全文获取类型
收费全文 | 645篇 |
免费 | 29篇 |
国内免费 | 14篇 |
专业分类
688篇 |
出版年
2023年 | 7篇 |
2022年 | 2篇 |
2021年 | 16篇 |
2020年 | 11篇 |
2019年 | 5篇 |
2018年 | 9篇 |
2017年 | 13篇 |
2016年 | 5篇 |
2015年 | 12篇 |
2014年 | 33篇 |
2013年 | 36篇 |
2012年 | 27篇 |
2011年 | 37篇 |
2010年 | 40篇 |
2009年 | 26篇 |
2008年 | 36篇 |
2007年 | 36篇 |
2006年 | 36篇 |
2005年 | 35篇 |
2004年 | 38篇 |
2003年 | 28篇 |
2002年 | 19篇 |
2001年 | 7篇 |
2000年 | 14篇 |
1999年 | 10篇 |
1998年 | 7篇 |
1997年 | 4篇 |
1996年 | 8篇 |
1995年 | 9篇 |
1994年 | 11篇 |
1993年 | 11篇 |
1992年 | 9篇 |
1991年 | 7篇 |
1990年 | 8篇 |
1989年 | 6篇 |
1988年 | 8篇 |
1987年 | 8篇 |
1986年 | 9篇 |
1985年 | 7篇 |
1984年 | 12篇 |
1983年 | 7篇 |
1982年 | 8篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 3篇 |
1973年 | 1篇 |
排序方式: 共有688条查询结果,搜索用时 15 毫秒
291.
Rees-Milton KJ Terry D Anastassiades TP 《Biochemical and biophysical research communications》2004,317(3):844-850
The addition of TGF-beta1 to bovine articular chondrocytes resulted in increased synthesis and secretion of two anionic glycoproteins, including a previously studied but unidentified high molecular weight anionic glycoconjugate (HMW-AG). Sequencing by mass spectroscopy identified these anionic glycoproteins as fibronectin. Western blot analysis confirmed the identity of these two overexpressed glycoproteins as fibronectin. In the presence and absence of TGF-beta1 both V(+) and V(-) isoforms of fibronectin, which are EDA(-) and EDB(-), are synthesized. Dual labeling experiments suggest that the HMW-AG, the larger of the two overexpressed glycoproteins (apparent molecular weight of monomer approximately 260,000 Da), is more heavily glycosylated than the lower molecular weight anionic glycoprotein. Since fibronectin proteolytic fragments appear to enhance matrix metalloproteinase synthesis, TGF-beta1-mediated hyperglycosylation of fibronectin could regulate cartilage metabolism by providing protection of fibronectin from proteolysis, a mechanism that would also favor articular cartilage health. 相似文献
292.
DuBay KF Pawar AP Chiti F Zurdo J Dobson CM Vendruscolo M 《Journal of molecular biology》2004,341(5):1317-1326
Protein aggregation is associated with a variety of pathological conditions, including Alzheimer's and Creutzfeldt-Jakob diseases and type II diabetes. Such degenerative disorders result from the conversion of the normal soluble state of specific proteins into aggregated states that can ultimately form the characteristic amyloid fibrils found in diseased tissue. Under appropriate conditions it appears that many, perhaps all, proteins can be converted in vitro into amyloid fibrils. The aggregation propensities of different polypeptide chains have, however, been observed to vary substantially. Here, we describe an approach that uses the knowledge of the amino acid sequence and of the experimental conditions to reproduce, with a correlation coefficient of 0.92 and over five orders of magnitude, the in vitro aggregation rates of a wide range of unstructured peptides and proteins. These results indicate that the formation of protein aggregates can be rationalised to a considerable extent in terms of simple physico-chemical parameters that describe the properties of polypeptide chains and their environment. 相似文献
293.
