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101.
Structural determinants of antimicrobial and antiplasmodial activity and selectivity in histidine-rich amphipathic cationic peptides 总被引:1,自引:0,他引:1
Mason AJ Moussaoui W Abdelrahman T Boukhari A Bertani P Marquette A Shooshtarizaheh P Moulay G Boehm N Guerold B Sawers RJ Kichler A Metz-Boutigue MH Candolfi E Prévost G Bechinger B 《The Journal of biological chemistry》2009,284(1):119-133
Designed histidine-rich amphipathic cationic peptides, such as LAH4, have enhanced membrane disruption and antibiotic properties when the peptide adopts an alignment parallel to the membrane surface. Although this was previously achieved by lowering the pH, here we have designed a new generation of histidine-rich peptides that adopt a surface alignment at neutral pH. In vitro, this new generation of peptides are powerful antibiotics in terms of the concentrations required for antibiotic activity; the spectrum of target bacteria, fungi, and parasites; and the speed with which they kill. Further modifications to the peptides, including the addition of more hydrophobic residues at the N terminus, the inclusion of a helix-breaking proline residue or using D-amino acids as building blocks, modulated the biophysical properties of the peptides and led to substantial changes in toxicity to human and parasite cells but had only a minimal effect on the antibacterial and antifungal activity. Using a range of biophysical methods, in particular solid-state NMR, we show that the peptides are highly efficient at disrupting the anionic lipid component of model membranes. However, we also show that effective pore formation in such model membranes may be related to, but is not essential for, high antimicrobial activity by cationic amphipathic helical peptides. The information in this study comprises a new layer of detail in the understanding of the action of cationic helical antimicrobial peptides and shows that rational design is capable of producing potentially therapeutic membrane active peptides with properties tailored to their function. 相似文献
102.
Background
Adeno-associated virus has attracted great attention as vehicle for body-wide gene delivery. However, for the successful treatment of a disease such as Duchenne muscular dystrophy infusion of very large amounts of vectors is required. This not only raises questions about the technical feasibility of the large scale production but also about the overall safety of the approach. One way to overcome these problems would be to find strategies able to increase the in vivo efficiency.Methodology
Here, we investigated whether polymers can act as adjuvants to increase the in vivo efficiency of AAV2. Our strategy consisted in the pre-injection of polymers before intravenous administration of mice with AAV2 encoding a murine secreted alkaline phosphatase (mSeAP). The transgene expression, vector biodistribution and tissue transduction were studied by quantification of the mSeAP protein and real time PCR. The injection of polyinosinic acid and polylysine resulted in an increase of plasmatic mSeAP of 2- and 12-fold, respectively. Interestingly, polyinosinic acid pre-injection significantly reduced the neutralizing antibody titer raised against AAV2.Conclusions
Our results show that the pre-injection of polymers can improve the overall transduction efficiency of systemically administered AAV2 and reduce the humoral response against the capsid proteins. 相似文献103.
Cathy Poillot Kaouthar Dridi Hicham Bichraoui Julien Pêcher Sebastien Alphonse Badreddine Douzi Michel Ronjat Hervé Darbon Michel De Waard 《The Journal of biological chemistry》2010,285(44):34168-34180
Maurocalcine has been the first demonstrated animal toxin acting as a cell-penetrating peptide. Although it possesses competitive advantages, its use as a cell-penetrating peptide (CPP) requires that analogues be developed that lack its characteristic pharmacological activity on ryanodine-sensitive calcium channels without affecting its cell-penetrating and vector efficiencies. Here, we present the synthesis, three-dimensional 1H NMR structure, and activity of d-maurocalcine. We demonstrate that it possesses all of the desired features for an excellent CPP: preserved structure, lack of pharmacological action, conserved vector properties, and absence of cell toxicity. This is the first report of a folded/oxidized animal toxin in its d-diastereomer conformation for use as a CPP. The protease resistance of this new peptide analogue, combined with its efficient cell penetration at concentrations devoid of cell toxicity, suggests that d-maurocalcine should be an excellent vector for in vivo applications. 相似文献
104.
Jos H.M. Lange Martina A.W. van der Neut Henri C. Wals Gijs D. Kuil Alice J.M. Borst Arie Mulder Arnold P. den Hartog Hicham Zilaout Wouter Goutier Herman H. van Stuivenberg Bernard J. van Vliet 《Bioorganic & medicinal chemistry letters》2010,20(3):1084-1089
The synthesis and structure–activity relationship studies of imidazoles are described. The target compounds 6–20 represent a novel chemotype of potent and CB2/CB1 selective cannabinoid CB2 receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable log P and calculated polar surface area values. Compound 12 exhibited the highest CB2 receptor affinity (Ki = 1.03 nM) in this series, as well as the highest CB2/CB1 subtype selectivity (>9708-fold). 相似文献
105.
Jos H.M. Lange Amos Attali Martina A.W. van der Neut Henri C. Wals Arie Mulder Hicham Zilaout Ate Duursma Hans H.M. van Aken Bernard J. van Vliet 《Bioorganic & medicinal chemistry letters》2010,20(17):4992-4998
The synthesis and SAR of 3-alkyl-4-aryl-4,5-dihydropyrazole-1-carboxamides 1–23 and 1-alkyl-5-aryl-4,5-dihydropyrazole-3-carboxamides 24–27 as two novel cannabinoid CB1 receptor agonist classes were described. The target compounds elicited high affinities to the CB1 as well as the CB2 receptor and were found to act as CB1 receptor agonists. The key compound 19 elicited potent CB1 agonistic and CB2 inverse agonistic properties in vitro and showed in vivo activity in a rodent model for multiple sclerosis after oral administration. 相似文献
106.
