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141.
Peptide bonds between residues 7 and 8 residues 8 and 9, postulated internal cleavage sites of the peptide hormone somatostatin, were subjected to "pairwise" retro-inverso modification, where atoms of these peptide bonds were interchanged to give the analogues [gPhe7-m-(RS)-Trp8]somatostatin (I) and [gTrp8-m-(RS)-Lys9]somatostatin (II). Key fragments containing the modifications were synthesized by using [bis(trifluoroacetoxy)iodo]benzene for the generation of gem-diaminoalkyl-containing precursors from peptide amides. The versatility of solution synthetic methods was utilized to allow the incorporation of the modified segments. Protecting groups, removable selectively and under mild conditions, included tert-butyl-based groups for the side chains and the tert-butylmercapto group for the cysteine thiols. The excellent results obtained in the syntheses of analogues I and II, and previously of somatostatin on a larger scale [Moroder, L., Gemeiner, M., Goehring, W., Faeger, E., Thamm, P., & Wunsch, E. (1981) Biopolymers 20, 17-31], suggest the general feasibility of this route for the synthesis of centrally modified analogues. The purification of the products by Sephadex LH-20 chromatography afforded the separation of diastereomers of both analogues. The two isomers of I showed significant but different activities while those of analogue II were marginally active. 相似文献
142.
Nuclear magnetic resonance analysis and conformational characterization of a cyclic decapeptide antagonist of gonadotropin-releasing hormone 总被引:1,自引:0,他引:1
Two-dimensional proton nuclear magnetic resonance spectroscopy at 500 MHz has been carried out on the cyclic decapeptide antagonist of gonadotropin-releasing hormone: cyclo-(delta 3-Pro1-D-pClPhe2-D-Trp3-Ser4-Tyr5-D-Trp6-NMeLeu7-Arg8- Pro9-beta-Ala 10). The antagonist exists in two slowly interconverting conformations. All data are consistent with the conclusion that one form has all-trans peptide bonds and the other has a cis beta-Ala10-delta3-Pro1 bond. With the use of sequential assignment methods, chemical shift assignments were obtained for all backbone and side-chain protons of both conformational isomers except for the serine and tyrosine hydroxyl groups and the C gamma, C delta, and guanidinium group protons of the arginine. Temperature dependence of spectral parameters and magnitudes of observed nuclear Overhauser effects support the interpretation that both conformers of the antagonist consist of two beta-turns (type II', D-Trp6-NMeLeu7; type II, delta 3-Pro1-D-pClPhe2) connected by extended antiparallel beta-like strands. 相似文献
143.
Predicted three-dimensional structure of the protease inhibitor domain of the Alzheimer's disease beta-amyloid precursor 总被引:1,自引:0,他引:1
Alzheimer's disease is characterized by the deposition of amyloid beta-protein as plaques and tangles in the brains of its victims. The amyloid precursor can be expressed with or without the inclusion of a protease inhibitor domain, the potential role of which in amyloidogenesis has prompted the generation of a model of its three-dimensional structure based on the known structure of a related inhibitor. The model structure predicts that the mutated residues are almost entirely on the surface of the inhibitor domain, while conserved residues constitute the hydrophobic core. In addition, several pairs of structurally complementary, or concerted, mutations are seen. These structural features provide strong evidence for the validity of the modeled structure, and it is suggested that the presence of complementary mutations may be used as a criterion for evaluating protein structures built by homology, in addition to the (spatial) location of the mutations. The terminal residues delimiting the domain are among those furthest from the protease binding site and are in close proximity to one another, thus suggesting the ability of the domain to function as a structural cassette within the context of a larger protein. The electrostatic potentials of the inhibitor and of the related bovine pancreatic trypsin inhibitor reveal how two inhibitors with very different net charges can bind with approximately the same binding constant to trypsin and suggest a mutation of trypsin that might selectively enhance the binding of the amyloid inhibitor domain. The model provides a structural basis for understanding the functional roles of residues in the domain and for designing simpler molecules to test as pharmacologic agents for intervention in Alzheimer's disease. 相似文献
144.
