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101.
Stephen A. Thomson Pierette Banker D. Mark Bickett Joyce A. Boucheron H. Luke Carter Daphne C. Clancy Joel P. Cooper Scott H. Dickerson Dulce M. Garrido Robert T. Nolte Andrew J. Peat Lauren R. Sheckler Steven M. Sparks Francis X. Tavares Liping Wang Tony Y. Wang James E. Weiel 《Bioorganic & medicinal chemistry letters》2009,19(4):1177-1182
Key binding interactions of the anthranilimide based glycogen phosphorylase a (GPa) inhibitor 2 from X-ray crystallography studies are described. This series of compounds bind to the AMP site of GP. Using the binding information the core and the phenyl urea moieties were optimized. This work culminated in the identification of compounds with single nanomolar potency as well as in vivo efficacy in a diabetic model. 相似文献
102.
Bin Chen Xuefeng Ren Tracey Neville W. Gray Jerome David W. Hoyt Daniel Sparks Gang Ren Jianjun Wang 《Protein science : a publication of the Protein Society》2009,18(5):921-935
Human high‐density lipoprotein (HDL) plays a key role in the reverse cholesterol transport pathway that delivers excess cholesterol back to the liver for clearance. In vivo, HDL particles vary in size, shape and biological function. The discoidal HDL is a 140–240 kDa, disk‐shaped intermediate of mature HDL. During mature spherical HDL formation, discoidal HDLs play a key role in loading cholesterol ester onto the HDL particles by activating the enzyme, lecithin:cholesterol acyltransferase (LCAT). One of the major problems for high‐resolution structural studies of discoidal HDL is the difficulty in obtaining pure and, foremost, homogenous sample. We demonstrate here that the commonly used cholate dialysis method for discoidal HDL preparation usually contains 5–10% lipid‐poor apoAI that significantly interferes with the high‐resolution structural analysis of discoidal HDL using biophysical methods. Using an ultracentrifugation method, we quickly removed lipid‐poor apoAI. We also purified discoidal reconstituted HDL (rHDL) into two pure discoidal HDL species of different sizes that are amendable for high‐resolution structural studies. A small rHDL has a diameter of 7.6 nm, and a large rHDL has a diameter of 9.8 nm. We show that these two different sizes of discoidal HDL particles display different stability and phospholipid‐binding activity. Interestingly, these property/functional differences are independent from the apoAI α‐helical secondary structure, but are determined by the tertiary structural difference of apoAI on different discoidal rHDL particles, as evidenced by two‐dimensional NMR and negative stain electron microscopy data. Our result further provides the first high‐resolution NMR data, demonstrating a promise of structural determination of discoidal HDL at atomic resolution using a combination of NMR and other biophysical techniques. 相似文献
103.
Paul Lewer Donald R. Hahn Laura L. Karr Dennis O. Duebelbeis Jeffrey R. Gilbert Gary D. Crouse Thomas Worden Thomas C. Sparks Pat McKamey Rex Edwards Paul R. Graupner 《Bioorganic & medicinal chemistry》2009,17(12):4185-4196
A new bacterium, Saccharopolyspora pogona (NRRL30141) was discovered which produced a series of very potent insecticidal compounds structurally related to the ‘classical’ (i.e., C-21-ethyl) spinosyns. A series of fermentations gave sufficient extract to allow the isolation and characterization of a total of 31 new metabolites. The majority of these compounds contained a but-1-enyl group at C-21 of the macrolide in place of the ethyl group in the ‘classical’ spinosyn series, corresponding to an additional acetate group incorporated during their biosynthesis. Additionally a variety of other new functionality was seen including hydroxylations, several novel forosamine sugar replacements, and a novel 14-membered macrolide ring analog. 相似文献
104.