Li TF Chen D Wu Q Chen M Sheu TJ Schwarz EM Drissi H Zuscik M O'Keefe RJ 《The Journal of biological chemistry》2006,281(30):21296-21304
Transforming growth factor-beta (TGF-beta) plays an essential role in chondrocyte maturation. It stimulates chondrocyte proliferation but inhibits chondrocyte differentiation. In this study, we found that TGF-beta rapidly induced beta-catenin protein levels and signaling in murine neonatal sternal primary chondrocytes. TGF-beta-increased beta-catenin induction was reproduced by overexpression of SMAD3 and was absent in Smad3(-/-) chondrocytes treated with TGF-beta. SMAD3 inhibited beta-transducin repeat-containing protein-mediated degradation of beta-catenin and immunoprecipitated with beta-catenin following TGF-beta treatment. Both SMAD3 and beta-catenin co-localized to the nucleus after TGF-beta treatment. Although both TGF-beta and beta-catenin stimulated cyclin D(1) expression in chondrocytes, the effect of TGF-beta was inhibited with beta-catenin gene deletion or SMAD3 loss of function. These results demonstrate that TGF-beta stimulates cyclin D(1) expression at least in part through activation of beta-catenin signaling. 相似文献
107.
Hicham El Bakouri José Usero José Morillo Abdelhamid Ouassini 《Bioresource technology》2009,100(18):4147-4155
The adsorption behavior of drin pesticides from aqueous solution onto acid treated olive stones (ATOS) was investigated using stir bar sorptive extraction and gas chromatography coupled with mass spectroscopy. The effects of sorbent particle size, adsorbent dose, contact time, concentration of pesticide solution and temperature on the adsorption processes were systematically studied in batch shaking sorption experiments. Maximum removal efficiency (94.8%) was reached for aldrin (0.5 mg L−1) using the fraction 63–100 μm of ATOS (solid/liquid ratio: 1 g L−1). Experimental data were modeled by Langmuir, Freundlich and Dubinin–Radushkevich (D–R) isotherms. The Freundlich isotherm model (R2 = 0.98–0.99) fitted the equilibrium data better than the Langmuir and D–R isotherm models, with low sum of error values (SE = 1.4–9.2%). The mean adsorption free energy derived from the D–R isotherm model (R2 = 0.95–0.99) showed that the adsorption of drin pesticides was taken place by weak physical forces, such as van der Waals forces and hydrogen bonding. The calculated thermodynamic parameters, ΔH, ΔS and ΔG prove that drin pesticides adsorption on ATOS was feasible, spontaneous and exothermic under examined conditions. The pseudo first order, pseudo second order kinetic and the intra-particle diffusion models were used to describe the kinetic data and rate constants were evaluated. 相似文献
108.
Moulay Abdelaziz El Alaoui Marouane Melloul Sanaa Alaoui Amine Hamid Stambouli Aziz El Bouri Abdelmajid Soulaymani Elmostafa El Fahime 《PloS one》2013,8(10)
The extraction and purification of nucleic acids is the first step in most molecular biology analysis techniques. The objective of this work is to obtain highly purified nucleic acids derived from Cannabis sativa resin seizure in order to conduct a DNA typing method for the individualization of cannabis resin samples. To obtain highly purified nucleic acids from cannabis resin (Hashish) free from contaminants that cause inhibition of PCR reaction, we have tested two protocols: the CTAB protocol of Wagner and a CTAB protocol described by Somma (2004) adapted for difficult matrix. We obtained high quality genomic DNA from 8 cannabis resin seizures using the adapted protocol. DNA extracted by the Wagner CTAB protocol failed to give polymerase chain reaction (PCR) amplification of tetrahydrocannabinolic acid (THCA) synthase coding gene. However, the extracted DNA by the second protocol permits amplification of THCA synthase coding gene using different sets of primers as assessed by PCR. We describe here for the first time the possibility of DNA extraction from (Hashish) resin derived from Cannabis sativa. This allows the use of DNA molecular tests under special forensic circumstances. 相似文献
109.
110.
Hicham El Miri Mohamed Rhajaoui Oumnia Himmi Souâd Ouahabi Abdelaziz Benhoussa Chafika Faraj 《法国昆虫学会纪事》2013,49(2):154-159
Résumé. La leishmaniose cutanée est un important problème de santé publique dans la province de Sidi Kacem au nord-ouest du Maroc. L'incidence de cette affetion, due aussi bien à Leishmania tropica qu'à L. infantum est en augmentation progressive depuis 1997. La présente étude a été menée dans le but d'étudier l'écologie et la dynamique des populations des vecteurs de cette maladie dans les principaux foyers de cette province. Un total de 4504 spécimens appartenant à deux genres et six espèces a été capturé à l'aide de pièges adhésifs et lumineux, dans cinq foyers. Les espèces dominantes sont Phlebotomus sergenti représentant 42,6% du total des phlébotomes capturés et P. longicuspis avec 27,2% des captures. Ces deux espèces sont présentes de mai à novembre et évoluent en deux générations avec deux pics de densité, le premier en juin et le second en septembre. En considérant la grande spécificité vecteur-parasite connue en épidémiologie des leishmanioses ainsi que l'abondance des espèces capturées pendant la saison favorable à la transmission, P. sergenti et P. longicuspis seraient respectivement les vecteurs les plus probables des leishmanioses à L. tropica et à L. infantum dans la région étudiée. Le risque de transmission de la maladie serait plus grand durant le deuxième pic de densité en fin été- début automne. 相似文献