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101.
Geneviève Dupont Laurent Combettes Gary S. Bird James W. Putney 《Cold Spring Harbor perspectives in biology》2011,3(3)
Calcium signaling results from a complex interplay between activation and inactivation of intracellular and extracellular calcium permeable channels. This complexity is obvious from the pattern of calcium signals observed with modest, physiological concentrations of calcium-mobilizing agonists, which typically present as sequential regenerative discharges of stored calcium, a process referred to as calcium oscillations. In this review, we discuss recent advances in understanding the underlying mechanism of calcium oscillations through the power of mathematical modeling. We also summarize recent findings on the role of calcium entry through store-operated channels in sustaining calcium oscillations and in the mechanism by which calcium oscillations couple to downstream effectors.Calcium ions participate in a multiplicity of physiological and pathological functions. Among the most intensely studied, and the major focus of this article, is the role of Ca2+ as a cellular signal. Elevations in cytoplasmic Ca2+ mediate a plethora of cellular responses, ranging from extremely rapid events (muscle contraction, neurosecretion), to slower more subtle responses (cell division, differentiation, apoptosis). In contrast to most cellular signals, it is a relatively simple matter to observe changes in cytoplasmic Ca2+ in real time in living cells. As a result, the truly complex nature of Ca2+ signaling pathways has been revealed. The challenge is to understand what regulates these signals and what the biological significance of their complexity is.In the majority of laboratory experiments examining effects of various stimulants on Ca2+ signaling, supramaximal concentrations of activating agonists are employed resulting in rapid, robust, and often sustained increases in cytoplasmic Ca2+. It has long been appreciated that these signals result from a coordinated release of intracellular stores and increased Ca2+ influx across the plasma membrane (Bohr, 1973; Putney et al. 1981). The intracellular release of Ca2+ most commonly results from the Ca2+ releasing action of the phospholipase C-derived second messenger, inositol 1,4,5-trisphosphate (InsP3) (Streb et al. 1983), whereas the entry of Ca2+ is because of the activation of store-operated channels in the plasma membrane (Putney 1986). However, it is becoming increasingly clear that these large sustained elevations seldom occur with physiological levels of stimulants. Rather the more common pattern of Ca2+ signaling, in both excitable and nonexcitable cells is a pattern of periodic discharges and/or entry of Ca2+. In excitable cells, such as the heart for example, these may be comprised of, or initiated by regenerative all-or-none plasma membrane channel activation, the Ca2+ action potential (Tsien et al. 1986) with amplification by intracellular Ca2+ release (Fabiato 1983). In nonexcitable cells, these spikes of cytoplasmic Ca2+ arise from regenerative discharge of stored Ca2+, a process generally termed Ca2+ oscillations (Prince and Berridge 1973; Woods et al. 1986). Like Ca2+ action potentials, these all-or-none discharges of Ca2+ represent a form of excitable behavior of the intracellular Ca2+ release signaling mechanism. However, because it is not possible to easily monitor and control the transmembrane chemical and biophysical parameters, as is the case for excitable plasma membrane behavior, it has been more difficult to fully understand the basic mechanisms by which these Ca2+ oscillations arise. Thus, although the question has been exhaustively studied for well over twenty years, there is still uncertainty and controversy over the underlying processes that give rise to Ca2+ oscillations. A number of reviews have discussed these issues at some length (Berridge and Galione 1988; Rink and Jacob 1989; Berridge 1990; Petersen and Wakui 1990; Berridge 1991; Cuthbertson and Cobbold 1991; Meyer and Stryer 1991; Hellman et al. 1992; Tepikin and Petersen 1992; Thomas et al. 1992; Dupont and Goldbeter 1993; Keizer 1993; Sneyd et al. 1994; Li et al. 1995; Thomas et al. 1996; Shuttleworth 1999; Lewis 2003; Dupont et al. 2007). In the current treatment, we have chosen to focus on two important aspects of Ca2+ oscillations. First, we review the available evidence for various computational models of Ca2+ oscillations that employ a quantitative approach to validate or repudiate specific mechanisms. Second, we consider the interrelationship between Ca2+ oscillations and plasma membrane Ca2+ influx mechanisms, with the view that we may learn more of the physiological function that these intracellular discharges of Ca2+ provide. 相似文献
102.
