全文获取类型
收费全文 | 331篇 |
免费 | 51篇 |
专业分类
382篇 |
出版年
2022年 | 2篇 |
2020年 | 5篇 |
2019年 | 5篇 |
2018年 | 9篇 |
2017年 | 10篇 |
2016年 | 4篇 |
2015年 | 8篇 |
2014年 | 11篇 |
2013年 | 21篇 |
2012年 | 19篇 |
2011年 | 7篇 |
2010年 | 15篇 |
2009年 | 14篇 |
2008年 | 14篇 |
2007年 | 20篇 |
2006年 | 22篇 |
2005年 | 18篇 |
2004年 | 12篇 |
2003年 | 11篇 |
2002年 | 11篇 |
2001年 | 16篇 |
2000年 | 15篇 |
1999年 | 4篇 |
1998年 | 3篇 |
1997年 | 2篇 |
1995年 | 3篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 10篇 |
1991年 | 5篇 |
1990年 | 8篇 |
1989年 | 7篇 |
1988年 | 9篇 |
1987年 | 4篇 |
1986年 | 3篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1979年 | 6篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1976年 | 3篇 |
1973年 | 3篇 |
1971年 | 3篇 |
1970年 | 3篇 |
1959年 | 2篇 |
1951年 | 1篇 |
1938年 | 2篇 |
1914年 | 1篇 |
排序方式: 共有382条查询结果,搜索用时 15 毫秒
41.
L J Wardzala I A Simpson M M Rechler S W Cushman 《The Journal of biological chemistry》1984,259(13):8378-8383
Previous studies have proposed that insulin increases the binding of insulin-like growth factor II (IGF-II) in isolated rat adipose cells at 24 degrees C by increasing receptor affinity (Ka). This study re-examines these observations under conditions in which receptor-ligand internalization is blocked by 1 mM KCN. In the absence of KCN, adipose cells bind 0.71 amol of IGF-II/cell with low apparent affinity (0.030 nM-1), of which greater than 75% is not accessible to trypsin. In contrast, in the presence of KCN, IGF-II binding is decreased by 95% and its apparent affinity increased to 0.21 nM-1. Moreover, greater than 60% of the bound IGF-II now is sensitive to trypsin. In either the absence or presence of KCN, approximately 20% of the cell's total IGF-II receptors are present in the plasma membranes and approximately 80% in the low density microsomes. Insulin induces a 5-fold increase in cell surface IGF-II receptors without a change in affinity when IGF-II binding is measured in the presence of KCN. Similarly, insulin increases IGF-II receptor concentration in the plasma membranes and concomitantly decreases that in the low density microsomes. Receptor affinity in these two subcellular membrane fractions is not affected by incubation of intact cells with either insulin or KCN and is similar to that observed in intact cells in the presence of KCN. Addition of KCN prior to insulin abolishes all of these effects of insulin. These data suggest that (a) the effects of KCN reflect a selective blockade of endocytosis; (b) in the absence of KCN, IGF-II binds to receptors of constant affinity that cycle between the plasma membrane and an intracellular pool resulting in an accumulation of intracellular IGF-II; (c) insulin induces an increase in IGF-II binding by causing a steady state redistribution of receptors from this intracellular pool to the plasma membrane; and (d) this redistribution in the intact cell can only be detected using Scatchard analysis when recycling of the receptors is prevented by KCN. 相似文献
42.
M Cushman P Chinnasamy A K Chakraborti J Jurayj R L Geahlen R D Haugwitz 《International journal of peptide and protein research》1990,36(6):538-543
An asymmetric synthesis of [beta-(4-pyridyl-1-oxide)-L-alanine4]-angiotensin I (1a), which is a potential suicide substrate (mechanism-based inhibitor) for protein-tyrosine kinases, has been performed. Deprotonation of 6 with n-butyllithium in THF gave the anion 7, which was alkylated with 4-(chloromethyl)pyridine-1-oxide to afford intermediate 9 as a crystalline solid. Hydrolysis of 9 afforded a mixture of 11 and 12 in a ratio of 96:4 as estimated by conversion to the diastereomeric dipeptides 13 and 14 followed by HPLC analysis. The 96:4 mixture of 11 and 12 was used in the solid phase synthesis of the target angiotensin analog 1a and its diastereomer 1b, which were separated and tested for inhibitory activity against two thymocyte protein-tyrosine kinases: p40 and p56lck. Neither peptide displayed significant inhibitory activity toward p40 and both served as weak competitive inhibitors of p56lck. 相似文献
43.
