全文获取类型
收费全文 | 919篇 |
免费 | 120篇 |
国内免费 | 3篇 |
出版年
2022年 | 12篇 |
2021年 | 6篇 |
2019年 | 8篇 |
2018年 | 9篇 |
2017年 | 16篇 |
2016年 | 15篇 |
2015年 | 33篇 |
2014年 | 38篇 |
2013年 | 45篇 |
2012年 | 65篇 |
2011年 | 57篇 |
2010年 | 36篇 |
2009年 | 39篇 |
2008年 | 32篇 |
2007年 | 51篇 |
2006年 | 31篇 |
2005年 | 39篇 |
2004年 | 40篇 |
2003年 | 36篇 |
2002年 | 37篇 |
2001年 | 32篇 |
2000年 | 30篇 |
1999年 | 10篇 |
1998年 | 10篇 |
1997年 | 12篇 |
1996年 | 11篇 |
1995年 | 15篇 |
1994年 | 10篇 |
1993年 | 10篇 |
1992年 | 15篇 |
1991年 | 14篇 |
1990年 | 18篇 |
1989年 | 14篇 |
1988年 | 10篇 |
1987年 | 17篇 |
1986年 | 11篇 |
1985年 | 10篇 |
1984年 | 8篇 |
1983年 | 6篇 |
1981年 | 9篇 |
1980年 | 6篇 |
1978年 | 9篇 |
1977年 | 9篇 |
1974年 | 15篇 |
1973年 | 7篇 |
1972年 | 6篇 |
1971年 | 9篇 |
1968年 | 9篇 |
1967年 | 6篇 |
1966年 | 5篇 |
排序方式: 共有1042条查询结果,搜索用时 15 毫秒
111.
Allison Kraus Jody Groenendyk Karen Bedard Troy A. Baldwin Karl-Heinz Krause Michel Dubois-Dauphin Jason Dyck Erica E. Rosenbaum Lawrence Korngut Nansi J. Colley Simon Gosgnach Douglas Zochodne Kathryn Todd Luis B. Agellon Marek Michalak 《The Journal of biological chemistry》2010,285(24):18928-18938
Calnexin is a molecular chaperone and a component of the quality control of the secretory pathway. We have generated calnexin gene-deficient mice (cnx−/−) and showed that calnexin deficiency leads to myelinopathy. Calnexin-deficient mice were viable with no discernible effects on other systems, including immune function, and instead they demonstrated dysmyelination as documented by reduced conductive velocity of nerve fibers and electron microscopy analysis of sciatic nerve and spinal cord. Myelin of the peripheral and central nervous systems of cnx−/− mice was disorganized and decompacted. There were no abnormalities in neuronal growth, no loss of neuronal fibers, and no change in fictive locomotor pattern in the absence of calnexin. This work reveals a previously unrecognized and important function of calnexin in myelination and provides new insights into the mechanisms responsible for myelin diseases. 相似文献
112.
Štepánka Dlouhá Anne Thielsch Robert H. S. Kraus Jaromír Seda Klaus Schwenk Adam Petrusek 《Hydrobiologia》2010,643(1):107-122
Daphnia galeata Sars, D. longispina O. F. Müller and D. cucullata Sars (Crustacea: Cladocera) are closely related species which often produce interspecific hybrids in natural populations.
Several marker systems are available for taxon determination in this hybridizing complex, but their performance and reliability
has not been systematically assessed. We compared results from identifications by three molecular methods. More than 1,200
individuals from 10 localities in the Czech Republic were identified as parental species or hybrids by allozyme electrophoresis
and the analysis of the restriction fragment length polymorphism of the internal transcribed spacer (ITS-RFLP); over 440 of
them were additionally analyzed and identified by 12 microsatellite loci. Identification by microsatellite markers corresponded
well with allozyme analyses. However, consistent discrepancies between ITS-RFLP and other markers were observed in two out
of 10 studied localities. Although some marker discrepancies may have been caused by occasional recent introgression, consistent
deviations between ITS-RFLP and other markers suggest a long-term maintenance of introgressed alleles. These results warn
against its use as a sole identification method in field studies. Additionally, we quantitatively evaluated the discriminatory
power of geometric morphometric (elliptic Fourier) analysis of body shapes based on photos of over 1,300 individuals pre-classified
by allozyme markers. Furthermore, a randomly selected subset of 240 individuals was independently determined from photos by
several experts. Despite a tendency for morphological divergence among parental Daphnia species, some taxa (especially D. galeata, D. longispina, and their hybrids) substantially overlapped in their body shapes. This was reflected in different determination success
for particular species and hybrids in discriminant analysis based on shape data as well as from photographs. 相似文献
113.
