全文获取类型
收费全文 | 37744篇 |
免费 | 3211篇 |
国内免费 | 2714篇 |
出版年
2024年 | 62篇 |
2023年 | 460篇 |
2022年 | 848篇 |
2021年 | 2062篇 |
2020年 | 1301篇 |
2019年 | 1660篇 |
2018年 | 1591篇 |
2017年 | 1160篇 |
2016年 | 1594篇 |
2015年 | 2341篇 |
2014年 | 2755篇 |
2013年 | 3062篇 |
2012年 | 3447篇 |
2011年 | 3164篇 |
2010年 | 1938篇 |
2009年 | 1657篇 |
2008年 | 1999篇 |
2007年 | 1717篇 |
2006年 | 1523篇 |
2005年 | 1280篇 |
2004年 | 1093篇 |
2003年 | 958篇 |
2002年 | 853篇 |
2001年 | 593篇 |
2000年 | 524篇 |
1999年 | 532篇 |
1998年 | 335篇 |
1997年 | 329篇 |
1996年 | 333篇 |
1995年 | 312篇 |
1994年 | 299篇 |
1993年 | 202篇 |
1992年 | 312篇 |
1991年 | 216篇 |
1990年 | 179篇 |
1989年 | 180篇 |
1988年 | 112篇 |
1987年 | 103篇 |
1986年 | 81篇 |
1985年 | 98篇 |
1984年 | 47篇 |
1983年 | 50篇 |
1982年 | 42篇 |
1981年 | 38篇 |
1980年 | 32篇 |
1979年 | 23篇 |
1978年 | 17篇 |
1976年 | 20篇 |
1975年 | 14篇 |
1974年 | 19篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
941.
Di Zhang Yamin Li Liang Xu Maosheng Cheng Ying Zhou Junlin He 《Nucleosides, nucleotides & nucleic acids》2013,32(10):734-747
Tert-butyldiphenylsilyl (TBDPS) was testified to be an appropriate orthogonal protecting group for novel 7-hydroxyl-functionalized 8-aza-7-deaza-2′-deoxyadenosine analogues. It was stable in partial and complete hydrogenation reactions used for the different linker preparation. The corresponding phosphoramidites and hydroxyl-functionalized oligodeoxynucleotides were synthesized and identified. The thermal effect of the hydroxyl group with different linkers on DNA duplexes was evaluated. It provided a feasible strategy for the preparation of hydroxyl-functionalized DNAs for the nucleic acid research. 相似文献
942.
Isabelle Barber-Peoc'h Muthiah Manoharan P. Dan Cook 《Nucleosides, nucleotides & nucleic acids》2013,32(7-9):1407-1410
Abstract The drug properties of antisense and antigene oligonucleotides can he enhanced by strategic positioning of ligands capable of ameliorating these properties.1,2 Certain ligands may improve the cellular delivery of oligomers and increase their affinity for the target gene and resistance to nucleases. The 2′-O-position is an attractive modification site.3 Oligonucleotides possessing the 2′-O-akyl modifications exhibit higher chemical stability under depurination conditions, higher stability to enzymatic cleavage by both endo- and exonucleases, and increased affinity for target mRNA. In addition, they form highly stable triple helices. Thus they promise to be versatile compounds in controlling gene expression by antisense and antigene technologies. 相似文献
943.
Yang Liu Gaofeng Liu Zhiwen Li Wei Rong Jianping Yu Ying Zhou 《Nucleosides, nucleotides & nucleic acids》2013,32(10):645-655
T-Hg-T base pair formation has been demonstrated to be compatible with duplex DNA context, with considerable thermal stability contribution. Here, the T-Hg-T stem in two small DNAzymes 8–17 and 10–23 was studied for its structural and functional roles. The recognition arm 5′ to the cleavage site of 10–23 DNAzyme complex and the stem in the catalytic loop of 8–17 DNAzyme could be replaced by consecutive T-Hg-T stem of different length. The linear relationship between the activity of the complex 10–23DZ-6T+D19–6T and the concentration of Hg2+ demonstrated that the T-Hg-T stem contributes thermal stability of the recognition arm binding. The effect of T-Hg-T stem in the catalytic core of 8–17 DNAzyme and the position-dependent effect in 10–23 DNAzyme demonstrated that T-Hg-T base pair is not compatible with canonical base pairs in playing the functions of nucleic acids. 相似文献
944.
