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171.
Deletion of deoxyribonucleic acid binding domain of the vitamin D receptor abrogates genomic and nongenomic functions of vitamin D 总被引:14,自引:0,他引:14
Erben RG Soegiarto DW Weber K Zeitz U Lieberherr M Gniadecki R Möller G Adamski J Balling R 《Molecular endocrinology (Baltimore, Md.)》2002,16(7):1524-1537
The vitamin D hormone 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the biologically active form of vitamin D, is essential for an intact mineral metabolism. Using gene targeting, we sought to generate vitamin D receptor (VDR) null mutant mice carrying the reporter gene lacZ driven by the endogenous VDR promoter. Here we show that our gene-targeted mutant mice express a VDR with an intact hormone binding domain, but lacking the first zinc finger necessary for DNA binding. Expression of the lacZ reporter gene was widely distributed during embryogenesis and postnatally. Strong lacZ expression was found in bones, cartilage, intestine, kidney, skin, brain, heart, and parathyroid glands. Homozygous mice are a phenocopy of mice totally lacking the VDR protein and showed growth retardation, rickets, secondary hyperparathyroidism, and alopecia. Feeding of a diet high in calcium, phosphorus, and lactose normalized blood calcium and serum PTH levels, but revealed a profound renal calcium leak in normocalcemic homozygous mutants. When mice were treated with pharmacological doses of vitamin D metabolites, responses in skin, bone, intestine, parathyroid glands, and kidney were absent in homozygous mice, indicating that the mutant receptor is nonfunctioning and that vitamin D signaling pathways other than those mediated through the classical nuclear receptor are of minor physiological importance. Furthermore, rapid, nongenomic responses to 1,25-(OH)(2)D(3) in osteoblasts were abrogated in homozygous mice, supporting the conclusion that the classical VDR mediates the nongenomic actions of 1,25-(OH)(2)D(3). 相似文献
172.
Neumann K Eppler E Filgueira L Groscurth P Gasal E Schaffner A Schoedon G Schneemann M 《Immunology and cell biology》2003,81(6):431-439
Listeria monocytogenes is the causative agent of infections like sepsis and meningitis, especially in immunocompromised hosts. Human macrophages are able to phagocytose and digest L. monocytogenes but IL-4 prevents human macrophages from killing the bacteria, the mechanisms of which are unknown. In the present study, we examined various listeria species and strains including wild-type and deletion mutants in human macrophages pretreated with IL-4. To analyse the IL-4-mediated deactivation process, we combined quantitative infection assays with various morphologic methods. IL-4 facilitates survival and escape of the pathogenic L. monocytogenes wild-type strain 10403S from the macrophage phagosomes. In untreated macrophages, the isogenic listeriolysin deletion mutant strain DP-L2161 was killed and did not escape from the phagolysosomes. However, after macrophage deactivation with IL-4 DP-L2161 survived and escaped from the phagosomes. This was also the case, but to a lesser extent, even for the naturally avirulent L. innocua. As detected by confocal laser-scanning fluorescence microscopy and electron microscopy, IL-4 permitted the escape of all listeria species tested, including DP-L2161 and L. innocua from the phagosomal compartment of the macrophages. We conclude that escape from the phagosome and survival of the listeria species tested in IL-4-deactivated human macrophages is independent of the virulence factor listeriolysin. 相似文献
173.
Werner ER Gorren AC Heller R Werner-Felmayer G Mayer B 《Experimental biology and medicine (Maywood, N.J.)》2003,228(11):1291-1302
In previous minireviews in this journal, we discussed work on induction of tetrahydrobiopterin biosynthesis by cytokines and its significance for nitric oxide (NO) production of intact cells as well as functions of H4-biopterin identified at this time for NO synthases (Proc Soc Exp Biol Med 203: 1-12, 1993; Proc Soc Exp Biol Med 219: 171-182, 1998). Meanwhile, the recognition of the importance of tetrahydrobiopterin for NO formation has led to new insights into complex biological processes and revealed possible novel pharmacological strategies to intervene in certain pathological conditions. Recent work could also establish that tetrahydrobiopterin, in addition to its allosteric effects, is redox-active in the NO synthase reaction. In this review, we summarize the current view of how tetrahydrobiopterin functions in the generation of NO and focus on pharmacological aspects of tetrahydrobiopterin availability with emphasis on endothelial function. 相似文献
174.
Despite the recently enlarged field of available RNA knock-down technologies, e.g., antisense oligonucleotides (ASOs) and duplexes of synthetic 21 nucleotides RNAs (siRNAs), no versatile transfection reagent has been reported to deliver different nucleic acids formats at high rates of efficiency. We have evaluated the versatility and efficacy of linear PEI in transfecting and properly delivering a broad panel of nucleic acids such as short oligonucleotides and double-stranded RNA into cells in culture. 相似文献
175.
The longitudinal muscle of isolated rat ileum is a sensitive bioassay suitable for testing compounds with antagonistic effects on the B(1) receptor. Bradykinin analogues with replacement of proline by alkyl-substituted phenylalanine at position 7 are effective on this receptor as entire molecules and have a stronger antagonistic effect than on the B(2) receptor. A corresponding desArg(9)-compound has a specific effect on the B(1) receptor and a very high antagonistic potency. [LNMPhe(2)]bradykinin as a compound without any replacement at position 7 or 8 shows antagonistic activity as well. 相似文献
176.
