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991.
Dolman ME Fretz MM Segers GJ Lacombe M Prakash J Storm G Hennink WE Kok RJ 《International journal of pharmaceutics》2008,364(2):249-257
Activation of proximal tubular cells by fibrotic and inflammatory mediators is an important hallmark of chronic kidney disease. We have developed a novel strategy to intervene in renal fibrosis, by means of locally delivered kinase inhibitors. Such compounds will display enhanced activity within tubular cells and reduced unwanted systemic effects. In our approach kinase inhibitors are linked to the renal carrier lysozyme using a platinum-based linker that binds drugs via a coordinative linkage. Many kinase inhibitors contain aromatic nitrogen atoms able to bind to this linker without the need of prior derivatization. The resulting drug-lysozyme conjugates are rapidly filtered in the glomerulus into the tubular lumen and subsequently reabsorbed via the endocytic pathway for clearance of low-molecular weight proteins. An important property of the formed conjugates is their in vivo stability and the sustained drug release profile within target cells. This review summarizes the state-of-the-art of drug targeting to the kidney. Furthermore, we will highlight recent results obtained with kinase inhibitor-lysozyme conjugates targeted to different kinases, i.e. the transforming growth factor (TGF)-beta-receptor kinase, p38 MAPkinase and Rho-associated kinase. Both in vitro and in vivo results demonstrated their efficient tubular uptake and beneficial therapeutic effects, superior to treatment with free kinase inhibitors. These proof-of-concept studies clearly indicate the feasibility of drug targeting for improving the renal specificity of kinase inhibitors. 相似文献
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Micro‐Focus X‐Ray Tomography Study of the Microstructure and Morphometry of the Eggshell of Ostriches (Struthio Camerus)
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Bronwyn Willoughby Lindi Steyn Lunga Bam Adriaan J. Olivier Richard Devey John N. Maina 《Anatomical record (Hoboken, N.J. : 2007)》2016,299(8):1015-1026
In ostrich husbandry, economic losses have mainly been attributed to low hatchability of eggs, which has mostly been attributed to the structure of the eggshell. The main aim of this study was to investigate the morphology and the morphometry of the ostrich eggshell using micro‐focus X‐ray computer tomography and scanning electron microscopy. The mean weight and volume of the eggs were 1,312 ± 56SE g and 1,333 ± 44SE cm3, respectively. The mean thickness and the mean surface area of the eggshell was 1.83 ± 0.10SE mm and 619 ± 15SE cm2 respectively and the mean total number of pores in the shell was 40,596 ± 1832SE. No significant correlations were found between the thickness of the shell and the weight of the eggs, the volume of the egg and the thickness of the shell, the diameter of the pores and the number of pores, the volume of the pores and the number of pores or the surface area of the pores and the number of pores. The mean diameters of the pores on the blunt (air cell) ? (0.02 ± 0.04SE mm) and the sharp (0.26 ± 0.36SE mm) parts of the eggshell were significantly different (P = 0.0001) while the mean volumes and the surface areas of the pores in these parts were not significantly different (P = 0.203 and P = 0.089, respectively). The sizes of the pores differed in different parts of the eggshell, which consisted mainly of tightly arranged mammillary cones that that fused to the palisade columns. The external surface of the ostrich eggshell was covered by a cuticle. Anat Rec, 299:1015–1026, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
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目的揭示正常日本大耳白兔同步12导联心电图特征,为心血管疾病的实验研究提供心电图基本数据。方法雄性日本大耳白兔55只,20%乌拉坦腹腔麻醉,描记兔同步12导联心电图,并拍胸部X线正位片。结果心电图:1日本大耳白兔心电图波形与人类相似,均为窦性心律。心率较快,265.5±36.8次/min,未见心律失常发生;2仰卧位平均心电轴:19°~250°,波动范围较大;3 P波:形态钝圆或略尖,均符合窦性P波规律,在肢体Ⅱ、a VF导联及胸导联较为明显;4 P-R间期:(0.063±0.007)s;5 QRS波:QRS波时间为(0.040±0.005)s,主波在Ⅱ、Ⅲ、a VF导联多数向上,胸导联与人类相似,R/S比值逐渐递增;6 ST段:较短,均位于等电位线;7 T波:T波形态多圆顿,部分双峰,多数导联T波直立,部分倒置,平坦或双向。T波在肢体II、III、a VR、a VF及胸导联较为明显;8 QT间期:QT间期(0.142±0.015)s,QTc(0.306±0.034)s。胸部X线正位片:心影大多位于胸腔正中及右侧。结论获得了兔标准12导联心电图波形及其各波段的正常值范围,在心血管疾病的实验研究中具有一定的应用价值。 相似文献
997.