CSMD1 is a novel multiple domain complement-regulatory protein highly expressed in the central nervous system and epithelial tissues 总被引:3,自引:0,他引:3
Kraus DM Elliott GS Chute H Horan T Pfenninger KH Sanford SD Foster S Scully S Welcher AA Holers VM 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(7):4419-4430
In this study, we describe the identification and in vitro functional activity of a novel multiple domain complement regulatory protein discovered based on its homology to short consensus repeat (SCR)-containing proteins of the regulators of complement activation (RCA) gene family. The rat cDNA encodes a predicted 388-kDa protein consisting of 14 N-terminal CUB domains that are separated from each other by a SCR followed by 15 tandem SCR domains, a transmembrane domain, and a short cytoplasmic tail. This protein is the homolog of the human protein of unknown function called the CUB and sushi multiple domains 1 (CSMD1) protein. A cloning strategy that incorporates the two C-terminal CUB-SCR domains and 12 of the tandem SCR repeats was used to produce a soluble rat CSMD1 protein. This protein blocked classical complement pathway activation in a comparable fashion with rat Crry but did not block alternative pathway activation. Analysis of CSMD1 mRNA expression by in situ hybridization and immunolabeling of neurons indicates that the primary sites of synthesis are the developing CNS and epithelial tissues. Of particular significance is the enrichment of CSMD1 in the nerve growth cone, the amoeboid-leading edge of the growing neuron. These results suggest that CSMD1 may be an important regulator of complement activation and inflammation in the developing CNS, and that it may also play a role in the context of growth cone function. 相似文献
114.
Asokan R Hua J Young KA Gould HJ Hannan JP Kraus DM Szakonyi G Grundy GJ Chen XS Crow MK Holers VM 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(1):383-394
Human complement receptor type 2 (CR2/CD21) is a B lymphocyte membrane glycoprotein that plays a central role in the immune responses to foreign Ags as well as the development of autoimmunity to nuclear Ags in systemic lupus erythematosus. In addition to these three well-characterized ligands, C3d/iC3b, EBV-gp350, and CD23, a previous study has identified CR2 as a potential receptor for IFN-alpha. IFN-alpha, a multifunctional cytokine important in the innate immune system, has recently been proposed to play a major pathogenic role in the development of systemic lupus erythematosus in humans and mice. In this study, we have shown using surface plasmon resonance and ELISA approaches that CR2 will bind IFN-alpha in the same affinity range as the other three well-characterized ligands studied in parallel. In addition, we show that IFN-alpha interacts with short consensus repeat domains 1 and 2 in a region that serves as the ligand binding site for C3d/iC3b, EBV-gp350, and CD23. Finally, we show that treatment of purified human peripheral blood B cells with the inhibitory anti-CR2 mAb 171 diminishes the induction of IFN-alpha-responsive genes. Thus, IFN-alpha represents a fourth class of extracellular ligands for CR2 and interacts with the same domain as the other three ligands. Defining the role of CR2 as compared with the well-characterized type 1 IFN-alpha receptor 1 and 2 in mediating innate immune and autoimmune roles of this cytokine should provide additional insights into the biologic roles of this interaction. 相似文献
115.
Kraus YA 《The International journal of developmental biology》2006,50(2-3):267-275
The factors governing the pattern formation process in the early morphogenesis of a marine colonial hydroid, Dynamena pumila, have been studied. Two different types of morphogenesis have been distinguished. Morphogenesis of the first type goes on via changes in cell shape and cell axis orientation, while morphogenesis of the second type is based upon the active coordinated cell movements associated with cell rearrangements. It was shown that morphogenesis of both types can be considered as cascades in which any event is a consequence of the previous one. The spatial structure of each developmental stage contains information about the direction and the initial conditions of further morphogenesis. So, an "epigenetic program" of morphogenesis gradually originates in the course of development and provides the stable reproduction of spatial structures. It is reasonable to consider the activity of epigenetic factors guiding Dynamena morphogenesis (geometry/topology of an embryo, heterogeneity of an embryo spatial structure, configuration of the field of mechanical stresses of the embryo surface) as "morphomechanical programming" of morphogenesis. 相似文献
116.