145.
Studies of the hyaluronan (HA) tetrasaccharides are important for
understanding hydrogen-bonding in the HA polymer, as they are probably the
smallest oligomers in which characteristics of the constituent
monosaccharides and the polymer are simultaneously exhibited. Here we
present extensive molecular dynamics simulations of the two
tetrasaccharides of HA in dilute aqueous solution. These simulations have
confirmed the existence of intramolecular hydrogen-bonds between the
neighboring sugar residues of HA in solution, as proposed by Scott (1989).
However, our simulations predict that these intramolecular hydrogen-bonds
are not static as previously proposed, but are in constant dynamic exchange
on the sub-nanosecond time-scale. This process results in discrete internal
motion of the HA tetrasaccharides where they rapidly move between low
energy conformations. Specific interactions between water and
intramolecular hydrogen-bonds involving the hydroxymethyl group were found
to result in differing conformations and dynamics for the two alternative
tetrasaccharides of HA. This new observation suggests that this residue may
play a key role in the entropy and stability of HA in solution, allowing it
to stay soluble up to high concentration. The vicinal coupling constants3 J
NHCH of the acetamido groups have been calculated from our aqueous
simulations of HA. We found that high values of 3J NHCH approximately 8 Hz,
as experimentally measured for HA, are consistent with mixtures of both
trans and cis conformations, and thus3 J NHCH cannot be used to imply a
purely trans conformation of the acetamido. The rapid exchange of
intramolecular hydrogen-bonds indicates that although the structure is at
any moment stabilized by these hydrogen-bonds, no one hydrogen-bond exists
for an extended period of time. This could explain why NMR often fails to
provide evidence for intramolecular hydrogen-bonds in HA and other aqueous
carbohydrate structures.
相似文献
146.
147.
Chen C Chen Y Pontillo J Guo Z Huang CQ Wu D Madan A Chen T Wen J Xie Q Tucci FC Rowbottom M Zhu YF Wade W Saunders J Bozigian H Struthers RS 《Bioorganic & medicinal chemistry letters》2008,18(11):3301-3305
Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4. 相似文献
148.
Brent R. Whitehead Michael M.-C. Lo Amjad Ali Min K. Park Scott B. Hoyt Yusheng Xiong Jiaqiang Cai Emma Carswell Andrew Cooke John MacLean Paul Ratcliffe John Robinson D. Jonathan Bennett Joseph A. Clemas Tom Wisniewski Mary Struthers Doris Cully Douglas J. MacNeil 《Bioorganic & medicinal chemistry letters》2017,27(2):143-146
The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1. 相似文献
149.
150.
Adrenaline causes potassium influx in skeletal muscle and potassium efflux in cardiac muscle in rats: the role of Na/K ATPase 总被引:1,自引:0,他引:1
A D Struthers D L Davies D Harland J S Price R A Brown C Quigley M J Brown 《Life sciences》1987,40(1):101-108
Previous in vitro evidence suggests that adrenaline causes K influx in skeletal muscle by stimulating a ouabain sensitive Na/K ATPase membrane pump. However in rabbits, adrenaline induced hypokalaemia was not significantly altered by pretreatment with digoxin (50 micrograms/kg). Rats were infused with adrenaline or saline after being given a tracer dose of 42KCl. Adrenaline caused a highly significant uptake of 42K in skeletal muscle and a decrease in 42K uptake in ventricle. Rats were also studied after receiving a high dose of digoxin (1.4 mg/kg) which by itself produced a significant increase in plasma K, a decrease in plasma Na and a decreased uptake of 42K in ventricle and lung. These results suggest that adequate widespread Na/K ATPase inhibition had been achieved by this dose of digoxin but despite this, adrenaline still caused hypokalaemia and also still caused significant 42K tissue uptake by skeletal muscle. These results suggest that adrenaline causes K influx by skeletal muscle and K efflux by cardiac tissue. Furthermore, the former mechanism was not inhibited by pretreatment with digoxin. 相似文献