-Al complex. In addition, treatment with beta-amyloid-Al increased membrane fluidity much more than other beta-amyloid-metal complexes, whose contribution was negligible. Furthermore, the cellular morphology, as observed by electron microscopy, was deeply altered by beta-amyloid-Al. Importantly, beta-amyloid-Al toxicity is closely and significantly associated with a great difference in the structure/aggregation of this complex with respect to that of beta-amyloid alone and other beta-amyloid-metal complexes. In addition, beta-amyloid, as a consequence of Al binding, becomes strongly hydrophobic in character. These findings show a significant involvement of Al, compared to the other metal ions used in our experiments, in promoting a specific amyloid(1-42) aggregation, which is able to produce marked toxic effects on neuroblastoma cells, as clearly demonstrated for the first time in this study. 相似文献
110.
A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein 总被引:4,自引:0,他引:4 下载免费PDF全文
The cloning and functional characterization of a novel interferon regulatory factor (IRF), IRF-10, are described. IRF-10 is most closely related to IRF-4 but differs in both its constitutive and inducible expression. The expression of IRF-10 is inducible by interferons (IFNs) and by concanavalin A. In contrast to that of other IRFs, the inducible expression of IRF-10 is characterized by delayed kinetics and requires protein synthesis, suggesting a unique role in the later stages of an antiviral defense. Accordingly, IRF-10 is involved in the upregulation of two primary IFN-gamma target genes (major histocompatibility complex [MHC] class I and guanylate-binding protein) and interferes with the induction of the type I IFN target gene for 2',5'-oligo(A) synthetase. IRF-10 binds the interferon-stimulated response element site of the MHC class I promoter. In contrast to that of IRF-1, which has some of the same functional characteristics, the expression of IRF-10 is not cytotoxic for fibroblasts or B cells. The expression of IRF-10 is induced by the oncogene v-rel, the proto-oncogene c-rel, and IRF-4 in a tissue-specific manner. Moreover, v-Rel and IRF-4 synergistically cooperate in the induction of IRF-10 in fibroblasts. The level of IRF-10 induction in lymphoid cell lines by Rel proteins correlates with Rel transformation potential. These results suggest that IRF-10 plays a role in the late stages of an immune defense by regulating the expression some of the IFN-gamma target genes in the absence of a cytotoxic effect. Furthermore, IRF-10 expression is regulated, at least in part, by members of the Rel/NF-kappa B and IRF families. 相似文献