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41.
Atanas G. Atanasov Jian N. Wang Shi P. Gu Jing Bu Matthias P. Kramer Lisa Baumgartner Nanang Fakhrudin Angela Ladurner Clemens Malainer Anna Vuorinen Stefan M. Noha Stefan Schwaiger Judith M. Rollinger Daniela Schuster Hermann Stuppner Verena M. Dirsch Elke H. Heiss 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators.Methods
We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists.Results
The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain.Conclusion
We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo.General significance
This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. 相似文献42.
Milena Lange Melanie Fiedler Dorothea Bankwitz William Osburn Sergei Viazov Olena Brovko Abdel-Rahman Zekri Yury Khudyakov Michael Nassal Paul Pumpens Thomas Pietschmann J?rg Timm Michael Roggendorf Andreas Walker 《PloS one》2014,9(7)
Hepatitis C virus (HCV) infection is still a serious global health burden. Despite improved therapeutic options, a preventative vaccine would be desirable especially in undeveloped countries. Traditionally, highly conserved epitopes are targets for antibody-based prophylactic vaccines. In HCV-infected patients, however, neutralizing antibodies are primarily directed against hypervariable region I (HVRI) in the envelope protein E2. HVRI is the most variable region of HCV, and this heterogeneity contributes to viral persistence and has thus far prevented the development of an effective HVRI-based vaccine. The primary goal of an antibody-based HCV vaccine should therefore be the induction of cross-reactive HVRI antibodies. In this study we approached this problem by presenting selected cross-reactive HVRI variants in a highly symmetric repeated array on capsid-like particles (CLPs). SplitCore CLPs, a novel particulate antigen presentation system derived from the HBV core protein, were used to deliberately manipulate the orientation of HVRI and therefore enable the presentation of conserved parts of HVRI. These HVRI-CLPs induced high titers of cross-reactive antibodies, including neutralizing antibodies. The combination of only four HVRI CLPs was sufficient to induce antibodies cross-reactive with 81 of 326 (24.8%) naturally occurring HVRI peptides. Most importantly, HVRI CLPs with AS03 as an adjuvant induced antibodies with a 10-fold increase in neutralizing capability. These antibodies were able to neutralize infectious HCVcc isolates and 4 of 19 (21%) patient-derived HCVpp isolates. Taken together, these results demonstrate that the induction of at least partially cross-neutralizing antibodies is possible. This approach might be useful for the development of a prophylactic HCV vaccine and should also be adaptable to other highly variable viruses. 相似文献
43.
Tahsin Shoala Basma H. Amin Ismail A. S. Rashid Fayz A. Abdel-Rahman Mohamed E. Khalil Khamis Youssef 《Phyton》2023,92(4):1139-1152
Production of peaches (Prunus persica (L.) Batsch) for both local market and export is increasing each year in
Egypt. Brown rot disease, caused by Monilinia laxa and Monilinia fructigena, is considered one of the most
important postharvest rots affecting peaches in Egypt and economic losses are increasing. Antifungal activity
of glycyrrhizic acid nanoparticles (GA-NPs) and glycyrrhizic acid (GA) at 0.2 and 0.4 mmol/L was investigated
as a control for both these brown rot pathogens on peach fruits in both in vitro and in vivo studies. In the in vitro
studies, GA-NPs were the most effective as shown by the ability to decrease linear growth of both brown rot
pathogens in potato dextrose agar (PDA) amended with 0.4 mmol/L GA-NPs. Micrographs of M. fructigena
exposed to 0.4 mmol/LGA showed mycelial deformations, nodule formation, detachment of the cell wall, shrinkage and inhomogeneous cytoplasmic materials with large vacuoles. Mycelium of M. laxa exposed to 0.4 mmol/
LGA-NPs resulted in thinner and distorted hyphae, nodule formation, cell wall thinning, and swellings. The GANPs and GA treatments improved fruit quality by maintaining firmness and total soluble solids (TSS). GA-NPs
were more effective in decreasing decay incidence than their bulk material. The 0.4 mmol/L GA-NPs completely
inhibited the disease on naturally infected peach fruits for both seasons of 2018 and 2019. Furthermore,
0.4 mmol/L GA-NPs reduced the disease incidence in inoculated fruits by 95 (M. laxa) and 88% (M. fructigena)
in 2018 season and 96 (M. laxa) and 85% (M. fructigena) in 2019 season. In conclusion, GA-NPs could enhance
the resistance of peaches against brown rot caused by M. laxa and M. fructigena. 相似文献
44.
Noha M. Abouseada Mahde Saleh A. Assafi Jafar Mahdavi Neil J. Oldfield Lee M. Wheldon Karl G. Wooldridge Dlawer A. A. Ala'Aldeen 《PloS one》2012,7(9)
Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae are major bacterial agents of meningitis. They each bind the 37/67-kDa laminin receptor (LamR) via the surface protein adhesins: meningococcal PilQ and PorA, H. influenzae OmpP2 and pneumococcal CbpA. We have previously reported that a surface-exposed loop of the R2 domain of CbpA mediates LamR-binding. Here we have identified the LamR-binding regions of PorA and OmpP2. Using truncated recombinant proteins we show that binding is dependent on amino acids 171–240 and 91–99 of PorA and OmpP2, respectively, which are predicted to localize to the fourth and second surface-exposed loops, respectively, of these proteins. Synthetic peptides corresponding to the loops bound LamR and could block LamR-binding to bacterial ligands in a dose dependant manner. Meningococci expressing PorA lacking the apex of loop 4 and H. influenzae expressing OmpP2 lacking the apex of loop 2 showed significantly reduced LamR binding. Since both loops are hyper-variable, our data may suggest a molecular basis for the range of LamR-binding capabilities previously reported among different meningococcal and H. influenzae strains. 相似文献
45.