Leduc F Faucher D Bikond Nkoma G Grégoire MC Arguin M Wellinger RJ Boissonneault G 《PloS one》2011,6(2):e17353
Determination of cellular DNA damage has so far been limited to global assessment of genome integrity whereas nucleotide-level mapping has been restricted to specific loci by the use of specific primers. Therefore, only limited DNA sequences can be studied and novel regions of genomic instability can hardly be discovered. Using a well-characterized yeast model, we describe a straightforward strategy to map genome-wide DNA strand breaks without compromising nucleotide-level resolution. This technique, termed "damaged DNA immunoprecipitation" (dDIP), uses immunoprecipitation and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin end-labeling (TUNEL) to capture DNA at break sites. When used in combination with microarray or next-generation sequencing technologies, dDIP will allow researchers to map genome-wide DNA strand breaks as well as other types of DNA damage and to establish a clear profiling of altered genes and/or intergenic sequences in various experimental conditions. This mapping technique could find several applications for instance in the study of aging, genotoxic drug screening, cancer, meiosis, radiation and oxidative DNA damage. 相似文献
103.
Bourassa CV Rivière JB Dion PA Bernard G Diab S Panisset M Chouinard S Dupré N Fournier H Raelson J Belouchi M Rouleau GA 《PloS one》2011,6(1):e16254
Essential tremor (ET) is a complex genetic disorder for which no causative gene has been found. Recently, a genome-wide association study reported that two variants in the LINGO1 locus were associated to this disease. The aim of the present study was to test if this specific association could be replicated using a French-Canadian cohort of 259 ET patients and 479 ethnically matched controls. Our genotyping results lead us to conclude that no association exists between the key variant rs9652490 and ET (Pcorr = 1.00). 相似文献
104.
105.
Insulin-mediated down-regulation of apolipoprotein A5 gene expression through the phosphatidylinositol 3-kinase pathway: role of upstream stimulatory factor 总被引:11,自引:0,他引:11 下载免费PDF全文
Nowak M Helleboid-Chapman A Jakel H Martin G Duran-Sandoval D Staels B Rubin EM Pennacchio LA Taskinen MR Fruchart-Najib J Fruchart JC 《Molecular and cellular biology》2005,25(4):1537-1548
The apolipoprotein A5 gene (APOA5) has been repeatedly implicated in lowering plasma triglyceride levels. Since several studies have demonstrated that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 is regulated by insulin. Here, we show that cell lines and mice treated with insulin down-regulate APOA5 expression in a dose-dependent manner. Furthermore, we found that insulin decreases human APOA5 promoter activity, and subsequent deletion and mutation analyses uncovered a functional E box in the promoter. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that this APOA5 E box binds upstream stimulatory factors (USFs). Moreover, in transfection studies, USF1 stimulates APOA5 promoter activity, and the treatment with insulin reduced the binding of USF1/USF2 to the APOA5 promoter. The inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway abolished insulin's effect on APOA5 gene expression, while the inhibition of the P70 S6 kinase pathway with rapamycin reversed its effect and increased APOA5 gene expression. Using an oligonucleotide precipitation assay for USF from nuclear extracts, we demonstrate that phosphorylated USF1 fails to bind to the APOA5 promoter. Taken together, these data indicate that insulin-mediated APOA5 gene transrepression could involve a phosphorylation of USFs through the PI3K and P70 S6 kinase pathways that modulate their binding to the APOA5 E box and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in men showed a decrease in the plasma ApoAV level. These results suggest a potential contribution of the APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia. 相似文献
106.
