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161.
O'Neill PM Verissimo E Ward SA Davies J Korshin EE Araujo N Pugh MD Cristiano ML Stocks PA Bachi MD 《Bioorganic & medicinal chemistry letters》2006,16(11):2991-2995
A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides. 相似文献
162.
Ronda L Bruno S Viappiani C Abbruzzetti S Mozzarelli A Lowe KC Bettati S 《Protein science : a publication of the Protein Society》2006,15(8):1961-1967
The relative contributions to changes in visible and near UV circular dichroism spectra of hemoglobin of heme ligation and tertiary and quaternary conformational transitions were separated by exploiting the slowing down of structural relaxations for proteins encapsulated in wet, nanoporous silica gels. Spectral signatures, previously assumed to be characteristic of T and R quaternary states, were demonstrated to be specific to different tertiary conformations. The results support the view that ligation and allosteric effectors can modulate the structural and functional properties of hemoglobin by regulating the equilibrium between the same tertiary species within both quaternary states. 相似文献
163.
Daniela Corda Takahiro Kudo Pasquale Zizza Cristiano Iurisci Eri Kawai Norihisa Kato Noriyuki Yanaka Stefania Mariggi�� 《The Journal of biological chemistry》2009,284(37):24848-24856
The glycerophosphodiester phosphodiesterase enzyme family involved in the hydrolysis of glycerophosphodiesters has been characterized in bacteria and recently identified in mammals. Here, we have characterized the activity and function of GDE3, one of the seven mammalian enzymes. GDE3 is up-regulated during osteoblast differentiation and can affect cell morphology. We show that GDE3 is a glycerophosphoinositol (GroPIns) phosphodiesterase that hydrolyzes GroPIns, producing inositol 1-phosphate and glycerol, and thus suggesting specific roles for this enzyme in GroPIns metabolism. Substrate specificity analyses show that wild-type GDE3 selectively hydrolyzes GroPIns over glycerophosphocholine, glycerophosphoethanolamine, and glycerophosphoserine. A single point mutation in the catalytic domain of GDE3 (GDE3R231A) leads to loss of GroPIns enzymatic hydrolysis, identifying an arginine residue crucial for GDE3 activity. After heterologous GDE3 expression in HEK293T cells, phosphodiesterase activity is detected in the extracellular medium, with no effect on the intracellular GroPIns pool. Together with the millimolar concentrations of calcium required for GDE3 activity, this predicts an enzyme topology with an extracellular catalytic domain. Interestingly, GDE3 ectocellular activity is detected in a stable clone from a murine osteoblast cell line, further confirming the activity of GDE3 in a more physiological context. Finally, overexpression of wild-type GDE3 in osteoblasts promotes disassembly of actin stress fibers, decrease in growth rate, and increase in alkaline phosphatase activity and calcium content, indicating a role for GDE3 in induction of differentiation. Thus, we have identified the GDE3 substrate GroPIns as a candidate mediator for osteoblast proliferation, in line with the GroPIns activity observed previously in epithelial cells.The glycerophosphodiester phosphodiesterases (GP-PDEs)5 were initially characterized in bacteria, where they have functional roles for production of metabolic carbon and phosphate sources from glycerophosphodiesters (1, 2) and in adherence to and degradation of mammalian host-cell membranes (3). The GP-PDEs have a catalytic region of 56 amino acids (4). After their characterization in bacteria, mammalian glycerophosphodiesterases were identified, with the definition of a family of seven members (5). The first of these, GDE1, is an interactor of regulator of G-protein signaling (RGS)16, and was subsequently defined as a GP-PDE regulated by G-protein signaling (4). Indeed, GDE1 expression in HEK293T cells showed increased enzymatic activity upon α/β-adrenergic and lysophospholipid receptor stimulation (4). The second member, GDE2, was isolated by homology searches in neuronal tissues and its physiological role involves neuronal differentiation (6, 7). In contrast, GDE3 has been characterized as a marker of osteoblast differentiation and was isolated through a differential display method (8). GDE4 was isolated only recently with three-dimensional modeling defining it as a GP-PDE, although no functional activity has been correlated to its expression (9). The remaining members were cloned following data base searches, with further studies required for the definition of their properties (5). The diversity among these family members, in terms of tissue distribution, subcellular localization, and substrate specificity, suggests they selectively regulate biological functions and have distinct physiological roles (5).The only GP-PDE activity that has been biochemically characterized to date followed GDE1 overexpression in HEK293T cells, which showed a selectivity for the glycerophosphoinositols (GPIs) as substrate (4), in contrast to the bacterial GP-PDEs that show broad substrate specificities with respect to the alcohol moiety of the glycerophosphodiesterases (1, 2). The GPIs are naturally occurring, biologically active metabolites of the phosphoinositides that were originally investigated in the context of Ras-transformed cells (10). They are present in virtually all cell types, where their intracellular levels can also be modulated according to cell activation, differentiation, and development (Refs. 11 and 12 and references therein). Recently, glycerophosphoinositol (GroPIns) was characterized as a mediator of purinergic and adrenergic regulation of PCCl3 thyroid cell proliferation (13), while GroPIns 4-phosphate (GroPIns4P) has been shown to induce reorganization of the actin cytoskeleton in fibroblasts and in T-lymphocytes, by promoting a sustained and robust activation of the Rho GTPases (14–16).The GPIs appear to rapidly equilibrate across the plasma membrane when added exogenously to cells, to exert their actions within the cell (12). The plasma membrane transporter for GroPIns characterized in yeast is the protein GIT1 (17), with one of its orthologs in mammalian cells identified as the human permease Glut2 (18). This specific transporter has been proposed to mediate both GroPIns uptake and release, which depends on the GroPIns concentration gradient across the plasma membrane. Under physiological conditions, this gradient can arise from the formation of GPIs from the phosphoinositides inside cells following activation of a specific isoform of phospholipase A2, PLA2IVα (13, 19).The release of the GPIs into the extracellular medium can affect their paracrine targets (16) or initiate their catabolism. This is supported by our characterization of GDE1 activity, and now of GDE3 activity, both of which show a substrate selectivity toward GroPIns, and catalytic activity after heterologous expression that can only be monitored in the extracellular space. Interestingly, GDE3 activity appears to be related to modulation of osteoblast functions, delineating a role for GDE3 in promoting osteoblast differentiation, and mainly regulating osteoblast proliferation. 相似文献
164.