Zlatko Janeba Noha Maklad Morris J. Robins 《Nucleosides, nucleotides & nucleic acids》2013,32(10-12):1729-1743
Copper(I)-catalyzed 5-endo-dig cyclizations of 5-(alkyn-1-yl)uracil derivatives had given poor yields of substituted furo[2, 3]pyrimidin-2-ones unless the uracil ring was substituted at N1 with alkyl or glycosyl groups. This limited flexibility for the synthesis of analogues with varied substituents at N3 and/or C6 of the furo[2, 3]pyrimidin-2-one core has been overcome with 5-(3-hydroxyalkyn-1-yl)uracil compounds with no substituent at N1. Manipulation of the side-chain hydroxyl group gives access to additional furo[2,3-d]pyrimidin-2-one analogues. 相似文献
46.
Hend A.A. Abd El-wahab Mauro Accietto Leonardo B. Marino Kirsty J. McLean Colin W. Levy Hamdy M. Abdel-Rahman Mahmoud A. El-Gendy Andrew W. Munro Ahmed S. Aboraia Claire Simons 《Bioorganic & medicinal chemistry》2018,26(1):161-176
Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC?=?12.5?μg/mL, 17a 50?μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2?Å. A model generated from a 1.5?Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target. 相似文献
47.
Wang X Abdel-Rahman AA 《American journal of physiology. Gastrointestinal and liver physiology》2005,289(3):G579-G585
Although chronic and excessive alcohol consumption is associated with liver disease, the mechanism of alcoholic liver injury is still not clear. Whether reduced hepatic production of nitric oxide, which is evident in models of liver injury, is associated with alcohol-induced liver injury has not been investigated. We measured nitric oxide synthase (NOS) activity in the liver of pair-fed rats receiving liquid diet with or without alcohol [3% (vol/vol)] for 12 wk. Compared with control rats, hepatic NOS activity was significantly reduced in alcohol-treated rats along with the evidence of liver injury. Interestingly, there was no difference in the hepatic expression of endothelial NOS (eNOS) between ethanol-fed and pair-fed rats. We then tested the hypothesis that an imbalance between the binding of eNOS with inhibitory and stimulatory proteins may underlie the reduced activity of eNOS because eNOS catalytic activity is regulated partly through dynamic interactions with the inhibitory protein caveolin-1 and the stimulatory protein calmodulin. We found that hepatic caveolin-1 was markedly increased in alcohol-treated rats compared with control rats, whereas calmodulin remained unaltered. The binding of caveolin-1 and calmodulin with eNOS was increased and decreased, respectively, in alcohol-treated rats. Our results suggest that chronic alcohol intake attenuates hepatic eNOS activity by increasing the expression of the inhibitory protein caveolin-1 and enhancing its binding with eNOS. 相似文献
48.
Mohamed S. Abdel-Rahman Gloria A. Skowronski Rita M. Turkall 《Soil & Sediment Contamination》2006,15(1):47-60
Phenol is released to soil through accidental spills, manufacturing processes, and waste disposal. With time, chemicals can become more sequestered in soil (aging). Since skin is the body's primary route of entry for phenol, the impact of aging time on the dermal penetration of phenol was assessed in Atsion and Keyport soils. In vitro studies were conducted on dermatomed male pig skin using a flow-through diffusion cell methodology and radiolabeled phenol. After 3 and 6 months of aging in the Atsion soil, dermal penetration decreased from 84% of the initial dose for pure phenol (without soil) to 15% and 8%, respectively, while the dermal penetration of phenol aged in the Keyport soil was reduced to 22% and 17%, respectively. Atsion soil has a higher organic matter content (4.4%) than Keyport soil (1.6%) suggesting that the lower bioavailability of phenol aged in the Atsion soil may be due to the amount of organic matter in that soil. Although the data indicate that the potential health risk from dermal exposure to phenol would be lower after aging in soil than to pure chemical, further experiments are warranted at lower soil loads and with additional concentrations of phenol to quantify the risk. 相似文献
49.
Jérémie Fournier-Dit-Chabert Victoria Vinader Ana Rita Santos Mariano Redondo-Horcajo Aurore Dreneau Ramkrishna Basak Laura Cosentino Gemma Marston Hamdy Abdel-Rahman Paul M. Loadman Steven D. Shnyder José Fernando Díaz Isabel Barasoain Robert A. Falconer Klaus Pors 《Bioorganic & medicinal chemistry letters》2012,22(24):7693-7696
Colchicine was modified at the 10-OCH3 position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62–99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III β-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery. 相似文献
50.
Abdel-Rahman SM 《Mycopathologia》2008,166(5-6):319-333
As molecular-based investigations begin to uncover the large degree of genetic variation that can exist within dermatophyte species, and population-based studies reveal exceedingly high rates of endemicity for these organisms, species typing has become inadequate to gain insight into these pathogens and the nature of the infections that they cause. This review examines studies that have applied strain typing strategies to explore intra-specific genetic diversity among the dermatophytes in attempts to address a number of relevant clinico-epidemiologic questions about these common fungal pathogens. 相似文献