Odorant signal transduction and neurogenesis are fundamental properties of the olfactory epithelium. Many preparations have been used to elucidate some of the mechanisms underlying these properties. In this article, we briefly review these research areas and describe some of the techniques used to obtain the data. We focus specifically on the cell-culture paradigm and the data obtained from various immortal cell lines in their attempts to reconstruct the olfactory epithelium in vitro. 相似文献
177.
Viral Determinants of Rotavirus Pathogenicity in Pigs: Evidence that the Fourth Gene of a Porcine Rotavirus Confers Diarrhea in the Homologous Host 总被引:1,自引:1,他引:0 下载免费PDF全文
Janice C. Bridger Gabriele I. Tauscher Ulrich Desselberger 《Journal of virology》1998,72(8):6929-6931
A porcine rotavirus (prv) monoreassortant, S-F4, which carries RNA segment 4 of the pig-pathogenic variant prv 4F in the genetic background of the pig-apathogenic variant prv 4S (G. I. Tauscher and U. Desselberger, J. Virol. 71:853–857, 1997), was found to be pathogenic in gnotobiotic piglets. This indicates that RNA segment 4 of the pig-pathogenic variant prv 4F is a major determinant of pathogenicity in its homologous host. 相似文献
178.
External sucrose, supplied by the endosperm in vivo, is the physiological source of sucrose for Ricinus communis L. seedlings. It is taken up by the cotyledons and exported via the sieve tubes to the growing hypocotyl and root. Two parallel
pathways of external sucrose to the sieve tubes, directly via the apoplasm and indirectly after transit through the mesophyll,
have already been established (G. Orlich and E. Komor, 1992). In this study, we analysed whether a symplasmic flow of sucrose
contributes to phloem loading. Uptake of external sucrose into the mesophyll and into the sieve tubes, and export of total
sucrose were measured with intact and exuding seedlings in the presence of p-chloromercuribenzenesulfonic acid (PCMBS). Sucrose uptake into the mesophyll and into the sieve tubes was inhibited by 80–90%.
Consequently, export of total sucrose slowed down. However, after the addition of PCMBS, sucrose was transiently exported
in such a high amount that could not be accounted for by the residual uptake activity nor by the amount of sucrose confined
to the sieve element-companion cell complex (seccc). From the results, we conclude that most of the sucrose exported transiently
had moved to the sieve tubes from a symplasmic domain larger than the seccc, comprising at least all the cells of the bundle
including the bundle sheath. We suggest that the symplasmic flow of sucrose observed is a mass flow driven by a turgor pressure.
As a structural prerequisite for a symplasmic flow, plasmodesmata interconnect all the cells from the bundle sheath to the
sieve tubes and also occur between the bundle sheath and the mesophyll. The phloem loading pathway of Ricinus cotyledons can thus be classified as a combination of three different routes.
Received: 17 October 1997 / Accepted: 9 March 1998 相似文献
179.
Kumud Majumder William Shawlot Gabriele Schuster Wilbur Harrison Frederick F.B. Elder Paul A. Overbeek 《Mammalian genome》1998,9(11):863-868
Mice with mutations at the downless (dl) locus have defects in hair follicle, tooth, sweat gland, preputial gland, Meibomian gland, and tail development. The dl phenotype is analogous to the human genetic disorder termed autosomal hypohidrotic (or anhidrotic) ectodermal dysplasia (HED).
On the basis of the identification of two related transgenic insertional mutations in the downless gene, yeast artificial
chromosomes (YACs) were identified that map to the critical region of mouse Chromosome (Chr) 10. To determine which of the
YACs contain the dl gene, we generated YAC transgenic mice by mouse embryo microinjections. The 200-kb YAC B25.D9 was found to rescue all of
the downless defects. In addition, the transgenic YAC rescued the dominant Sleek (Dl
slk
) allele. Since the sequences within the YAC are entirely deleted in one of the transgenic mutants, our results establish
that Sleek encodes a dominant-negative protein whose effects can be reversed by expression of extra copies of the wild-type
locus.
Received: 26 June 1998 / Accepted: 17 July 1998 相似文献
180.
The medial-Golgi Ion Pump Pmr1 Supplies the Yeast Secretory Pathway with Ca2+ and Mn2+ Required for Glycosylation, Sorting, and Endoplasmic Reticulum-Associated Protein Degradation 下载免费PDF全文
Gabriele Dürr Jochen Strayle Richard Plemper Saskia Elbs Saskia K. Klee Patrice Catty Dieter H. Wolf Hans K. Rudolph 《Molecular biology of the cell》1998,9(5):1149-1162
The yeast Ca2+ adenosine triphosphatase Pmr1, located in medial-Golgi, has been implicated in intracellular transport of Ca2+ and Mn2+ ions. We show here that addition of Mn2+ greatly alleviates defects of pmr1 mutants in N-linked and O-linked protein glycosylation. In contrast, accurate sorting of carboxypeptidase Y (CpY) to the vacuole requires a sufficient supply of intralumenal Ca2+. Most remarkably, pmr1 mutants are also unable to degrade CpY*, a misfolded soluble endoplasmic reticulum protein, and display phenotypes similar to mutants defective in the stress response to malfolded endoplasmic reticulum proteins. Growth inhibition of pmr1 mutants on Ca2+-deficient media is overcome by expression of other Ca2+ pumps, including a SERCA-type Ca2+ adenosine triphosphatase from rabbit, or by Vps10, a sorting receptor guiding non-native luminal proteins to the vacuole. Our analysis corroborates the dual function of Pmr1 in Ca2+ and Mn2+ transport and establishes a novel role of this secretory pathway pump in endoplasmic reticulum-associated processes. 相似文献