全文获取类型
收费全文 | 399篇 |
免费 | 50篇 |
出版年
2021年 | 3篇 |
2020年 | 3篇 |
2019年 | 4篇 |
2018年 | 6篇 |
2017年 | 11篇 |
2016年 | 5篇 |
2015年 | 14篇 |
2014年 | 11篇 |
2013年 | 13篇 |
2012年 | 16篇 |
2011年 | 12篇 |
2010年 | 18篇 |
2009年 | 13篇 |
2008年 | 19篇 |
2007年 | 23篇 |
2006年 | 27篇 |
2005年 | 20篇 |
2004年 | 26篇 |
2003年 | 20篇 |
2002年 | 25篇 |
2001年 | 18篇 |
2000年 | 8篇 |
1999年 | 5篇 |
1998年 | 4篇 |
1997年 | 7篇 |
1996年 | 3篇 |
1995年 | 6篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 8篇 |
1991年 | 9篇 |
1990年 | 7篇 |
1989年 | 3篇 |
1988年 | 8篇 |
1987年 | 9篇 |
1986年 | 5篇 |
1985年 | 2篇 |
1984年 | 12篇 |
1983年 | 6篇 |
1982年 | 8篇 |
1981年 | 2篇 |
1980年 | 5篇 |
1979年 | 2篇 |
1976年 | 2篇 |
1970年 | 2篇 |
1968年 | 4篇 |
1956年 | 1篇 |
1954年 | 1篇 |
1946年 | 1篇 |
1940年 | 1篇 |
排序方式: 共有449条查询结果,搜索用时 15 毫秒
31.
Mathematical methods are used for explaining the structural design of signal transduction networks, e.g. MAP kinase cascades, which control cell proliferation, differentation or apoptosis. Taking into account protein kinases and phosphatases the interrelation between the topology of signaling networks and the stability of their ground state are analysed. It is shown that the stability is closely related to the system's dimension and to the number of cycles within the network. Systems with a higher number of kinases and/or cycles tend to be more unstable. In contrast to that increasing phosphatase activity stabilises the ground state. 相似文献
32.
The biophysical properties of a tryptophan-shifted mutant of phosphofructokinase from Bacillus stearothermophilus (BsPFK) have been examined. The mutant, designated W179Y/Y164W, has kinetic and thermodynamic properties similar to the wild-type enzyme. A 2-fold decrease in kcat is observed, and the mutant displays a 3-fold smaller K(0.5) for the substrate, fructose-6-phosphate (Fru-6-P), as compared to the wild-type enzyme. The dissociation constant for the inhibitor, phospho(enol)pyruvate (PEP), increases 2-fold, and the coupling parameter, Q(ay), decreases 2-fold. This suggests that while the mutant displays a slightly decreased affinity for PEP, PEP is still an effective inhibitor once bound. The new position of the tryptophan in W179Y/Y164W is approximately 6 A from the Fru-6-P portion of the active site. A 25% decrease in fluorescence intensity is observed upon Fru-6-P binding, and an 80% decrease in fluorescence intensity is observed with PEP binding. In addition, the intrinsic fluorescence polarization increases from 0.327 +/- 0.001 to 0.353 +/- 0.001 upon Fru-6-P binding, but decreases to 0.290 +/- 0.001 when PEP binds. Most notably, the presence of PEP induces dissociation of the tetramer. Dissociation of the tetramer into dimers occurs along the active site interface and can be monitored by the loss in activity or the loss in tryptophan fluorescence that is observed when the enzyme is titrated with PEP. Activity can be protected or recovered by incubating the enzyme with Fru-6-P. Recovery of activity is enzyme concentration dependent, and the rate constant for association is 6.2 +/- 0.3 M(-1) x s(-1). Ultracentrifugation experiments revealed that in the absence of PEP the mutant enzyme exists in an equilibrium between the dimer and tetramer forms with a dissociation constant of 11.8 +/- 0.5 microM, while in the presence of PEP the enzyme exists in equilibrium between the dimer and monomer forms with a dissociation constant of 7.5 +/- 0.02 microM. A 3.1 A crystal structure of the mutant enzyme suggests that the amino acid substitutions have not dramatically altered the tertiary structure of the enzyme. While it is clear that wild-type BsPFK exists as a tetramer under these same conditions, these results suggest that quaternary structural changes probably play an important role in allosteric communication. 相似文献
33.
Starting from a limited set of reactions describing changes in the carbon skeleton of biochemical compounds complete sets
of metabolic networks are constructed. The networks are characterized by the number and types of participating reactions.
Elementary networks are defined by the condition that a specific chemical conversion can be performed by a set of given reactions
and that this ability will be lost by elimination of any of these reactions. Groups of networks are identified with respect
to their ability to perform a certain number of metabolic conversions in an elementary way which are called the network’s
functions. The number of the network functions defines the degree of multifunctionality. Transitions between networks and
mutations of networks are defined by exchanges of single reactions. Different mutations exist such as gain or loss of function
mutations and neutral mutations. Based on these mutations neighbourhood relations between networks are established which are
described in a graph theoretical way. Basic properties of these graphs are determined such as diameter, connectedness, distance
distribution of pairs of vertices. A concept is developed to quantify the robustness of networks against changes in their
stoichiometry where we distinguish between strong and weak robustness. Evolutionary algorithms are applied to study the development
of network populations under constant and time dependent environmental conditions. It is shown that the populations evolve
toward clusters of networks performing a common function and which are closely neighboured. Under changing environmental conditions
multifunctional networks prove to be optimal and will be selected. 相似文献
34.
