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991.
MEK-1 and MEK-2 are dual-specificity kinases and important components in the mitogen-activated protein kinase pathway. These enzymes are crucial for normal cell survival and are also expressed in several types of cancers, making them important targets for drug design. We have applied an integrated in silico approach that combines comparative molecular field analysis, comparative molecular similarity indices analysis, and molecular docking to study the structural determinants for the recognition of substituted isothiazole analogs as allosteric inhibitors against MEK-1 kinase. The best 3D-QSAR models for comparative molecular field analysis and comparative molecular similarity indices analysis were selected based on statistical parameters. 3D contour maps suggested that bulky or long-chain substitutions at the X position on the core part decrease the inhibitory activity, and the presence of a hydrogen bond donor substitution enhances the activity. The bulky and electronegative substitutions at the Y position on the core part enhance the activity of the inhibitors. Molecular docking studies reveal a large and hydrophobic pocket that accommodates the Y substitution and a polar pocket that accommodates substitutions on the X position and forms hydrogen bonding interactions with MEK-1 kinase. The results of the 3D-QSAR analysis corroborate with the molecular docking results, and our findings will serve as a basis for further development of better allosteric inhibitors of MEK-1 kinase against several cancers. 相似文献
992.
Four highly discriminating fourth-generation topological indices (TIs), termed as superaugmented eccentric distance sum connectivity indices, as well as their topochemical versions (denoted by , , and ), have been conceptualized in this study. The values of these indices for all possible structures with three, four, and five vertices containing one heteroatom were computed using an in-house computer program. The proposed superaugmented eccentric distance sum connectivity topochemical indices exhibited exceptionally high discriminating power, low degeneracy, and high sensitivity toward both the presence and the relative position of heteroatom(s) for all possible structures with five vertices containing at least one heteroatom. Intercorrelation analysis revealed the absence of correlation of proposed indices with Zagreb indices and the molecular connectivity index. Subsequently, the proposed TIs were successfully utilized for the development of models for the prediction of checkpoint kinase inhibitory activity of 2-arylbenzimidazoles. A data set comprising 47 differently substituted analogs of 2-arylbenzimidazoles was selected for the study. The values of various TIs for each analog in the data set were computed using an in-house computer program. The resulting data were analyzed, and suitable models were developed through decision tree (DT), random forest (RF), and moving average analysis (MAA). The performance of the models was assessed by calculating the specificity, sensitivity, overall accuracy, and Mathew's correlation coefficient. A decision tree was constructed for the checkpoint kinase inhibitory activity to determine the importance of topological indices. The decision tree identified the proposed TIs -, - as the most important indices. The decision tree learned the information from the input data with an accuracy of 96% and correctly predicted the cross-validated (10-fold) data with an accuracy of 77%. Random forest correctly predicted the checkpoint kinase inhibitory activity with an accuracy of 83%. The single index-based models were also developed for the prediction of checkpoint kinase inhibitory activity using MAA. The accuracy of prediction of single index-based models derived through MAA was found to vary from a minimum of 90% to a maximum of 95%. Exceptionally high discriminating power, low degeneracy, and high sensitivity toward branching and presence of heteroatom of proposed indices can be of immense use in drug design, isomer discrimination, similarity/dissimilarity studies, quantitative structure activity/property relationships, lead optimization, and combinatorial library design. 相似文献
993.
Castillo-Garit JA Del Toro-Cortés O Kouznetsov VV Puentes CO Romero Bohórquez AR Vega MC Rolón M Escario JA Gómez-Barrio A Marrero-Ponce Y Torrens F Abad C 《Chemical biology & drug design》2012,80(1):38-45
Atom‐based bilinear indices and linear discriminant analysis are used to discover novel trypanosomicidal compounds. The obtained linear discriminant analysis‐based quantitative structure–activity relationship models, using non‐stochastic and stochastic indices, provide accuracies of 89.02% (85.11%) and 89.60% (88.30%) of the chemicals in the training (test) sets, respectively. Later, both models were applied to the virtual screening of 18 in‐house synthesized compounds to find new pro‐lead antitrypanosomal agents. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Predictions agree with experimental results to a great extent (16/18) of the chemicals. Sixteen compounds show more than 70% of epimastigote inhibition at a concentration 100 μg/mL. In addition, three compounds ( CRIS 112 , CRIS 140 and CRIS 147 ) present more than 70% of epimastigote inhibition at a concentration of 10 μg/mL (79.95%, 73.97% and 78.13%, respectively) with low values of cytotoxicity (19.7%, 7.44% and 20.63%, correspondingly).Taking into account all these results, we could say that these three compounds could be optimized in forthcoming works. Even though none of them resulted more active than nifurtimox, the current results constitute a step forward in the search for efficient ways to discover new lead antitrypanosomals. 相似文献
994.
995.
This study investigated the relationship between different components of the full blood count, such as haemoglobin (Hb), total white cell count, total lymphocyte count on admission and total neutrophil count as possible surrogate markers of conditions that lead to increased mortality in hip-fracture patients. A total of 791 patients were studied with 81.2% being females. The 1-year mortality was 26.4% (32.9% in males compared with 24.9% in females). A significant increase in mortality was seen in anaemic patients, especially with Hb 80-100 g l−1 (1-year mortality was 49.2%, p-value < 0.001) and patients with lymphocyte count ≤1.1 × 109 l−1 (33.2% mortality, p-value < 0.0001). There was no relationship between total white cell count or neutrophil count and mortality. This information clearly suggests that Hb and total lymphocyte counts may be surrogate markers for increased mortality after a hip fracture and can be used for audit purposes to adjust for different case mixes between groups. 相似文献
996.
