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131.
Acetabular dysplasia is a known cause of hip osteoarthritis. In addition to abnormal anatomy, changes in kinematics, joint reaction forces (JRFs), and muscle forces could cause tissue damage to the cartilage and labrum, and may contribute to pain and fatigue. The objective of this study was to compare lower extremity joint angles, moments, hip JRFs and muscle forces during gait between patients with symptomatic acetabular dysplasia and healthy controls. Marker trajectories and ground reaction forces were measured in 10 dysplasia patients and 10 typically developing control subjects. A musculoskeletal model was scaled in OpenSim to each subject and subject-specific hip joint centers were determined using reconstructions from CT images. Joint kinematics and moments were calculated using inverse kinematics and inverse dynamics, respectively. Muscle forces and hip JRFs were estimated with static optimization. Inter-group differences were tested for statistical significance (p ≤ 0.05) and large effect sizes (d ≥ 0.8). Results demonstrated that dysplasia patients had higher medially directed JRFs. Joint angles and moments were mostly similar between the groups, but large inter-group effect sizes suggested some restriction in range of motion by patients at the hip and ankle. Higher medially-directed JRFs and inter-group differences in hip muscle forces likely stem from lateralization of the hip joint center in dysplastic patients. Joint force differences, combined with reductions in range of motion at the hip and ankle may also indicate compensatory strategies by patients with dysplasia to maintain joint stability. 相似文献
132.
The increasing resistance of pathogens to common antibiotics, as well as the need to control urease activity to improve the yield of soil nitrogen fertilization in agricultural applications, has stimulated the development of novel classes of molecules that target urease as an enzyme. In this context, the newly developed compounds on the basis of 1-heptanoyl-3-arylthiourea family were evaluated for Jack bean urease enzyme inhibition activity to validate their role as potent inhibitors of this enzyme. 1-Heptanoyl-3-arylthioureas were obtained in excellent yield and characterized through spectral and elemental analysis. All the compounds displayed remarkable potency against urease inhibition as compared to thiourea standard. It was found that novel compounds fulfill the criteria of drug-likeness by obeying Lipinski’s rule of five. Particularly compound 4a and 4c can serve as lead molecules in 4D (drug designing discovery and development). Kinetic mechanism and molecular docking studies also carried out to delineate the mode of inhibition and binding affinity of the molecules. 相似文献
133.
The design and synthesis of a new series of 1,4-dihydroquinazolin-3(2H)-yl benzamide derivatives (4a–o) as anti-inflammatory and analgesic agents and COX-1/2 inhibitors are reported. The target compounds (4a–o) were synthesized using a two-step scheme, and their chemical structures were confirmed with 1H NMR, 13C NMR, and mass spectra and elemental analysis. Compounds 4b, 4d, 4h, 4l, 4n and 4o showed the best in vitro COX-2 inhibitory activity (IC50 0.04–0.07 μM), which was nearly the same as that of the reference drug celecoxib (IC50 0.049 μM), but had a lower selectivity index, as dictated in our target design. In the in vivo anti-inflammatory inhibition assay, compounds 4b, 4c, 4e, 4f, 4m and 4o showed better oedema inhibition percentages, ranging from 38.1% to 54.1%, than did diclofenac sodium (37.8%). An in vivo analgesic assay revealed that compounds 4b and 4n had a potential analgesic effect 4- to 21-fold more potent than that of indomethacin and diclofenac sodium. All the tested compounds showed an improved ulcerogenic index when compared to indomethacin. In the synthesized series, compound 4b showed the best biological activity in all the experiments. The docking study results agreed with the in vitro COX inhibition assay results. Moreover, the predicted in silico studies of all the compounds support their potential as drug candidates. 相似文献
134.