Abnormal aspartyl residue formation such as L-isoaspartates occurs frequently during aging in long-lived proteins, resulting in the alteration of their structures and biological functions. In this study, we investigated the alteration of aspartyl residues in extracellular matrix (ECM) proteins, type-I collagen and fibronectin, and in integrin- and ECM-binding motifs during aging, as well as the resulting effects on cell biological functions such as migration and attachment. Using protein L-isoaspartyl methyltransferase (PIMT) to monitor the presence of L-isoaspartyl residues, we showed their accumulation during in vivo aging in type-I collagen from rats. In vitro aging of fibronectin as well as of peptides containing an integrin- or ECM-binding motif such as RGDSR, KDGEA and KDDL also resulted in the formation of L-isoaspartyl residues. While aged fibronectin does not alter cell adhesion and migration, type-I collagen aged 20 months reduced by 65% cell motility, but not adhesion, when compared to 3-month-aged type-I collagen. Finally, by repairing 20-month-old type-I collagen with recombinant PIMT (rPIMT), cell migration was recovered by 72%. These results strongly suggest that L-isoaspartyl residue formation in ECM proteins such as type-I collagen could play an important role in reducing cell migration and that PIMT could be a therapeutic tool to restore normal cell migration in pathological conditions where cell motility is crucial. 相似文献
294.
Structural changes in human type I collagen fibrils investigated by force spectroscopy 总被引:1,自引:0,他引:1
In the field of biomechanics, collagen fibrils are believed to be robust mechanical structures characterized by a low extensibility. Until very recently, information on the mechanical properties of collagen fibrils could only be derived from ensemble measurements performed on complete tissues such as bone, skin, and tendon. Here, we measure force-elongation/relaxation profiles of single collagen fibrils using atomic force microscopy (AFM)-based force spectroscopy (FS). The elongation profiles show that in vitro-assembled human type I collagen fibrils are characterized by a large extensibility. Numerous discontinuities and a plateau in the force profile indicate major reorganization occurring within the fibrils in the 1.5- to 4.5-nN range. Our study demonstrates that newly assembled collagen fibrils are robust structures with a significant reserve of elasticity that could play a determinant role in the extracellular matrix (ECM) remodeling associated with tissue growth and morphogenesis. 相似文献
295.
Longo D Peirce SM Skalak TC Davidson L Marsden M Dzamba B DeSimone DW 《Developmental biology》2004,271(1):210-222
In the blastocoel roof (BCR) of the Xenopus laevis embryo, epibolic movements are driven by the radial intercalation of deep cell layers and the coordinate spreading of the overlying superficial cell layer. Thinning of the lateral margins of the BCR by radial intercalation requires fibronectin (FN), which is produced and assembled into fibrils by the inner deep cell layer of the BCR. A cellular automata (CA) computer model was developed to analyze the spatial and temporal movements of BCR cells during epiboly. Simulation parameters were defined based on published data and independent results detailing initial tissue geometry, cell numbers, cell intercalation rates, and migration rates. Hypotheses regarding differential cell adhesion and FN assembly were also considered in setting system parameters. A 2-dimensional model simulation was developed that predicts BCR thinning time of 4.8 h, which closely approximates the time required for the completion of gastrulation in vivo. Additionally, the model predicts a temporal increase in FN matrix assembly that parallels fibrillogenesis in the embryo. The model is capable of independent predictions of cell rearrangements during epiboly, and here was used to predict successfully the lateral dispersion of a patch of cells implanted in the BCR, and increased assembly of FN matrix following inhibition of radial intercalation by N-cadherin over-expression. 相似文献
296.
Ito H Rucker E Steplewski A McAdams E Brittingham RJ Alabyeva T Fertala A 《Journal of molecular biology》2005,352(2):382-395
Among the structural components of extracellular matrices (ECM) fibrillar collagens play a critical role, and single amino acid substitutions in these proteins lead to pathological changes in tissues in which they are expressed. Employing a biologically relevant experimental model consisting of cells expressing R75C, R519C, R789C, and G853E procollagen II mutants, we found that the R789C mutation causing a decrease in the thermostability of collagen not only alters individual collagen molecules and collagen fibrils, but also has a negative impact on fibronectin. We propose that thermolabile collagen molecules are able to bind to fibronectin, thereby altering intracellular and extracellular processes in which fibronectin takes part, and we postulate that such an atypical interaction could change the architecture of the ECM of affected tissues in patients harboring mutations in genes encoding fibrillar collagens. 相似文献
297.