Tucci FC Zhu YF Guo Z Gross TD Connors PJ Struthers RS Reinhart GJ Saunders J Chen C 《Bioorganic & medicinal chemistry letters》2003,13(19):3317-3322
A new class of small molecule GnRH antagonists, the 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils, was designed and a novel stereoselective synthesis for these compounds was developed. The stereochemical integrities of key intermediates (S)-6 and (R)-6 were confirmed by a combination of X-ray crystallography and chiral HPLC determinations. SAR studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (K(i)=20 nM). 相似文献
35.
36.
Malamas MS Robichaud A Erdei J Quagliato D Solvibile W Zhou P Morris K Turner J Wagner E Fan K Olland A Jacobsen S Reinhart P Riddell D Pangalos M 《Bioorganic & medicinal chemistry letters》2010,20(22):6597-6605
The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogs exhibit good brain permeability (40-70%), low nanomolar potency for BACE1, and demonstrate >100-fold selectivity for the structurally related aspartyl proteases cathepsin D, renin and pepsin. Alkyl and alkoxy groups at the meta-position of the P1 phenyl, which extend toward the S3 region of the enzyme, have contributed to the ligand's reduced affinity for the efflux transporter protein P-gp, and decreased topological polar surface area, thus resulting in enhanced brain permeability. A fluorine substitution at the para-position of the P1 phenyl has contributed to 100-fold decrease of CYP3A4 inhibition and enhancement of compound metabolic stability. The plasma and brain protein binding properties of these new analogs are affected by substitutions at the P1 phenyl moiety. Higher compound protein binding was observed in the brain than in the plasma. Two structurally diverse potent BACE1 inhibitors (84 and 89) reduced 30% plasma Aβ40 in the Tg2576 mice in vivo model at 30 mg/kg p.o.. 相似文献
37.
Pawel Nowak Derek C. Cole Ann Aulabaugh Jonathan Bard Rajiv Chopra Rebecca Cowling Kristi Y. Fan Baihua Hu Steve Jacobsen Minakshi Jani Guixan Jin Mei-Chu Lo Michael S. Malamas Eric S. Manas Rani Narasimhan Peter Reinhart Albert J. Robichaud Joseph R. Stock Joan Subrath Kristine Svenson John W. Ellingboe 《Bioorganic & medicinal chemistry letters》2010,20(2):632-635
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S1 to the S3 pocket. 相似文献
38.
Michael S. Malamas Keith Barnes Yu Hui Matthew Johnson Frank Lovering Jeff Condon William Fobare William Solvibile Jim Turner Yun Hu Eric S. Manas Kristi Fan Andrea Olland Rajiv Chopra Jonathan Bard Menelas N. Pangalos Peter Reinhart Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2010,20(7):2068-2073
The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer’s disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood–brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network. 相似文献
39.
The long-term response of leaf photosynthesis to rising CO2 concentrations [CO2] depends on biochemical and morphological feedbacks. Additionally, responses to elevated [CO2] might depend on the nutrient availability and the light environment, affecting the net carbon uptake of a forest stand. After 6 yr of exposure to free-air CO2 enrichment (EUROFACE) during two rotation cycles (with fertilization during the second cycle), profiles of light, leaf characteristics and photosynthetic parameters were measured in the closed canopy of a poplar (Populus) short-rotation coppice. Net photosynthetic rate (A(growth)) was 49% higher in poplars grown in elevated [CO2], independently of the canopy position. Jmax significantly increased (15%), whereas leaf carboxylation capacity (Vcmax), leaf nitrogen (N(a)) and chlorophyll (Chl(a)) were unaffected in elevated [CO2]. Leaf mass per unit area (LMA) increased in the upper canopy. Fertilization created more leaves in the top of the crown. These results suggest that the photosynthetic stimulation by elevated [CO2] in a closed-canopy poplar coppice might be sustained in the long term. The absence of any down-regulation, given a sufficient sink capacity and nutrient availability, provides more carbon for growth and storage in this bioenergy plantation. 相似文献
40.
Keskanokwong T Shandro HJ Johnson DE Kittanakom S Vilas GL Thorner P Reithmeier RA Akkarapatumwong V Yenchitsomanus PT Casey JR 《The Journal of biological chemistry》2007,282(32):23205-23218
Kidney anion exchanger 1 (kAE1) mediates chloride/bicarbonate exchange at the basolateral membrane of kidney alpha-intercalated cells, thereby facilitating bicarbonate reabsorption into the blood. Human kAE1 lacks the N-terminal 65 residues of the erythroid form (AE1, band 3), which are essential for binding of cytoskeletal and cytosolic proteins. Yeast two-hybrid screening identified integrin-linked kinase (ILK), a serine/threonine kinase, and an actin-binding protein as an interacting partner with the N-terminal domain of kAE1. Interaction between kAE1 and ILK was confirmed in co-expression experiments in HEK 293 cells and is mediated by a previously unidentified calponin homology domain in the kAE1 N-terminal region. The calponin homology domain of kAE1 binds the C-terminal catalytic domain of ILK to enhance association of kAE1 with the actin cytoskeleton. Overexpression of ILK increased kAE1 levels at the cell surface as shown by flow cytometry, cell surface biotinylation, and anion transport activity assays. Pulse-chase experiments revealed that ILK associates with kAE1 early in biosynthesis, likely in the endoplasmic reticulum. ILK co-localized with kAE1 at the basolateral membrane of polarized Madin-Darby canine kidney cells and in alpha-intercalated cells of human kidneys. Taken together these results suggest that ILK and kAE1 traffic together from the endoplasmic reticulum to the basolateral membrane. ILK may provide a linkage between kAE1 and the underlying actin cytoskeleton to stabilize kAE1 at the basolateral membrane, resulting in higher levels of cell surface expression. 相似文献