Disruption of the langerin/CD207 gene abolishes Birbeck granules without a marked loss of Langerhans cell function 下载免费PDF全文
Kissenpfennig A Aït-Yahia S Clair-Moninot V Stössel H Badell E Bordat Y Pooley JL Lang T Prina E Coste I Gresser O Renno T Winter N Milon G Shortman K Romani N Lebecque S Malissen B Saeland S Douillard P 《Molecular and cellular biology》2005,25(1):88-99
Langerin is a C-type lectin expressed by a subset of dendritic leukocytes, the Langerhans cells (LC). Langerin is a cell surface receptor that induces the formation of an LC-specific organelle, the Birbeck granule (BG). We generated a langerin(-/-) mouse on a C57BL/6 background which did not display any macroscopic aberrant development. In the absence of langerin, LC were detected in normal numbers in the epidermis but the cells lacked BG. LC of langerin(-/-) mice did not present other phenotypic alterations compared to wild-type littermates. Functionally, the langerin(-/-) LC were able to capture antigen, to migrate towards skin draining lymph nodes, and to undergo phenotypic maturation. In addition, langerin(-/-) mice were not impaired in their capacity to process native OVA protein for I-A(b)-restricted presentation to CD4(+) T lymphocytes or for H-2K(b)-restricted cross-presentation to CD8(+) T lymphocytes. langerin(-/-) mice inoculated with mannosylated or skin-tropic microorganisms did not display an altered pathogen susceptibility. Finally, chemical mutagenesis resulted in a similar rate of skin tumor development in langerin(-/-) and wild-type mice. Overall, our data indicate that langerin and BG are dispensable for a number of LC functions. The langerin(-/-) C57BL/6 mouse should be a valuable model for further functional exploration of langerin and the role of BG. 相似文献
107.
Polymerase chain reaction assay specific for pathogenic Leptospira based on the gene hap1 encoding the hemolysis-associated protein-1 总被引:1,自引:0,他引:1
Branger C Blanchard B Fillonneau C Suard I Aviat F Chevallier B André-Fontaine G 《FEMS microbiology letters》2005,243(2):437-445
In this study, we used Southern hybridization of genomic DNA with the integral hap1 gene as a probe to show that this gene is only present in pathogenic Leptospira strains. We then selected PCR primers based on the hap1 gene, and tested them on several Leptospira strains and biological samples. Specific amplification was obtained for all pathogenic strains tested. Negative PCR results were observed with all saprophytic leptospire strains used as well as with other spirochetes and bacteria commonly found in biological samples. The results of direct PCR performed on biological samples, such as blood, urine or kidneys correlated with the results obtained with the classical Leptospira tests (culture and MAT). A PCR assay based on this gene would be a very useful tool for the rapid, sensitive and specific identification of pathogenic leptospires in samples for diagnosis or epidemiological survey. 相似文献
108.
Jouin H Garraud O Longacre S Baleux F Mercereau-Puijalon O Milon G 《Immunology and cell biology》2005,83(4):392-395
Antibodies to polymorphic block 2 of the Plasmodium falciparum merozoite surface protein 1 (MSP-1) present a paradoxical association with acquired protection against clinical malaria, while showing restricted and fixed specificity, reminiscent of antigenic sin. We report here that these antibodies present a highly imbalanced, peptide-specific light chain distribution. This was not observed with several other parasite-derived peptides or antigens. These data point to a skewed immune response to MSP-1 block 2 that is constrained both in specificity and chain usage. This is the first report of a biased response to polymorphic epitopes of a surface antigen in malaria parasites. 相似文献
109.
Histones are the fundamental structural proteins intimately associated with eukaryotic DNA to form a highly ordered and condensed nucleoproteic complex termed chromatin. They are the targets of various posttranslational modifications including acetylation, methylation, phosphorylation and ubiquitination that modulate the structure/function of chromatin. The combinatorial nature of histone modifications is hypothesized to define a "histone code" that considerably extends the information potential of the genetic code, giving rise to epigenetic information. Moreover, most core histones consist of several nonallelic variants that can mark specific loci and could play an important role in establishment and maintenance of epigenetic memory. Here we will briefly present our current knowledge about histone posttranslational modifications and their implications in the regulation of epigenetic information. We will next describe core histone variants, insisting on their mode of incorporation into chromatin to discuss their epigenetic function and inheritance. 相似文献
110.