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21.
Functional and antigenic characterization of human, rhesus macaque, pigtailed macaque, and murine DC-SIGN
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Baribaud F Pöhlmann S Sparwasser T Kimata MT Choi YK Haggarty BS Ahmad N Macfarlan T Edwards TG Leslie GJ Arnason J Reinhart TA Kimata JT Littman DR Hoxie JA Doms RW 《Journal of virology》2001,75(21):10281-10289
DC-SIGN, a type II membrane protein with a C-type lectin binding domain that is highly expressed on mucosal dendritic cells (DCs) and certain macrophages in vivo, binds to ICAM-3, ICAM-2, and human and simian immunodeficiency viruses (HIV and SIV). Virus captured by DC-SIGN can be presented to T cells, resulting in efficient virus infection, perhaps representing a mechanism by which virus can be ferried via normal DC trafficking from mucosal tissues to lymphoid organs in vivo. To develop reagents needed to characterize the expression and in vivo functions of DC-SIGN, we cloned, expressed, and analyzed rhesus macaque, pigtailed macaque, and murine DC-SIGN and made a panel of monoclonal antibodies (MAbs) to human DC-SIGN. Rhesus and pigtailed macaque DC-SIGN proteins were highly similar to human DC-SIGN and bound and transmitted HIV type 1 (HIV-1), HIV-2, and SIV to receptor-positive cells. In contrast, while competent to bind virus, murine DC-SIGN did not transmit virus to receptor-positive cells under the conditions tested. Thus, mere binding of virus to a C-type lectin does not necessarily mean that transmission will occur. The murine and macaque DC-SIGN molecules all bound ICAM-3. We mapped the determinants recognized by a panel of 16 MAbs to the repeat region, the lectin binding domain, and the extreme C terminus of DC-SIGN. One MAb was specific for DC-SIGN, failing to cross-react with DC-SIGNR. Most MAbs cross-reacted with rhesus and pigtailed macaque DC-SIGN, although none recognized murine DC-SIGN. Fifteen of the MAbs recognized DC-SIGN on DCs, with MAbs to the repeat region generally reacting most strongly. We conclude that rhesus and pigtailed macaque DC-SIGN proteins are structurally and functionally similar to human DC-SIGN and that the reagents that we have developed will make it possible to study the expression and function of this molecule in vivo. 相似文献
22.
Placental failure and impaired vasculogenesis result in embryonic lethality for neuropathy target esterase-deficient mice 总被引:8,自引:0,他引:8
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Moser M Li Y Vaupel K Kretzschmar D Kluge R Glynn P Buettner R 《Molecular and cellular biology》2004,24(4):1667-1679
Age-dependent neurodegeneration resulting from widespread apoptosis of neurons and glia characterize the Drosophila Swiss Cheese (SWS) mutant. Neuropathy target esterase (NTE), the vertebrate homologue of SWS, reacts with organophosphates which initiate a syndrome of axonal degeneration. NTE is expressed in neurons and a variety of nonneuronal cell types in adults and fetal mice. To investigate the physiological functions of NTE, we inactivated its gene by targeted mutagenesis in embryonic stem cells. Heterozygous NTE(+/-) mice displayed a 50% reduction in NTE activity but underwent normal organ development. Complete inactivation of the NTE gene resulted in embryonic lethality, which became evident after gastrulation at embryonic day 9 postcoitum (E9). As early as E7.5, mutant embryos revealed growth retardation which did not reflect impaired cell proliferation but rather resulted from failed placental development; as a consequence, massive apoptosis within the developing embryo preceded its resorption. Histological analysis indicated that NTE is essential for the formation of the labyrinth layer and survival and differentiation of secondary giant cells. Additionally, impairment of vasculogenesis in the yolk sacs and embryos of null mutant conceptuses suggested that NTE is also required for normal blood vessel development. 相似文献
23.
