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41.
R.J.M. Craik 《Applied Acoustics》1982,15(5):355-361
A simple method to measure structure-borne sound transmission is described. Measurement is made of the level difference in the acceleration between two structural elements using a plastic headed hammer as a noise source. The method is at least as accurate as conventional measurements made under steady-state conditions using continuous noise sources and can be carried out with less instrumentation on site and in about a tenth of the time.The portability of the source greatly simplifies the measurements as a hammer can be used to hit structures in a wide variety of positions whereas shakers can only be used in limited situations. In addition, attaching a shaker to a wall can damage the wall surface whereas, with care, a hammer hit will not. 相似文献
42.
The mechanism of target cell lysis in cytotoxic lymphocyte-mediated death is not well understood, and the role of granzymes in this process is unclear. Chemical functional probes were thus prepared for the major granzymes A and B to deconvolute their role in natural killer cell-mediated lysis of target cells. These biotinylated and substrate specificity-based diphenyl phosphonates allowed facile evaluation of selectivity through activity-based profiling in cell lysates and intact cells. Both inhibitors were found to be extremely selective in vitro and in cells. Use of these inhibitors in cell-based assays revealed granzyme A to be a minor effector and granzyme B to be a major effector of target cell lysis by natural killer cells. These studies indicate that the proapoptotic granzyme B functions also as a pronecrotic effector of target cell death. 相似文献
43.
The 19F substituent chemical shifts (SCS) of meta- and para-benzoyl fluorides are found to correlate well with substituent parameters using the dual substituent parameter (DSP) equation, indicating that they reflect electronic perturbations induced by the substituent. The direction of the SCS values is such that donating substituents cause upfield shifts whilst acceptors cause downfield shifts. STO-3G calculations indicate that substituents induce only very small changes in π-electron density about the fluorine atom, but that these changes correlate reasonably well with the observed SCS values. For the para series, the slope of the relationship between δq and 19F SCS is 5000 ppm/electron, indicating the great sensitivity of the flourine atom to small changes in electron density. 相似文献
44.
A rapid method has been developed for the quantification of the prototypic cyclotide kalata B1 in water and plasma utilizing matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry. The unusual structure of the cyclotides means that they do not ionise as readily as linear peptides and as a result of their low ionisation efficiency, traditional LC/MS analyses were not able to reach the levels of detection required for the quantification of cyclotides in plasma for pharmacokinetic studies. MALDI-TOF-MS analysis showed linearity (R2 > 0.99) in the concentration range 0.05-10 microg/mL with a limit of detection of 0.05 microg/mL (9 fmol) in plasma. This paper highlights the applicability of MALDI-TOF mass spectrometry for the rapid and sensitive quantification of peptides in biological samples without the need for extensive extraction procedures. 相似文献
45.
SFTI-1 is a bicyclic 14 amino acid peptide that was originally isolated from the seeds of the sunflower Helianthus annuus. It is a potent inhibitor of trypsin, with a sub-nanomolar K(i) value and is homologous to the active site region of the well-known family of serine protease inhibitors known as the Bowman-Birk trypsin inhibitors. It has a cyclic backbone that is cross-braced by a single disulfide bridge and a network of hydrogen bonds that result in a well-defined structure. SFTI-1 is amenable to chemical synthesis, allowing for the creation of synthetic variants. Alterations to the structure such as linearising the backbone or removing the disulfide bridge do not reduce the potency of SFTI-1 significantly, and minimising the peptide to as few as nine residues results in only a small decrease in reactivity. The creation of linear variants of SFTI-1 also provides a tool for investigating putative linear precursor peptides. The mechanism of biosynthesis of SFTI-1 is not yet known but it seems likely that it is a gene-coded product that has arisen from a precursor protein that may be evolutionarily related to classic Bowman-Birk inhibitors. 相似文献
46.
