全文获取类型
收费全文 | 300篇 |
免费 | 47篇 |
出版年
2023年 | 2篇 |
2022年 | 2篇 |
2021年 | 4篇 |
2020年 | 7篇 |
2019年 | 7篇 |
2018年 | 6篇 |
2017年 | 6篇 |
2016年 | 17篇 |
2015年 | 8篇 |
2014年 | 17篇 |
2013年 | 18篇 |
2012年 | 20篇 |
2011年 | 18篇 |
2010年 | 13篇 |
2009年 | 21篇 |
2008年 | 10篇 |
2007年 | 19篇 |
2006年 | 17篇 |
2005年 | 15篇 |
2004年 | 4篇 |
2003年 | 9篇 |
2002年 | 13篇 |
2001年 | 7篇 |
1999年 | 4篇 |
1998年 | 5篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 7篇 |
1987年 | 9篇 |
1986年 | 5篇 |
1985年 | 5篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1977年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1959年 | 1篇 |
1957年 | 2篇 |
1955年 | 2篇 |
1953年 | 1篇 |
排序方式: 共有347条查询结果,搜索用时 31 毫秒
71.
72.
Molecular heterogeneity in the infantile and juvenile forms of Sandhoff disease (O-variant GM2 gangliosidosis) 总被引:8,自引:0,他引:8
B F O'Dowd M H Klavins H F Willard R Gravel J A Lowden D J Mahuran 《The Journal of biological chemistry》1986,261(27):12680-12685
There are two major beta-hexosaminidase, EC 3.2.1.52, isozymes in normal human tissues. They exist as active dimers of alpha- and/or beta-subunits. A defect of their beta-subunit results in Sandhoff disease (O-variant GM2 gangliosidosis), an inherited, clinically heterogeneous, lysosomal storage disease. The status of the HEXB gene, pre beta-polypeptide chain mRNA, and residual beta-hexosaminidase activities were examined in a clinically and ethnically diverse collection of 16 fibroblast cell lines from patients with Sandhoff disease. Differentiation of the two major clinical types, infantile and juvenile onset, could be made by the determination of the activity of the residual beta-hexosaminidase eluting in the same pH range as hexosaminidase A. All the juvenile lines were found to have normal or reduced levels of pre beta-chain mRNA and no gross abnormalities in the HEXB gene. Of the 11 infantile type cell lines examined, four were found to contain no detectable pre beta-chain mRNA. Two cell lines in this group contained partial gene deletions localized to the 5' end of the HEXB gene. One of these cell lines has previously been assigned to the single complementation group in Sandhoff disease, conclusively demonstrating that the primary gene defect in the majority of Sandhoff cases is in the HEXB gene itself. These data suggest that each clinical group is made up of a collection of different HEXB mutations. 相似文献
73.
Marie Valerio-Lepiniec Magali Aumont-Nicaise Céline Roux Bertrand Raynal Marie-Ange Badet-Denisot 《Archives of biochemistry and biophysics》2010,498(2):95-12
Glucosamine-6-phosphate synthase (GlmS) is responsible for the first and rate-limiting step in the hexosamine biosynthetic pathway. It catalyzes the conversion of D-fructose-6P (F6P) into D-glucosamine-6P (GlcN6P) using L-glutamine (Gln) as nitrogen donor (synthase activity) according to an ordered bi-bi process where F6P binds first. In the absence of F6P, the enzyme exhibits a weak hydrolyzing activity of Gln into Glu and ammonia (glutaminase activity), whereas the presence of F6P strongly stimulates it (hemi-synthase activity). Until now, these different activities were indirectly measured using either coupled enzyme or colorimetric methods. In this work, we have developed a direct assay monitoring the heat released by the reaction. Isothermal titration calorimetry and differential scanning calorimetry were used to determine kinetic and thermodynamic parameters of GlmS. The direct determination at 37 °C of kinetic parameters and affinity constants for both F6P and Gln demonstrated that part of the ammonia produced by Gln hydrolysis in the presence of both substrates is not used for the formation of the GlcN6P. The full characterization of this phenomenon allowed to identify experimental conditions where this leak of ammonia is negligible. Enthalpy measurements at 25 °C in buffers of various heats of protonation demonstrated that no proton exchange with the medium occurred during the enzyme-catalyzed glutaminase or synthase reaction suggesting for the first time that both products are released as a globally neutral pair composed by the Glu carboxylic side chain and the GlcN6P amine function. Finally we showed that the oligomerization state of GlmS is concentration-dependent. 相似文献
74.