White-nose syndrome and wing damage index scores among summer bats in the northeastern United States
White-nose syndrome (WNS) adversely affects millions of bats hibernating in caves of the eastern United States. Beginning in 2009, the US Fish and Wildlife Service supported use of a wing damage index (WDI) scoring system (scale of 0 to 3, or no damage to severe) to assess wing damage of bats captured during summer. Based on bat captures at 459 mist net sites in Pennsylvania, New York, Maryland, Virginia, and New Jersey, USA, we questioned whether WDI scores varied by species group, date, and distance to the closest known affected hibernaculum. We also compared relative health (body mass index [BMI] scores) to WDI scores. Of 3,419 bats (nine species), only four individuals (0.1%; little brown [Myotis lucifugus] and northern bats [Myotis septentrionalis]) were scored as a 3 and 47 (1.4%; big brown [Eptesicus fuscus], little brown, and northern bats) as a 2. All tree bats (eastern red [Lasiurus borealis], hoary [Lasiurus cinereus], and silver-haired bats [Lasionycteris noctivagans]) scored a 0 or 1, suggesting that these species were not affected by WNS. The average WDI score decreased as summer progressed, although trends were weak. Average WDI score and number of bats with class 2 and 3 damage increased with proximity to a known WNS-positive hibernaculum. Similarly, the number of bats with severe wing damage (scoring 2 or 3) was greater at sites closer to infected hibernacula, but little variance was explained by the trend. When species-specific BMI was examined, trends were consistent by sex (female BMI scores were higher than those of males), but no relationship was discovered between BMI and WDI scores. We conclude that, at this larger geographic scale, WDI is not a clear indicator of bat health. 相似文献
105.
Jed P. Sparks Subhash Chandra Louis A. Derry Mandayam V. Parthasarathy Carole S. Daugherty Rory Griffin 《Biogeochemistry》2011,104(1-3):237-249
Silicon transport and incorporation into plant tissue is important to both plant physiological function and to the influence plants have on ecosystem silica cycling. However, the mechanisms controlling this transport have only begun to be explored. In this study, we used secondary ion mass spectrometry (SIMS) to image concentrations of Si in root and shoot tissues of annual blue grass (Poa annua L.) and orchard grass (Dactylis glomerata L.) with the goal of identifying control points in the plant silica uptake pathway. In addition, we used SIMS to describe the distributions of germanium (Ge); the element used to trace Si in biogeochemical studies. Within root tissue, Si and Ge were localized in the suberized thick-walled region of endodermal cells, i.e. the proximal side of endodermal cells which is in close association to the casparian strip. In leaves, Si was present in the cell walls, but Ge was barely detectable. The selective localization of Si and Ge in the proximal side of endodermal cell walls of roots suggests transport control is exerted upon Si and Ge by the plant. The absence of Si in most root cell walls and its presence in the cell walls of leaves (in areas outside of the transpiration terminus) suggests modifications in the chemical form of Si to a form that favors Si complexation in the cell walls of leaf tissue. The low abundance of Ge in leaf tissue is consistent with previous studies that suggest preferential transport of Si relative to Ge. 相似文献
106.
Tatsuya Amano Robert P. Freckleton Simon A. Queenborough Simon W. Doxford Richard J. Smithers Tim H. Sparks William J. Sutherland 《Proceedings. Biological sciences / The Royal Society》2014,281(1779)
To generate realistic projections of species’ responses to climate change, we need to understand the factors that limit their ability to respond. Although climatic niche conservatism, the maintenance of a species’s climatic niche over time, is a critical assumption in niche-based species distribution models, little is known about how universal it is and how it operates. In particular, few studies have tested the role of climatic niche conservatism via phenological changes in explaining the reported wide variance in the extent of range shifts among species. Using historical records of the phenology and spatial distribution of British plants under a warming climate, we revealed that: (i) perennial species, as well as those with weaker or lagged phenological responses to temperature, experienced a greater increase in temperature during flowering (i.e. failed to maintain climatic niche via phenological changes); (ii) species that failed to maintain climatic niche via phenological changes showed greater northward range shifts; and (iii) there was a complementary relationship between the levels of climatic niche conservatism via phenological changes and range shifts. These results indicate that even species with high climatic niche conservatism might not show range shifts as instead they track warming temperatures during flowering by advancing their phenology. 相似文献
107.