Context and objectives: Since most of developed therapeutic proteins are intended to treat chronic diseases, patients are prescribed multiple injections for long time periods, and therefore, sustained release formulations are much needed. However, challenges facing these formulations are quite significant. In this context, a model protein, lysozyme (Lys), was loaded on hydrogel microparticles (beads) and the ability of layer-by-layer (LbL) coating to control Lys release and maintain its activity over a one-month period was investigated.Methods: LbL coating was composed of chondroitin sulfate as a negatively charged polyelectrolyte and a biocompatible, hydrolytically degradable poly β-aminoester as a positively charged polyelectrolyte. Loading distribution was monitored by fluorescence imaging, and followed by depositing a series of LbL coatings of different thicknesses. Release of Lys from these formulations was studied and activity of released fraction was determined.Results: Lys was loaded effectively on hydrogel beads achieving about 9?mg protein/100?mg wet spheres. LbL coating was proven successful by monitoring the zeta potential of the beads, which was reversed after the addition of each layer. In vitro release studies showed sustained release profiles that depend on the thickness of the deposited coat, with t50 extended from 4.9 to 143.9?h. More importantly, released Lys possessed a high degree of biological activity during the course of release maintaining at least 72% of initial activity.Conclusions: Successful loading of Lys and extension of its release while maintaining a considerable degree of activity might make this formulation suitable for use with other active therapeutic proteins. 相似文献
998.
Bahman Asgharian Owen Price Senthil Kabilan Richard E. Jacob Daniel R. Einstein Andrew P. Kuprat 《Inhalation toxicology》2016,28(2):80-88
Despite using rabbits in several inhalation exposure experiments to study diseases such as anthrax, there is a lack of understanding regarding deposition characteristics and fate of inhaled particles (bio-aerosols and viruses) in the respiratory tracts of rabbits. Such information allows dosimetric extrapolation to humans to inform human outcomes. The lung geometry of the New Zealand white rabbit (referred to simply as rabbits throughout the article) was constructed using recently acquired scanned images of the conducting airways of rabbits and available information on its acinar region. In addition, functional relationships were developed for the lung and breathing parameters of rabbits as a function of body weight. The lung geometry and breathing parameters were used to extend the existing deposition model for humans and several other species to rabbits. Evaluation of the deposition model for rabbits was made by comparing predictions with available measurements in the literature. Deposition predictions in the lungs of rabbits indicated smaller deposition fractions compared to those found in humans across various particle diameter ranges. The application of the deposition model for rabbits was demonstrated by extrapolating deposition predictions in rabbits to find equivalent human exposure concentrations assuming the same dose-response relationship between the two species. Human equivalent exposure concentration levels were found to be much smaller than those for rabbits. 相似文献
999.
Flaxseeds are both a food ingredient and a natural source of antioxidants (e.g. lignans, PUFAs) and pro-oxidant contaminants (e.g. cadmium): the variable mixture of anti- and pro-oxidant substances may impact on the redox homeostasis of flaxseed-enriched foods. The antioxidant power is studied here as biochemical activity of flaxseeds in white wheat bread and as endpoint for possible screening of anomalous variations of bioactive mixtures (antioxidants vs. prooxidants) in food matrices.A bioprobe assay based on the superoxide dismutase (SOD) enzyme (6 channels of the multiprobe bioelectronic platform BEST) was performed on white wheat bread with and without flaxseeds. Nine BEST channels were simultaneously used for validation and monitoring of measuring conditions (temperature, pH, conductivity). Findings were compared with quantitative analysis of antioxidants and pro-oxidant contaminants. Organic and aqueous extracts of both bread types were examined in parallel.The SOD-probe detected the difference in antioxidant power given by 10% flaxseed, thus supporting the use of antioxidant power detected by bioenzymatic screening as sensitive biochemical endpoint. Mixtures of bioactive molecules in foods generate biochemical activities that can be monitored as time-effective indicators of invariability, which is pivotal in the daily control of anomalies in food production and therefore in the protection of consumers′ health. 相似文献
1000.
目的 探讨兔心包液内的细胞成分及其分化潜能,为心包液细胞基础研究和临床应用提供形态学依据。 方法 成年新西兰大白兔 30 只, 无菌开胸,用输液针软管抽取心包液,离心培养。取不同培养代次细胞,倒置显微镜下行细胞形态观察。利用免疫荧光技术对心包液细胞进行免疫显色,观察CD44、CD45、波形蛋白(vimentin)的表面标记。取第3代细胞进行成骨、成脂诱导。利用 PCR技术检测CD44、CD45、vimentin相关分子表达情况及分析表达量的差异。结果 成年兔心包液中含有形态较为均匀、生长状态良好、增殖能力强的细胞群。免疫荧光结果显示,CD44、vimentin阳性表达, 不表达CD45。成脂和成骨诱导后,可向成骨和成脂细胞分化。 结论 兔心包液中含有多项分化潜能的细胞,它们可能对心肌修复具有积极意义。 相似文献