Melanie Köllmer Carmen Popescu Prashanth Manda Leon Zhou Richard A. Gemeinhart 《AAPS PharmSciTech》2013,14(4):1333-1340
Pharmaceutical excipients contain reactive groups and impurities due to manufacturing processes that can cause decomposition of active drug compounds. The aim of this investigation was to determine if commercially available oral disintegrating tablet (ODT) platforms induce active pharmaceutical ingredient (API) degradation. Benzocaine was selected as the model API due to known degradation through ester and primary amino groups. Benzocaine was either compressed at a constant pressure, 20 kN, or at pressure necessary to produce a set hardness, i.e., where a series of tablets were produced at different compression forces until an average hardness of approximately 100 N was achieved. Tablets were then stored for 6 months under International Conference on Harmonization recommended conditions, 25°C and 60% relative humidity (RH), or under accelerated conditions, 40°C and 75% RH. Benzocaine degradation was monitored by liquid chromatography–mass spectrometry. Regardless of the ODT platform, no degradation of benzocaine was observed in tablets that were kept for 6 months at 25°C and 60% RH. After storage for 30 days under accelerated conditions, benzocaine degradation was observed in a single platform. Qualitative differences in ODT platform behavior were observed in physical appearance of the tablets after storage under different temperature and humidity conditions. 相似文献
945.
Stereoselective synthesis of antiviral synguanol (1) is described. Reaction of 6-benzyloxy-2-(dimethylaminomethyleneamino)purine (10) with ethyl (cis,trans)-2-chloro-2-(chloromethyl) cyclopropane-1-carboxylate (2c) under the conditions of alkylation-elimination gave (Z)-6- benzyloxy-2-formylamino-9-[(2-carbethoxycyclopropylidene)methyl]purine (11) but no E,N9-isomer. Minor amounts of (Z)-6-benzyloxy-2-formylamino-7-[(2-carbethoxy-cyclopropylidene)methyl]purine (13) were also obtained. Hydrolysis of compounds 11 and 13 in 80% acetic acid afforded (Z)-9-[2-(carbethoxycyclopropylidene)methyl]guanine (14) and (Z)-7-[2-(carbethoxy- cyclopropylidene)methyl]guanine (15). Reduction of 14 furnished synguanol (1). Reaction of N4-acetylcytosine (7) with ester 2c led to (Z,E)-1-(2-carbethoxycyclopropropylidenemethyl)cytosine (8, Z/E ratio 6.1:1). Basicity of purine base, lower reactivity of alkylation intermediates as well as interaction of the purine N3 or cytosine O2 atoms with the carbonyl group of ester moiety seem to be essential for the observed high stereoselectivity of the alkylation-elimination. The Z-selectivity is interpreted in terms of E1cB mechanism leading to a transitory “cyclic” cyclopropenes which undergo a cyclopropene-methylenecyclopropane rearrangement. 相似文献
946.