Influence of herbivores on a perennial plant: variation with life history stage and herbivore species 总被引:1,自引:0,他引:1
Herbivores have diverse impacts on their host plants, potentially altering survival, growth, fecundity, and other aspects of plant performance. Especially for longer-lived plant species, the effects of a single herbivore species can vary markedly throughout the life of the host plant. In addition, the effects of herbivory during any given life history stage of a host plant may also vary considerably with different types of herbivores. To investigate the effects of herbivory by black-tailed deer (Odocoileus hemionus columbianus) and snails (Helminthoglypta arrosa and Helix aspersa) on a nitrogen-fixing shrub, Lupinus chamissonis, we established three exclosure experiments in a sand dune system on the coast of northern California. These experiments documented that deer browsing significantly reduced the volume and growth rate of lupines in the seedling and juvenile life stages. Since plant volume was strongly correlated with aboveground dry biomass for lupines, such herbivore-induced reductions in volume should translate into losses of aboveground biomass. Deer browsing also significantly altered the likelihood of attack by and density of a leaf-galling cecidomyid fly (Dasineura lupinorum), suggesting that a vertebrate herbivore indirectly affected an invertebrate herbivore in this system. Although deer did not significantly affect the survival of lupine seedlings and juveniles, individuals protected from deer had consistently greater survival in the two separate experiments. Our results revealed that snails did not have a significant effect on the survival or growth of juvenile plants, despite being common on and around lupines. An exclosure experiment revealed that herbivory by deer significantly reduced the shoot lengths of mature shrubs, but led only to a minimal reduction in growth rates. In addition, we found that browsed shrubs had significantly greater inflorescence production, but also produced individual seeds with significantly reduced mass. Collectively, these data indicate that deer and snails have widely differing effects on their shared host plant; browsing by deer indirectly affects insect herbivores, and the impacts of deer change markedly with the life history stage of their host plant. 相似文献
44.
Are all data types and connectivity models created equal? Validating common connectivity approaches with dispersal data 下载免费PDF全文
Katherine A. Zeller Megan K. Jennings T. Winston Vickers Holly B. Ernest Samuel A. Cushman Walter M. Boyce 《Diversity & distributions》2018,24(7):868-879
Aim
There is enormous interest in applying connectivity modelling to resistance surfaces for identifying corridors for conservation action. However, the multiple analytical approaches used to estimate resistance surfaces and predict connectivity across resistance surfaces have not been rigorously compared, and it is unclear what methods provide the best inferences about population connectivity. Using a large empirical data set on puma (Puma concolor), we are the first to compare several of the most common approaches for estimating resistance and modelling connectivity and validate them with dispersal data.Location
Southern California, USA.Methods
We estimate resistance using presence‐only data, GPS telemetry data from puma home ranges and genetic data using a variety of analytical methods. We model connectivity with cost distance and circuit theory algorithms. We then measure the ability of each data type and connectivity algorithm to capture GPS telemetry points of dispersing pumas.Results
We found that resource selection functions based on GPS telemetry points and paths outperformed species distribution models when applied using cost distance connectivity algorithms. Point and path selection functions were not statistically different in their performance, but point selection functions were more sensitive to the transformation used to convert relative probability of use to resistance. Point and path selection functions and landscape genetics outperformed other methods when applied with cost distance; no methods outperformed one another with circuit theory.Main conclusions
We conclude that path or point selection functions, or landscape genetic models, should be used to estimate landscape resistance for wildlife. In cases where resource limitations prohibit the collection of GPS collar or genetic data, our results suggest that species distribution models, while weaker, may still be sufficient for resistance estimation. We recommend the use of cost distance‐based approaches, such as least‐cost corridors and resistant kernels, for estimating connectivity and identifying functional corridors for terrestrial wildlife.45.