Ethel Antunes Wilhelm Cristiano Ricardo Jesse Marina Prigol Diego Alves Ricardo Frederico Schumacher Cristina Wayne Nogueira 《Cell biology and toxicology》2010,26(6):569-577
The aim of this study was to investigate the protective effect of 3-alkynyl selenophene (3-ASP) on acute liver injury induced
by carbon tetrachloride (CCl4) and 2-nitropropane (2-NP) in rats. On the first day of treatment, the animals received 3-ASP (25 mg/kg, p.o.). On the second
day, the rats received CCl4 (1 mg/kg, i.p.) or 2-NP (100 mg/kg, p.o.). Twenty-four hours after CCl4 or 2-NP administration, the animals were euthanized, and their plasma and liver were removed for biochemical and histological
analyses. The histological analysis revealed extensive injury in the liver of CCl4-exposed and 2-NP-exposed rats, which was attenuated by 3-ASP. 3-ASP significantly attenuated (1) the increase in plasmatic
aspartate and alanine aminotransferase activities and lipid peroxidation levels induced by CCl4 and 2-NP; (2) the inhibition of δ-aminolevulinic dehydratase activity caused by 2-NP; and (3) the decrease in ascorbic acid
(AA) levels and catalase (CAT) activity caused by CCl4. AA levels and CAT activity remained unaltered in the liver of rats exposed to 2-NP. The protective effect of 3-ASP on acute
liver injury induced by CCl4 and 2-NP in rats was demonstrated. 相似文献
165.
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167.
Anna Chiara Maria Biressi Ting Zou Samuel Dupont Carl Dahlberg Cristiano Di Benedetto Francesco Bonasoro Michael Thorndyke Maria Daniela Candia Carnevali 《Zoomorphology》2010,129(1):1-19
All species of the Ophiuroidea have exceptional regenerative capabilities; in particular, they can replace arms lost following
traumatic or self-induced amputation. In order to reconstruct this complex phenomenon, we studied arm regeneration in two
different ophiuroids, Ophioderma longicaudum (Retzius, 1805) and Amphiura filiformis O. F. Müller, 1776, which are quite distantly related. These species present contrasting regeneration and differentiation
rates and differ in several ecological traits. The aim of this paper is to interpret the primary sequence of morphogenetic
and histogenetic events leading to the complete reconstruction of a new arm, comparing the arm regenerative processes of these
two ophiuroid species with those described in crinoids. Arm regeneration in ophiuroids is considered an epimorphic process
in which new structures develop from a typical blastema formed from an accumulation of presumptive undifferentiated cells.
Our results showed that although very different in some respects such as, for instance, the regeneration rate (0.17 mm/week
for O. longicaudum and 0.99 mm/week for A. filiformis), morphogenetic and histogenetic aspects are surprisingly similar in both species. The regenerative process presents similar
characteristics and follows a developmental scheme which can be subdivided into four phases: a repair phase, an early regenerative
phase, an intermediate regenerative phase and an advanced regenerative phase. In terms of histogenesis, the regenerative events
involve the development of new structures from migratory pluripotent cells, which proliferate actively, in addition in both
cases there is a significant contribution from dedifferentiated cells, in particular dedifferentiating myocytes, although
to varying extents. This evidence confirms the plasticity of the regenerative phenomenon in echinoderms, which can apparently
follow different pathways in terms of growth and morphogenesis, but nevertheless involve both epimorphic and morphallactic
contributions at the cellular level. 相似文献
168.
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170.
Inna Kuperstein Kerensa Broersen Iryna Benilova Jef Rozenski Wim Jonckheere Maja Debulpaep Annelies Vandersteen Ine Segers-Nolten Kees Van Der Werf Vinod Subramaniam Dries Braeken Geert Callewaert Carmen Bartic Rudi D'Hooge Ivo Cristiano Martins Frederic Rousseau Joost Schymkowitz Bart De Strooper 《The EMBO journal》2010,29(19):3408-3420
The amyloid peptides Aβ40 and Aβ42 of Alzheimer's disease are thought to contribute differentially to the disease process. Although Aβ42 seems more pathogenic than Aβ40, the reason for this is not well understood. We show here that small alterations in the Aβ42:Aβ40 ratio dramatically affect the biophysical and biological properties of the Aβ mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the Aβ42:Aβ40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Aβ species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Aβ peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti‐amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non‐toxic intermediates. 相似文献