You-Bin Si Yan Xiang Chao Tian Xiong-Yuan Si Jing Zhou Dong-Mei Zhou 《Soil & Sediment Contamination》2013,22(1):72-84
Glyphosate [N-(phosphonomethyl)-glycine] is a herbicide widely used in large quantities in agricultural applications. It is also known to form complexes with metal ions, although its influence on metal behavior, such as lead (Pb) in soil, is not well understood. In this study, the adsorption and co-adsorption of Pb and glyphosate were determined on two soils [a red (RS) soil, Udic Ferrisol, and a yellow-brown (YB) soil, Udic Luvisol] of distinctly different chemical characteristics at varying pH conditions. Results indicate that the adsorption of lead and glyphosate strongly depends on soil types: the RS soil, characterized by a relatively high iron/aluminum content but a low pH and organic matter content, shows a much lower adsorption capacity for Pb but a higher sorption for glyphosate than the YB soil. The co-existence of Pb and glyphosate in soils resulted in complex interactions among Pb, glyphosate, Pb-glyphosate complexes, and soil minerals. The presence of glyphosate decreased Pb adsorption on the two soils, which was attributed primarily to the formation of soluble Pb-glyphosate complexes having relatively low affinities to soil surfaces. On the other hand, addition of Pb increased the adsorption of glyphosate on both soils, which was attributed to: (1) a decreased solution pH due to the ion exchange between Pb2+ and H+ on soil surfaces; and (2) increased sorption sites where Pb was adsorbed and acted as a bridge between glyphosate and the soil. The present study illustrates that the complex interactions among glyphosate, Pb, and soil may have important implications for the mobility and bioavailability of Pb in soil and should thus be considered in future environmental risk assessments. 相似文献
947.
Haohao Zhang Meiwan Chen Zixin He Zhouhua Wang Meimei Zhang Zhouyang He Qian Wan Dan Liang Michael A. Repka Chuanbin Wu 《AAPS PharmSciTech》2013,14(1):10-18
The aim of the present study was to prepare a stable complex of doxycycline (Doxy) and hydroxypropyl-β-cyclodextrin (HPβCD) for ophthalmic delivery and investigate the inclusion mechanism and the inclusion effects on the stability of Doxy. The Doxy/HPβCD complex was prepared by solution stirring and then characterized by scanning electron microscopy and ultraviolet spectroscopy. Based on results of nuclear magnetic resonance, molecular model of Doxy/HPβCD complex was established using computational simulation of PM3 method implemented in Gaussian 03. Stabilities of Doxy/HPβCD complex in both aqueous solution and solid state at 25°C were evaluated by HPLC. Finally, in vitro antibacterial activity of the Doxy/HPβCD complex was evaluated by disk diffusion test. It was found that the stabilities of Doxy/HPβCD complex in both aqueous solution and solid state were improved obviously as compared with Doxy alone. This stability enhancement is consistent with the inclusion mechanism between HPβCD and Doxy, which showed that the unstable site of Doxy molecule at 6-CH3 was protected in the hydrophobic cavity of HPβCD, additionally, the chelation of Mg2+ provided a synergetic protection of the other unstable site of Doxy at 4-N(CH3)2. The antibacterial activity results indicated that Doxy/HPβCD complex might have potential for clinical applications. 相似文献
948.
949.