The details of how high density lipoprotein (HDL) microstructure affects the conformation and net charge of apolipoprotein (apo) A-I in various classes of HDL particles have been investigated in homogeneous recombinant HDL (rHDL) particles containing apoA-I, palmitoyl-oleoyl phosphatidylcholine (POPC) and cholesteryl oleate. Isothermal denaturation with guanidine HCl was used to monitor alpha-helix structural stability, whereas electrokinetic analyses and circular dichroism were used to determine particle charge and apoA-I secondary structure, respectively. Electrokinetic analyses show that at pH 8.6 apoA-I has a net negative charge on discoidal (POPC.apoA-I) particles (-5.2 electronic units/mol of apoA-I) which is significantly greater than that of apoA-I either free in solution or on spherical (POPC.cholesteryl oleate.apoA-I) rHDL (approximately -3.5 electronic units). Raising the POPC content (32-128 mol/ml of apoA-I) of discoidal particles 1) increases the particle major diameter from 9.3 to 12.1 nm, 2) increases the alpha-helix content from 62 to 77%, and 3) stabilizes the helical segments by increasing the free energy of unfolding (delta GD degree) from 1.4 to 3.0 kcal/mol of apoA-I. Raising the POPC content (28-58 mol/mol of apoA-I) of spherical particles 1) increases the particle diameter from 7.4 to 12.6 nm, 2) increases the percent alpha-helix from 62 to 69%, and 3) has no significant effect on delta GD degree (2.2 kcal/mol of apoA-I). This study shows that different HDL subspecies maintain particular apoA-I conformations that confer unique charge and structural characteristics on the particles. It is likely that the charge and conformation of apoA-I are critical molecular properties that modulate the metabolism of HDL particles and influence their role in cholesterol transport. 相似文献
108.
Factors influencing Agrobacterium-mediated transient expression of uidA in wheat inflorescence tissue. 总被引:12,自引:0,他引:12
A critical step in the development of Agrobacterium tumifaciens-mediated transformation is the establishment of optimal conditions for T-DNA delivery into tissue from which whole plants can be regenerated. The efficient transformation of inflorescence tissue from 'Baldus', a commercial wheat variety, using the Agrobacterium strain AGLI harbouring the binary vector pAL156 is reported here. The effects of various factors on delivery and the transient expression of the uidA gene were studied including the duration of preculture, vacuum infiltration, the effect of sonication treatments, and Agrobacterium cell density. Optimal T-DNA delivery (as measured by uidA activity) was obtained from inflorescence tissues precultured for 21 d and sonicated. Increasing Agrobacterium cell density, the duration of inoculation/co-cultivation, and vacuum pressure, up to a threshold, increased uidA expression. The investigation of factors that influence T-DNA delivery is an important first step in the utilization of Agrobacterium in the transformation of immature wheat inflorescence tissue. 相似文献
109.
Ala PJ Gonneville L Hillman M Becker-Pasha M Yue EW Douty B Wayland B Polam P Crawley ML McLaughlin E Sparks RB Glass B Takvorian A Combs AP Burn TC Hollis GF Wynn R 《The Journal of biological chemistry》2006,281(49):38013-38021
Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe(182) of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular pi-stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail. 相似文献
110.
Capsule Arrival date strongly influenced date of breeding and breeding success. Aim To check our hypothesis that in years with low April temperatures, i.e. when storks started to breed, the relationship between timing of breeding and success would be absent, meaning that migrants would have no advantage by returning early to their breeding area. Methods We collected data in Poznań province, western Poland during the period 1983–2002. Based on local climatological data we selected eight cold spring years and compared them with the 12 ‘normal’ years. We analysed how weather affected the timing and arrival pattern of White Stork. Results The two groups of years did not differ significantly in population size, but in normal years the arrival date of both parents was earlier. Arrival date strongly influenced (was positively correlated with) date of breeding and (negatively correlated with) breeding success. Conclusion The slopes describing the above relationships did not differ significantly between the two groups of years. Therefore, we speculate that natural selection strongly favours birds that return early from the wintering grounds. 相似文献