Yan Zhou Dr. Peta J. Harvey Dr. Johannes Koehbach Dr. Lai Yue Chan Alun Jones Åsa Andersson Prof. Irina Vetter Dr. Thomas Durek Prof. David J. Craik 《Angewandte Chemie (International ed. in English)》2023,62(29):e202302812
Ziconotide (ω-conotoxin MVIIA) is an approved analgesic for the treatment of chronic pain. However, the need for intrathecal administration and adverse effects have limited its widespread application. Backbone cyclization is one way to improve the pharmaceutical properties of conopeptides, but so far chemical synthesis alone has been unable to produce correctly folded and backbone cyclic analogues of MVIIA. In this study, an asparaginyl endopeptidase (AEP)-mediated cyclization was used to generate backbone cyclic analogues of MVIIA for the first time. Cyclization using six- to nine-residue linkers did not perturb the overall structure of MVIIA, and the cyclic analogues of MVIIA showed inhibition of voltage-gated calcium channels (CaV2.2) and substantially improved stability in human serum and stimulated intestinal fluid. Our study reveals that AEP transpeptidases are capable of cyclizing structurally complex peptides that chemical synthesis cannot achieve and paves the way for further improving the therapeutic value of conotoxins. 相似文献
47.
Marlon H. Cardoso Lai Y. Chan Elizabete S. Cndido Danieli F. Buccini Samilla B. Rezende Marcelo D. T. Torres Karen G. N. Oshiro Ítala C. Silva Snia Gonalves Timothy K. Lu Nuno C. Santos Cesar de la Fuente-Nunez David J. Craik Octvio L. Franco 《Chemical science》2022,13(32):9410
Structural diversity drives multiple biological activities and mechanisms of action in linear peptides. Here we describe an unusual N-capping asparagine-lysine-proline (NKP) motif that confers a hybrid multifunctional scaffold to a computationally designed peptide (PaDBS1R7). PaDBS1R7 has a shorter α-helix segment than other computationally designed peptides of similar sequence but with key residue substitutions. Although this motif acts as an α-helix breaker in PaDBS1R7, the Asn5 presents exclusive N-capping effects, forming a belt to establish hydrogen bonds for an amphipathic α-helix stabilization. The combination of these different structural profiles was described as a coil/N-cap/α-helix scaffold, which was also observed in diverse computational peptide mutants. Biological studies revealed that all peptides displayed antibacterial activities. However, only PaDBS1R7 displayed anticancer properties, eradicated Pseudomonas aeruginosa biofilms, decreased bacterial counts by 100–1000-fold in vivo, reduced lipopolysaccharide-induced macrophages stress, and stimulated fibroblast migration for wound healing. This study extends our understanding of an N-capping NKP motif to engineering hybrid multifunctional peptide drug candidates with potent anti-infective and immunomodulatory properties.An unusual N-capping asparagine-lysine-proline (5NKP7) motif yields a coil/N-cap/α-helix multifunctional scaffold in a computer-made peptide selective for anionic surfaces and with anticancer, antibacterial, antibiofilm, anti-infective (in vivo), and immunomodulatory potential. 相似文献
48.
49.
50.
Kalata B1 (4) is a prototypical, 29-residue, Möbius cyclotide with a cis prolyl peptide bond in loop 5. Two analogs were synthesized in which Pro24 was substituted by trans-4-hydroxy-l-proline (peptide 5) and cis-4-hydroxy-l-proline (peptide 6). Linear peptides were assembled by solid phase peptide synthesis using Fmoc/tBu chemistry. Head-to-tail cyclization was performed using HATU, side-chain protecting groups removed and the cyclic peptides 2 and 3 isolated by RP-HPLC. Oxidation led to the formation of peptides 5 and 6, each incorporating three disulfide bonds. Analysis of TOCSY and NOESY spectra of the purified peptides enabled assignment of the backbone amide and Hα resonances. These showed a striking correlation with those of native kalata B1, indicating that folding had produced the same disulfide bridge topology. While somewhat surprising that stereoelectronic effects introduced by the hydroxyl substituents in this key region of the peptide had little impact, this reflects the strong thermodynamic driving force toward formation of the cyclic cystine knot scaffold. 相似文献