The alpha- and beta-subunits of beta-hexosaminidase (beta-N-acetylhexosaminidase, EC 3.2.1.52) are synthesized in the rough endoplasmic reticulum as prepropolypeptides. After the loss of the signal peptide and formation of enzymatically active dimers, the pro-isoenzymes are transported through the Golgi and into the lysosome for proteolytic and glycolytic processing to their stable mature forms. Maturation includes the hydrolysis, and previously presumed loss, of small N-terminal peptides from each propolypeptide. A recent report characterizing the processing of the beta-prepropolypeptide in beta-hexosaminidase from a human fibroblast cell line [(1989) J. Biol. Chem. 264, 3380-3384] reported that the small pro-beta peptide was retained through a disulfide bond in the mature subunit, and that it was glycosylated. We have confirmed this result in normal human tissue. However, we report a different N-terminal for the mature pro-beta peptide. Furthermore, we have found that the pro-alpha peptide is similarly retained in the mature alpha-subunit through its single cysteine residue and that each pro-peptide undergoes C-terminal processing. 相似文献
75.
Bernhard Eitzinger Nerea Abrego Dominique Gravel Tea Huotari Eero J Vesterinen Tomas Roslin 《Molecular ecology》2019,28(2):266-280
Analysing the structure and dynamics of biotic interaction networks and the processes shaping them is currently one of the key fields in ecology. In this paper, we develop a novel approach to gut content analysis, thereby deriving a new perspective on community interactions and their responses to environment. For this, we use an elevational gradient in the High Arctic, asking how the environment and species traits interact in shaping predator–prey interactions involving the wolf spider Pardosa glacialis. To characterize the community of potential prey available to this predator, we used pitfall trapping and vacuum sampling. To characterize the prey actually consumed, we applied molecular gut content analysis. Using joint species distribution models, we found elevation and vegetation mass to explain the most variance in the composition of the prey community locally available. However, such environmental variables had only a small effect on the prey community found in the spider's gut. These observations indicate that Pardosa exerts selective feeding on particular taxa irrespective of environmental constraints. By directly modelling the probability of predation based on gut content data, we found that neither trait matching in terms of predator and prey body size nor phylogenetic or environmental constraints modified interaction probability. Our results indicate that taxonomic identity may be more important for predator–prey interactions than environmental constraints or prey traits. The impact of environmental change on predator–prey interactions thus appears to be indirect and mediated by its imprint on the community of available prey. 相似文献
76.
Feng P Liang C Shin YC Xiaofei E Zhang W Gravel R Wu TT Sun R Usherwood E Jung JU 《PLoS pathogens》2007,3(12):e174
Upon viral infection, cells undergo apoptosis as a defense against viral replication. Viruses, in turn, have evolved elaborate mechanisms to subvert apoptotic processes. Here, we report that a novel viral mitochondrial anti-apoptotic protein (vMAP) of murine gamma-herpesvirus 68 (gammaHV-68) interacts with Bcl-2 and voltage-dependent anion channel 1 (VDAC1) in a genetically separable manner. The N-terminal region of vMAP interacted with Bcl-2, and this interaction markedly increased not only Bcl-2 recruitment to mitochondria but also its avidity for BH3-only pro-apoptotic proteins, thereby suppressing Bax mitochondrial translocation and activation. In addition, the central and C-terminal hydrophobic regions of vMAP interacted with VDAC1. Consequently, these interactions resulted in the effective inhibition of cytochrome c release, leading to the comprehensive inhibition of mitochondrion-mediated apoptosis. Finally, vMAP gene was required for efficient gammaHV-68 lytic replication in normal cells, but not in mitochondrial apoptosis-deficient cells. These results demonstrate that gammaHV-68 vMAP independently targets two important regulators of mitochondrial apoptosis-mediated intracellular innate immunity, allowing efficient viral lytic replication. 相似文献
77.