目的 建立Beagle犬和食蟹猴血液及血清生化指标的正常参考值范围,为判定血液和血清生化指标异常提供依据。方法 普通级健康Beagle犬,6~9个月龄,食蟹猴,2~3岁。Beagle犬前肢桡静脉采血(食蟹猴为前臂静脉),分别采用Hitachi 7060自动生化分析仪和Advia 120自动血球分析仪检测生化和血液指标,对测定结果作统计检验。结果/b> 经过统计分析,分别得出Beagle犬及食蟹猴血清生化和血液指标的正常参考均值以及标准差。结论 初步建立不同性别间Beagle犬和食蟹猴的血液学指标和血生化指标正常值的参考范围。 相似文献
997.
Background
Medicinal plant traditional knowledge is one of the most widely known traditional ecosystem services, as it provides primary healthcare, contributes to subsistence livelihoods, and for its potential value as a source of novel pharmaceuticals. People living in close contact with their surroundings for many generations are hypothesized to have developed, through trial-and-error, in-depth knowledge of ecosystems, biodiversity, and their management and utility. In the case of medicinal plant knowledge it could lead to an asymptotic climax or a constantly evolving equilibrium of cures with proven efficacy and those under assessment.Methods
An in-depth study of 97 plant species used in traditional medicine by the Brou, Saek and Kry ethnic groups in Lao PDR was made to test similarity in medicinal plant knowledge.Results
Medicinal plants were used in 99 different ways in 510 species-use combinations. Medicinal uses could be generalized into 12 use categories with 747 species-category combinations. Similarity indices show Brou and Saek plant use appears to be most similar (QSBS: 60.0; JIBS: 75.1) followed by Kry and Saek (QSKS: 51.6; JIKS: 53.4), and then Kry and Brou (QSBK: 46.9; JIBK: 44.1).Discussion
Intercultural similarities found are quite low, considering that all three groups share the same geographical and ecological area and have the same dependence on medicinal plants. Intercultural transmission is unimpeded but many treatments are likely to be ineffective. Comparison of the similarities found here with similarities computed from other data show that these results are homologous with other sympatric ethnic groups, and much higher than those for allopatrically living groups.Conclusion
Medicinal plant knowledge does not reach a stable climax, but appears to evolve continually by trial-and-error, as effective cures to many ailments are unavailable. 相似文献998.
目的 研究羟乙基淀粉(HES) 200/0.5在急性高容量血液稀释(AHH)中对小儿血流动力学及凝血功能的影响.方法 选取行围术前期AHH治疗的1~12岁ASA Ⅰ~Ⅱ级患儿64例,将所有患儿按随机数字表法分为治疗组(HES 200/0.5)和对照组(乳酸林格液)各32例.所有患儿人手术室后行麻醉诱导及麻醉维持,待麻醉平衡后对治疗组输注HES 200/0.5,对照组输注乳酸林格液,两组均用乳酸林格液补充其余液体需要量.分别在行AHH前(T0)、AHH结束后30 min(T1)及AHH结束后60 min(T2)检测血流动力学指标和凝血功能指标.结果 两组患儿AHH治疗前后平均动脉压(MAP)、HR、中心静脉压(CVP)、国际标准化比(INR)、活化部分凝血酶时间(APTT)、凝血时间(CT)、血浆纤维蛋白原含量(FIB)组内差异无统计学意义,且组间差异也无统计学意义(均P >0.05).两组AHH治疗后红细胞计数(RBC)、红细胞比容(Hct)、血红蛋白(Hb) Hct及Hb较治疗前均有所下降(均P<0.05),组间差异无统计学意义(P>0.05).两组AHH治疗后心脏指数(CI)及凝血指标[凝血酶原时间(PT)]较治疗前均有所增加(均P <0.05),组间差异无统计学意义(P>0.05).结论 HES 200/0.5在AHH治疗过程中不会对小儿血流动力学及凝血功能产生不良影响. 相似文献
999.
Background and hypothesis: Supraventricular tachycardia and ventricular tachycardia are often observed in patients with hypertrophic cardiomyopathy (HCM) and they often alter the clinical features of HCM. We examine the influence of supra-ventricular tachycardia on cardiac function and assess the clinical characteristics of patients with HCM. Methods: We studied 32 patients with HCM and 8 normal volunteers using echocardiography under transesophageal rapid atrial pacing. Results: Presyncope-associated hypotension was observed during rapid atrial pacing in 8 HCM patients, but in none of the normal controls. During rapid atrial pacing (144 ± 8 beats/min in HCM, 146 ± 5 beats/min in controls), systolic blood pressure (SBP), the product of left ventricular filling volume (FV) and heart rate, and fractional shortening (%FS) in the HCM patients decreased significantly compared with the basal values (138 ± 19 mmHg vs. 99 ± 24 mmHg, 5.0 ± 1.21/min vs. 2.9 ± 0.91/min, 41.7 ± 6.2 % vs. 35.2 ± 6.0%, respectively), but these decreases were not observed in normal controls. The decrement of SBP during rapid atrial pacing in HCM patients with a history of syncope was more marked than that in those without such history. The decrement correlated positively with the indices of left ventricular hypertrophy (maximal wall thickness and wall thickness index) and with %FS, and correlated negatively with the endsystolic left ventricular diameter at rest. Conclusions: In some patients with HCM, supraventricular tachycardia causes marked hemodynamic deterioration that may be related to a history of syncope, marked hypertrophy, hyperkinesis, small cavity size, and small filling volume of the left ventricle. 相似文献
1000.