《Bioorganic & medicinal chemistry》2014,22(7):2052-2059
In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07 μM. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07 μM against wild-type HIV-1 and very high selectivity index (SI, 3999). Compound 5a was more effective than the reference drugs nevirapine (by 2-fold) and delavirdine (by 2-fold). In order to further confirm their binding target, an HIV-1 RT inhibitory assay was also performed. Furthermore, SAR analysis among the newly synthesized compounds was discussed and the binding mode of the active compound 5a was rationalized by molecular modeling studies. 相似文献
135.
Based on the high-resolution X-ray crystallographic structure of phospholipase C from Bacillus cereus, the orientation of the phosphatidylcholine substrate in the active site of the enzyme is proposed. The proposal is based on extensive calculations using the GRID program and molecular mechanics geometry relaxations. The substrate model has been constructed by successively placing phosphate, choline and diacylglycerol moieties in the positions indicated from GRID calculations. On the basis of the resulting orientation of a complete phosphatidylcholine molecule, we propose a mechanism for the hydrolysis of the substrate. 相似文献
136.
《Bioorganic & medicinal chemistry letters》2020,30(7):127019
A series of novel HIV-1 protease inhibitors has been designed and synthesized, which contained morpholine derivatives as the P2 ligands and hydrophobic cyclopropyl as the P1′ ligand at the meantime in this study, with the aim of improving the interactions between the active sites of HIV-1 protease and the inhibitors. Twenty-eight compounds were synthesized and assessed, among which inhibitors m18 and m1 exhibited excellent inhibitory effect on the activity of HIV-1 protease with IC50 value of 47 nM and 53 nM, respectively. The molecular modeling of m1 revealed possible hydrogen bondings or van der Waals between the inhibitor and the protease, worthy of in-depth study. 相似文献
137.
138.
Nora M. Bello Juan P. Steibel Robert J. Tempelman 《Biometrical journal. Biometrische Zeitschrift》2010,52(3):297-313
Bivariate mixed effects models are often used to jointly infer upon covariance matrices for both random effects ( u ) and residuals ( e ) between two different phenotypes in order to investigate the architecture of their relationship. However, these (co)variances themselves may additionally depend upon covariates as well as additional sets of exchangeable random effects that facilitate borrowing of strength across a large number of clusters. We propose a hierarchical Bayesian extension of the classical bivariate mixed effects model by embedding additional levels of mixed effects modeling of reparameterizations of u‐ level and e ‐level (co)variances between two traits. These parameters are based upon a recently popularized square‐root‐free Cholesky decomposition and are readily interpretable, each conveniently facilitating a generalized linear model characterization. Using Markov Chain Monte Carlo methods, we validate our model based on a simulation study and apply it to a joint analysis of milk yield and calving interval phenotypes in Michigan dairy cows. This analysis indicates that the e ‐level relationship between the two traits is highly heterogeneous across herds and depends upon systematic herd management factors. 相似文献
139.
Hona Hosseinpoor Aida Iraji Najmeh Edraki Somayeh Pirhadi Mahshid Attarroshan Mahsima Khoshneviszadeh Mehdi Khoshneviszadeh 《化学与生物多样性》2020,17(8)
Tyrosinase is a type 3 copper enzyme responsible for skin pigmentation disorders, skin cancer, and enzymatic browning of vegetables and fruits. In the present article, 12 small molecules of 2‐benzylidenehydrazine‐1‐carbothioamide were designed, synthesized and evaluated for their anti‐tyrosinase activities followed by molecular docking and pharmacophore‐based screening. Among synthesized thiosemicarbazone derivatives, one compound, (2E)‐2‐[(4‐nitrophenyl)methylidene]hydrazine‐1‐carbothioamide, is the strongest inhibitor of mushroom tyrosinase with IC50 of 0.05 μM which demonstrated a 128‐fold increase in potency compared to the positive control. Kinetic studies also revealed mix type inhibition by this compound. Docking studies confirmed the complete fitting of the synthesized compounds into the tyrosinase active site. The results underline the potential of 2‐benzylidenehydrazine‐1‐carbothioamides as potent pharmacophore to extend the tyrosinase inhibition in drug discovery. 相似文献
140.