Polymerization of the soluble beta-amyloid peptide into highly ordered fibrils is hypothesized to be a causative event in the development of Alzheimer's disease. Understanding the interactions of Abeta with inhibitors on an atomic level is fundamental for the development of diagnostics and therapeutic approaches, and can provide, in addition, important indirect information of the amyloid fibril structure. We have shown recently that trRDCs can be measured in solution state NMR for peptide ligands binding weakly to amyloid fibrils. We present here the structures for two inhibitor peptides, LPFFD and DPFFL, and their structural models bound to fibrillar Abeta(14-23) and Abeta(1-40) based on transferred nuclear Overhauser effect (trNOE) and transferred residual dipolar coupling (trRDC) data. In a first step, the inhibitor peptide structure is calculated on the basis of trNOE data; the trRDC data are then validated on the basis of the trNOE-derived structure using the program PALES. The orientation of the peptide inhibitors with respect to Abeta fibrils is obtained from trRDC data, assuming that Abeta fibrils orient such that the fibril axis is aligned in parallel with the magnetic field. The trRDC-derived alignment tensor of the peptide ligand is then used as a restraint for molecular dynamics docking studies. We find that the structure with the lowest rmsd value is in agreement with a model in which the inhibitor peptide binds to the long side of an amyloid fibril. Especially, we detect interactions involving the hydrophobic core, residues K16 and E22/D23 of the Abeta sequence. Structural differences are observed for binding of the inhibitor peptide to Abeta14-23 and Abeta1-40 fibrils, respectively, indicating different fibril structure. We expect this approach to be useful in the rational design of amyloid ligands with improved binding characteristics. 相似文献
298.
Galea C Bowman P Kriwacki RW 《Protein science : a publication of the Protein Society》2005,14(12):2993-3003
We describe in molecular detail how disruption of an intermonomer salt bridge (Arg337-Asp352) leads to partial destabilization of the p53 tetramerization domain and a dramatically increased propensity to form amyloid fibrils. At pH 4.0 and 37 degrees C, a p53 tetramerization domain mutant (p53tet-R337H), associated with adrenocortical carcinoma in children, readily formed amyloid fibrils, while the wild-type (p53tet-wt) did not. We characterized these proteins by equilibrium denaturation, 13C(alpha) secondary chemical shifts, (1H)-15N heteronuclear NOEs, and H/D exchange. Although p53tet-R337H was thermodynamically less stable, NMR data indicated that the two proteins had similar secondary structure and molecular dynamics. NMR derived pK(a) values indicated that at low pH the R337H mutation partially disrupted an intermonomer salt bridge. Backbone H/D exchange results showed that for at least a small population of p53tet-R337H molecules disruption of this salt bridge resulted in partial destabilization of the protein. It is proposed that this decrease in p53tet-R337H stability resulted in an increased propensity to form amyloid fibrils. 相似文献
299.
人血浆纤连蛋白(Fibronectin,Fn)与人胎盘纤连蛋白两者在肽链结构上基本相同,但人血浆Fn的N-糖链结构为二天线结构,而人胎盘Fn不仅N-糖链的数量增加,同时还含有多天线结构,分别用~(125)I标记这两种具有不同糖链结构的Fn,观察两者与HT1080细胞的饱和结合的亲和性,结果发现,在4℃,人血浆Fn与HT1080细胞的饱和结合为129ng/10~5细胞,解离常数为2.83×10~(-8)mol/L,人胎盘Fn与HT1080细胞的饱和结合为133ng/10~6细胞,解离常数为2.64×10~(-8)mol/L.因而,人血浆Fn与人胎盘Fn上N-糖链的不同并未影响其与受体的结合. 相似文献
300.
Desmond G. Higgins Siegfried Labeit Mathias Gautel Toby J. Gibson 《Journal of molecular evolution》1994,38(4):395-404
Titin and twitchin are giant proteins expressed in muscle. They are mainly composed of domains belonging to the fibronectin class III and immunoglobulin c2 families, repeated many times. In addition, both proteins have a protein kinase domain near the C-terminus. This paper explores the evolution of these and related muscle proteins in an attempt to determine the order of events that gave rise to the different repeat patterns and the order of appearance of the proteins. Despite their great similarity at the level of sequence organization, titin and twitchin diverged from each other at least as early as the divergence between vertebrates and nematodes. Most of the repeating units in titin and twitchin were estimated to derive from three original domains. Chicken smooth-muscle myosin light-chain kinase (smMLCK) also has a kinase domain, several immunoglobulin domains, and a fibronectin domain. From a comparison of the kinase domains, titin is predicted to have appeared first during the evolution of the family, followed by twitchin and with the vertebrate MLCKs last to appear. The so-called C-protein from chicken is also a member of this family but has no kinase domain. Its origin remains unclear but it most probably pre-dates the titin/twitchin duplication.
Correspondence to: D.G. Higgins 相似文献