78.
Isolation of mouse mammary epithelial progenitor cells with basal characteristics from the Comma-Dbeta cell line 总被引:2,自引:0,他引:2
Deugnier MA Faraldo MM Teulière J Thiery JP Medina D Glukhova MA 《Developmental biology》2006,293(2):414-425
A mouse mammary epithelial cell line with morphogenetic properties in vivo, Comma-Dbeta, was used to isolate and to characterize mammary progenitor cells. We found that a homogeneous cell population expressing high surface levels of stem cell antigen 1 (Sca-1) was able to give rise in vivo to ductal and alveolar structures comprising luminal secretory and basal myoepithelial cells. Unlike the Sca-1(high), the Sca-1(neg/low) cell population displayed a reduced morphogenetic potential. The Sca-1(high) cells presented moderate CD24, high CD44 and alpha6 integrin surface levels, expressed basal cell markers p63, keratins 5 and 14, but no luminal and myoepithelial lineage markers. In culture, the Sca-1(high) cells generated identical daughter cells that retained their in vivo developmental potential, indicating that these cells were maintained by self-renewal. Plated at clonogenic density in Matrigel, Sca-1(high) cells formed spheroids that included luminal and myoepithelial cells. Thus, the isolated Sca-1(high) basal cells possess several features of stem/progenitor cells, including specific markers, self-renewal capacity, and the ability to generate the two major mammary lineages, luminal and myoepithelial. These data provide evidence for the existence of basal-type mouse mammary progenitors able to participate in the morphogenetic processes characteristic of mammary gland development. 相似文献
79.
Natural cell death is critical for normal development of the nervous system, but the extracellular regulators of developmental cell death remain poorly characterized. Here, we studied the role of the CNTF/LIF signaling pathway during mouse retinal development in vivo. We show that exposure to CNTF during neonatal retinal development in vivo retards rhodopsin expression and results in an important and specific deficit in photoreceptor cells. Detailed analysis revealed that exposure to CNTF during retinal development causes a sharp increase in cell death of postmitotic rod precursor cells. Importantly, we show that blocking the CNTF/LIF signaling pathway during mouse retinal development in vivo results in a significant reduction of naturally occurring cell death. Using retroviral lineage analysis, we demonstrate that exposure to CNTF causes a specific reduction of clones containing only rods without affecting other clone types, whereas blocking the CNTF/LIF receptor complex causes a specific increase of clones containing only rods. In addition, we show that stimulation of the CNTF/LIF pathway positively regulates the expression of the neuronal and endothelial nitric oxide synthase (NOS) genes, and blocking nitric oxide production by pre-treatment with a NOS inhibitor abolishes CNTF-induced cell death. Taken together, these results indicate that the CNTF/LIF signaling pathway acts via regulation of nitric oxide production to modulate developmental programmed cell death of postmitotic rod precursor cells. 相似文献
80.
Floquet N Marechal JD Badet-Denisot MA Robert CH Dauchez M Perahia D 《FEBS letters》2006,580(22):5130-5136
We demonstrate the utility of normal mode analysis in correctly predicting the binding modes of inhibitors in the active sites of matrix metalloproteinases (MMPs). We show the accuracy in predicting the positions of MMP-3 inhibitors is strongly dependent on which structure is used as the target, especially when it has been energy minimized. This dependency can be overcome by using intermediate structures generated along one of the normal modes previously calculated for a given target. These results may be of prime importance for further in silico drug discovery. 相似文献