Biological control through regulated transcriptional coactivators 总被引:16,自引:0,他引:16
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The structural design of ATP and NADH producing systems, such as glycolysis and the citric acid cycle (TCA), is analysed using
optimization principles. It is assumed that these pathways combined with oxidative phosphorylation have reached, during their
evolution, a high efficiency with respect to ATP production rates. On the basis of kinetic and thermodynamic principles, conclusions
are derived concerning the optimal stoichiometry of such pathways. Extending previous investigations, both the concentrations
of adenine nucleotides as well as nicotinamide adenine dinucleotides are considered variable quantities. This implies the
consideration of the interaction of an ATP and NADH producing system, an ATP consuming system, a system coupling NADH consumption
with ATP production and a system consuming NADH decoupled from ATP production. It is examined in what respect real metabolic
pathways can be considered optimal by studying a large number of alternative pathways. The kinetics of the individual reactions
are described by linear or bilinear functions of reactant concentrations. In this manner, the steady-state ATP production
rate can be calculated for any possible ATP and NADH producing pathway. It is shown that most of the possible pathways result
in a very low ATP production rate and that the very efficient pathways share common structural properties. Optimization with
respect to the ATP production rate is performed by an evolutionary algorithm. The following results of our analysis are in
close correspondence to the real design of glycolysis and the TCA cycle. (1) In all efficient pathways the ATP consuming reactions
are located near the beginning. (2) In all efficient pathways NADH producing reactions as well as ATP producing reactions
are located near the end. (3) The number of NADH molecules produced by the consumption of one energy-rich molecule (glucose)
amounts to four in all efficient pathways. A distance measure and a measure for the internal ordering of reactions are introduced
to study differences and similarities in the stoichiometries of metabolic pathways. 相似文献
27.
Isolation of a single activating allosteric interaction in phosphofructokinase from Escherichia coli
Escherichia coli phosphofructokinase 1 (EcPFK) is a homotetramer with four active and four allosteric sites. Understanding of the structural basis of allosteric activation of EcPFK by MgADP is complicated by the multiplicity of binding sites. To isolate a single heterotropic allosteric interaction, hybrid tetramers were formed between wild-type and mutant EcPFK subunits in which the binding sites of the mutant subunits have decreased affinity for their respective ligands. The 1:3 (wild-type:mutant) hybrid that contained only one native active site and one native allosteric site was isolated. The affinity for the substrate fructose-6-phosphate (Fru-6-P) of a single wild-type active site is greatly decreased over that displayed by the wild-type tetramer due to the lack of homotropic activation. The free energy of activation by MgADP for this heterotropic interaction is -0.58 kcal/mol at 8.5 degrees C. This compares to -2.87 kcal/mol for a hybrid with no homotropic coupling but all four unique heterotropic interactions. Therefore, the isolated interaction contributes 20% of the total heterotropic coupling. By comparison, wild-type EcPFK exhibits a coupling free energy between Fru-6-P and MgADP of -1.56 kcal/mol under these conditions, indicating that the effects of MgADP are diminished by a homotropic activation equal to -1.3 kcal/mol. These data are not consistent with a concerted allosteric mechanism. 相似文献
28.
Zhu YF Wilcoxen K Saunders J Guo Z Gao Y Connors PJ Gross TD Tucci FC Struthers RS Reinhart GJ Xie Q Chen C 《Bioorganic & medicinal chemistry letters》2002,12(3):403-406
In the process of developing GnRH receptor antagonists, a novel base-catalyzed cyclization of compounds 5a-b was discovered, which led to the formation of the 2-aryl pyrrolo[1,2-a]pyrimid-7-one core structures 6a-b. These intermediates were further modified at positions 1, 2, 4 and 6 to afford a series of potent GnRH antagonists with low nanomolar K(i) values. 相似文献
29.
For most imprinted genes, a difference in expression between the maternal and paternal alleles is associated with a corresponding difference in DNA methylation that is localized to a differentially methylated domain (DMD). Removal of a gene's DMD leads to a loss of imprinting. These observations suggest that DMDs have a determinative role in genomic imprinting. To examine this possibility, we introduced sequences from the DMDs of the imprinted Igf2r, H19, and Snrpn genes into a nonimprinted derivative of the normally imprinted RSVIgmyc transgene, created by excising its own DMD. Hybrid transgenes with sequences from the Igf2r DMD2 were consistently imprinted, with the maternal allele being more methylated than the paternal allele. Only the repeated sequences within DMD2 were required for imprinting these transgenes. Hybrid transgenes containing H19 and Snrpn DMD sequences and ones containing sequences from the long terminal repeat of a murine intracisternal A particle retrotransposon were not imprinted. The Igf2r hybrid transgenes are comprised entirely of mouse genomic DNA and behave as endogenous imprinted genes in inbred wild-type and mutant mouse strains. These types of hybrid transgenes can be used to elucidate the functions of DMD sequences in genomic imprinting. 相似文献
30.
Mathematical methods are used for explaining the structural design of signal transduction networks, e.g. MAP kinase cascades, which control cell proliferation, differentation or apoptosis. Taking into account protein kinases and phosphatases the interrelation between the topology of signaling networks and the stability of their ground state are analysed. It is shown that the stability is closely related to the system's dimension and to the number of cycles within the network. Systems with a higher number of kinases and/or cycles tend to be more unstable. In contrast to that increasing phosphatase activity stabilises the ground state. 相似文献