Kraus JL Bouygues M Courcambeck J Chermann JC 《Bioorganic & medicinal chemistry letters》2000,10(17):2023-2026
The synthesis of new phenylalanine-2-thiophenoxy-3-pyrrolidinones is described. Anti-HIV recombinant protease assays and HIV infected cell culture assays (observation of syncytia) demonstrated the potent anti-HIV activity of this new class of pseudopeptides. 相似文献
117.
Zhang T Berrocal JG Yao J DuMond ME Krishnakumar R Ruhl DD Ryu KW Gamble MJ Kraus WL 《The Journal of biological chemistry》2012,287(15):12405-12416
NMNAT-1 and PARP-1, two key enzymes in the NAD(+) metabolic pathway, localize to the nucleus where integration of their enzymatic activities has the potential to control a variety of nuclear processes. Using a variety of biochemical, molecular, cell-based, and genomic assays, we show that NMNAT-1 and PARP-1 physically and functionally interact at target gene promoters in MCF-7 cells. Specifically, we show that PARP-1 recruits NMNAT-1 to promoters where it produces NAD(+) to support PARP-1 catalytic activity, but also enhances the enzymatic activity of PARP-1 independently of NAD(+) production. Furthermore, using two-photon excitation microscopy, we show that NMNAT-1 catalyzes the production of NAD(+) in a nuclear pool that may be distinct from other cellular compartments. In expression microarray experiments, depletion of NMNAT-1 or PARP-1 alters the expression of about 200 protein-coding genes each, with about 10% overlap between the two gene sets. NMNAT-1 enzymatic activity is required for PARP-1-dependent poly(ADP-ribosyl)ation at the promoters of commonly regulated target genes, as well as the expression of those target genes. Collectively, our studies link the enzymatic activities of NMNAT-1 and PARP-1 to the regulation of a set of common target genes through functional interactions at target gene promoters. 相似文献
118.
Schnute ME McReynolds MD Kasten T Yates M Jerome G Rains JW Hall T Chrencik J Kraus M Cronin CN Saabye M Highkin MK Broadus R Ogawa S Cukyne K Zawadzke LE Peterkin V Iyanar K Scholten JA Wendling J Fujiwara H Nemirovskiy O Wittwer AJ Nagiec MM 《The Biochemical journal》2012,444(1):79-88
SphK (sphingosine kinase) is the major source of the bioactive lipid and GPCR (G-protein-coupled receptor) agonist S1P (sphingosine 1-phosphate). S1P promotes cell growth, survival and migration, and is a key regulator of lymphocyte trafficking. Inhibition of S1P signalling has been proposed as a strategy for treatment of inflammatory diseases and cancer. In the present paper we describe the discovery and characterization of PF-543, a novel cell-permeant inhibitor of SphK1. PF-543 inhibits SphK1 with a K(i) of 3.6 nM, is sphingosine-competitive and is more than 100-fold selective for SphK1 over the SphK2 isoform. In 1483 head and neck carcinoma cells, which are characterized by high levels of SphK1 expression and an unusually high rate of S1P production, PF-543 decreased the level of endogenous S1P 10-fold with a proportional increase in the level of sphingosine. In contrast with past reports that show that the growth of many cancer cell lines is SphK1-dependent, specific inhibition of SphK1 had no effect on the proliferation and survival of 1483 cells, despite a dramatic change in the cellular S1P/sphingosine ratio. PF-543 was effective as a potent inhibitor of S1P formation in whole blood, indicating that the SphK1 isoform of sphingosine kinase is the major source of S1P in human blood. PF-543 is the most potent inhibitor of SphK1 described to date and it will be useful for dissecting specific roles of SphK1-driven S1P signalling. 相似文献
119.
120.