S Eberhardt N Zingler K Kemter G Richter M Cushman A Bacher 《European journal of biochemistry》2001,268(15):4315-4323
Riboflavin synthase of Escherichia coli is a homotrimer of 23.4 kDa subunits catalyzing the formation of the carbocyclic ring of the vitamin, riboflavin, by dismutation of 6,7-dimethyl-8-ribityllumazine. Intramolecular sequence similarity suggested that each subunit folds into two topologically similar domains. In order to test this hypothesis, sequence segments comprising amino-acid residues 1-97 or 101-213 were expressed in recombinant E. coli strains. The recombinant N-terminal domain forms a homodimer that can bind riboflavin, 6,7-dimethyl-8-ribityllumazine and trifluoromethyl-substituted 8-ribityllumazine derivatives as shown by absorbance, circular dichroism, and NMR spectroscopy. Most notably, the recombinant domain dimer displays the same diastereoselectivity for ligands as the full length protein. The minimum N-terminal peptide segment required for ligand binding comprises amino-acid residues 1-87. The recombinant C-terminal domain comprising amino-acid residues 101-213 is relatively unstable and was shown not to bind riboflavin but to differentiate between certain diastereomeric trifluoromethyl-8-ribityllumazine derivatives. The data show that a single domain comprises the intact binding site for one substrate molecule. The enzyme-catalyzed dismutation requires two substrate molecules to be bound in close proximity, and each active site of the enzyme appears to be located at the interface of an N-terminal and C-terminal domain. 相似文献
46.
STRUCTURE-FUNCTION RELATIONSHIPS IN THE ADIPOSE CELL : III. Effects of Bovine Serum Albumin on the Metabolism of Glucose and the Release of Nonesterified Fatty Acids and Glycerol by the Isolated Adipose Cell 下载免费PDF全文
Serum albumin stimulates the uptake of U-glucose-14C and the incorporation of 14C-counts into triglyceride glycerol and inhibits the incorporation of 14C-counts into triglyceride fatty acids by isolated adipose cells; insulin and epinephrine enhance these effects. In the absence of hormones, these responses to albumin increase with increasing albumin concentration. In the presence of insulin, a qualitatively similar pattern of increasing responses to albumin is observed; the enhancement of each response by insulin is, however, only slightly potentiated by higher albumin concentrations. In contrast, in the presence of epinephrine, these responses to albumin are maximal at the lowest albumin concentration tested, 0.1%; the enhancement of each response by epinephrine is similarly maximal at 0.1% albumin, but decreases rapidly as the albumin concentration is raised. Increasing serum albumin concentrations do, however, stimulate the release of fatty acids and glycerol by epinephrine-treated cells increasingly until a plateau, determined by the epinephrine dose, is reached. These data support the suggestion that intracellular fatty acid levels function in the regulation of adipose cell activity, and further suggest that serum albumin plays a role in determining the metabolic fate of these fatty acids. 相似文献
47.
48.
49.
Design of angiotensin converting enzyme inhibitors. 总被引:6,自引:0,他引:6
50.
Ramsperger A Augustin M Schott AK Gerhardt S Krojer T Eisenreich W Illarionov B Cushman M Bacher A Huber R Fischer M 《The Journal of biological chemistry》2006,281(2):1224-1232
Whereas eubacterial and eukaryotic riboflavin synthases form homotrimers, archaeal riboflavin synthases from Methanocaldococcus jannaschii and Methanothermobacter thermoautrophicus are homopentamers with sequence similarity to the 6,7-dimethyl-8-ribityllumazine synthase catalyzing the penultimate step in riboflavin biosynthesis. Recently it could be shown that the complex dismutation reaction catalyzed by the pentameric M. jannaschii riboflavin synthase generates riboflavin with the same regiochemistry as observed for trimeric riboflavin synthases. Here we present crystal structures of the pentameric riboflavin synthase from M. jannaschii and its complex with the substrate analog inhibitor, 6,7-dioxo-8-ribityllumazine. The complex structure shows five active sites located between adjacent monomers of the pentamer. Each active site can accommodate two substrate analog molecules in anti-parallel orientation. The topology of the two bound ligands at the active site is well in line with the known stereochemistry of a pentacyclic adduct of 6,7-dimethyl-8-ribityllumazine that has been shown to serve as a kinetically competent intermediate. The pentacyclic intermediates of trimeric and pentameric riboflavin synthases are diastereomers. 相似文献