Peng Zheng Ying Wang Liang Chen Deyu Yang Huaqing Meng Dezhi Zhou Jiaju Zhong Yang Lei N. D. Melgiri Peng Xie 《Molecular & cellular proteomics : MCP》2013,12(1):207-214
Major depressive disorder (MDD) is a widespread and debilitating mental disorder. However, there are no biomarkers available to aid in the diagnosis of this disorder. In this study, a nuclear magnetic resonance spectroscopy–based metabonomic approach was employed to profile urine samples from 82 first-episode drug-naïve depressed subjects and 82 healthy controls (the training set) in order to identify urinary metabolite biomarkers for MDD. Then, 44 unselected depressed subjects and 52 healthy controls (the test set) were used to independently validate the diagnostic generalizability of these biomarkers. A panel of five urinary metabolite biomarkers—malonate, formate, N-methylnicotinamide, m-hydroxyphenylacetate, and alanine—was identified. This panel was capable of distinguishing depressed subjects from healthy controls with an area under the receiver operating characteristic curve (AUC) of 0.81 in the training set. Moreover, this panel could classify blinded samples from the test set with an AUC of 0.89. These findings demonstrate that this urinary metabolite biomarker panel can aid in the future development of a urine-based diagnostic test for MDD.Major depressive disorder (MDD)1 is a debilitating mental disorder affecting up to 15% of the general population and accounting for 12.3% of the global burden of disease (1, 2). Currently, the diagnosis of MDD still relies on the subjective identification of symptom clusters rather than empirical laboratory tests. The current diagnostic modality results in a considerable error rate (3), as the clinical presentation of MDD is highly heterogeneous and the current symptom-based method is not capable of adequately characterizing this heterogeneity (4). An approach that can be used to circumvent these limitations is to identify disease biomarkers to support objective diagnostic laboratory tests for MDD.Metabonomics, which can measure the small molecules in given biosamples such as plasma and urine without bias (5), has been extensively used to characterize the metabolic changes of diseases and thus facilitate the identification of novel disease-specific signatures as putative biomarkers (6–10). Nuclear magnetic resonance (NMR) spectroscopy–based metabonomic approaches characterized by sensitive, high-throughput molecular screening have been employed previously in identifying novel biomarkers for a variety of neuropsychiatric disorders, including stroke, bipolar disorder, and schizophrenia (11–13).Specifically with regard to MDD, several animal studies have already characterized the metabolic changes in the blood and urine (14–19). These studies provide valuable clues as to the pathophysiological mechanism of MDD. However, no study has been designed with the aim of diagnosing this disease. Recently, using an NMR-based metabonomic approach, this research group identified a unique plasma metabolic signature that enables the discrimination of MDD from healthy controls with both high sensitivity and specificity (20). These findings motivated further study on urinary diagnostic metabolite biomarkers for MDD, which would be more valuable from a clinical applicability standpoint, as urine can be more non-invasively collected. Moreover, previous studies have also demonstrated the feasibility of identifying diagnostic metabolite biomarkers of psychiatric disorders in the urine. For example, using an NMR-based metabonomics approach, Yap et al. (21) identified a unique urinary metabolite signature that clearly discriminated autism patients from healthy controls. As systemic metabolic disturbances have been observed in the urine of a depressed animal model, it is likely that diagnostic metabolite markers for MDD can be detected in human urine.Therefore, in this study, NMR spectroscopy combined with multivariate pattern recognition techniques were used to profile 82 first-episode drug-naïve MDD subjects and 82 healthy controls (the training set) in order to identify potential metabolite biomarkers for MDD. Furthermore, 44 unselected MDD subjects and 52 healthy controls (the test set) were employed to independently validate the diagnostic performance of these urinary metabolite biomarkers. 相似文献
950.
Liwei Ren Honghua Jia Min Yu Wenzhong Shen Hua Zhou Ping Wei 《Biotechnology and Bioprocess Engineering》2013,18(5):888-896
Candida rugosa lipase (CRL) is one of the most widely used lipases. To enhance the catalytic abilities of CRL in both aqueous and non-aqueous phases, hollow silica microspheres (HSMSs) with a pore size of 18.07 nm were used as an immobilization support, and aldehydecontaining dextrans were employed to further cross-link the adsorbed CRL. In the experimental ranges examined, the loading amount of lipase linearly increased to 171 ± 3.4 mgprotein/gsupport with the CRL concentration and all the adsorption equilibriums were reached within 30 min. After simple cross-linking, the tolerance to pH 4.0 ~ 8.0 as well as the thermal stability of immobilized CRL at 40 ~ 80°C were both substantially increased, and 82 ± 2.1% activity remaining after the sixth reuse. The immobilized CRL was successfully applied to the resolution of racemic ibuprofen in non-aqueous phase. The initial reaction rate increased by 1.4- and 3.6-fold compared with the rates of adsorbed and native lipases, respectively. Furthermore, the R-ibuprofen was obtained at ee > 93%, and the enantiomeric ratio reached E > 140 at the conversion of 50 ± 1.5% within 48 h. 相似文献