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991.
Lidia Szulc-Dąbrowska Piotr Wojtyniak Justyna Struzik Felix N. Toka Anna Winnicka Małgorzata Gieryńska 《Immunological investigations》2019,48(4):392-409
Ectromelia virus (ECTV) is the etiological agent of mousepox, an acute and systemic disease with high mortality rates in susceptible strains of mice. Resistance and susceptibility to mousepox are triggered by the dichotomous T-helper (Th) immune response generated in infected animals, with strong protective Th1 or nonprotective Th2 profile, respectively. Th1/Th2 balance is influenced by dendritic cells (DCs), which were shown to differ in their ability to polarize naïve CD4+ T cells in different mouse strains. Therefore, we have studied the inner-strain differences in the ability of conventional DCs (cDCs), generated from resistant (C57BL/6) and susceptible (BALB/c) mice, to stimulate proliferation and activation of Th cells upon ECTV infection. We found that ECTV infection of GM-CSF-derived bone marrow (GM-BM) cells, composed of cDCs and macrophages, affected initiation of allogeneic CD4+ T cells proliferation in a mouse strain-independent manner. Moreover, infected GM-BM cells from both mouse strains failed to induce and even inhibited the production of Th1 (IFN-γ and IL-2), Th2 (IL-4 and IL-10) and Th17 (IL-17A) cytokines by allogeneic CD4+ T cells. These results indicate that in in vitro conditions ECTV compromises the ability of cDCs to initiate/polarize adaptive antiviral immune response independently of the host strain resistance/susceptibility to lethal infection. 相似文献
992.
993.
Andrey V. Marakhonov Andreas Brodehl Roman P. Myasnikov Peter A. Sparber Anna V. Kiseleva Olga V. Kulikova Alexey N. Meshkov Anastasia A. Zharikova Serguey N. Koretsky Maria S. Kharlap Caroline Stanasiuk Elena A. Mershina Valentin E. Sinitsyn Alexey O. Shevchenko Natalia P. Mozheyko Oksana M. Drapkina Sergey A. Boytsov Hendrik Milting Mikhail Yu. Skoblov 《Human mutation》2019,40(6):734-741
Mutations in DES, encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. The genetic analysis revealed a novel small in‐frame deletion within the DES gene, p.Q113_L115del, affecting the α‐helical rod domain. Immunohistochemistry analysis of explanted myocardial tissue from the index patient revealed an abnormal cytoplasmic accumulation of desmin and a degraded sarcomeric structure. Cell transfection experiments with wild‐type and mutant desmin verified the cytoplasmic aggregation and accumulation of mutant desmin. Cotransfection experiments were performed to model the heterozygous state of the patients and revealed a dominant negative effect of the mutant desmin on filament assembly. DES:p.Q113_L115del is classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT. 相似文献
994.
尼拉帕尼(Niraparib,商品名ZejulaTM)是聚腺苷二磷酸-核糖聚合酶(PARP)的口服小分子抑制剂,PARP抑制是治疗由DNA修复基因(如BRCA1和BRCA2)特异性畸变引起的DNA修复机制缺陷的癌症的有效策略。尼拉帕尼于2017年3月在美国获批,维持治疗复发性上皮性卵巢癌、输卵管癌、原发性腹膜癌的成年患者,这些患者对铂类化疗有完全或部分反应,推荐剂量为口服300 mg/d,直到疾病发生恶化或产生无法接受的不良反应。临床研究结果表明该药可以延长患者的无恶化生存期,为治疗卵巢癌提供了有效和可靠的治疗手段。 相似文献
995.
目的 考察2-脱氧葡萄糖(2-DG)联合二甲双胍(Met)协同抗人肝癌HepG2细胞作用并探索其机制。方法 刃天青法测定2-DG及Met单独及联合应用对HepG2细胞的生长抑制作用,利用金氏公式计算联合用药Q值;利用高内涵细胞成像系统考察单独及联合用药对细胞线粒体膜电位及活性氧产生的影响;Western blotting检测Cleave-Caspase 3、p-AMPK及p-mTOR的蛋白变化;考察AMPK及mTOR抑制剂对联合用药后细胞生长抑制作用的影响。结果 2-DG、Met单独应用的IC50值分别为2.45及16.35 mmol/L,联合用药对细胞生长抑制具有协同作用,Q值均大于1.15;联合用药能显著降低细胞内线粒体膜电位及p-mTOR蛋白表达,显著增加细胞内活性氧产生及Cleave-Caspase3、p-AMPK蛋白表达;抑制AMPK或mTOR能显著增加联合用药对细胞的生长抑制作用(P<0.05、0.01)。结论 2-DG联合Met具有协同抑制HepG2细胞增殖作用,其机制与降低细胞线粒体膜电位,促进活性氧产生、细胞凋亡,以及非AMPK依赖性的抑制mTOR活化有关。 相似文献
996.
Felipe J. Cavichioli Graylin N.B. Bernal Iandra Holzmann Juliana Bagatini Klein Ricardo Escarcena Esther Del Olmo Arturo San Feliciano Valdir Cechinel Filho Nara L.M. Quintão 《Pharmacological reports : PR》2018,70(4):753-759
Background
The study evaluated the effects of two sphingosine derivatives N-(2-tert-butoxycarbamylhexadecyl)glutaramide (AA) and N-(1-benzyloxyhexadec-2-yl)glutaramide (OA) in different models of hypersensitivity in mice.Methods
Male Swiss mice were orally pre-treated with AA or OA (0.3–3 mg/kg). After 1 h, they received λ-carrageenan (300 μg/paw), lipopolysaccharide (LPS; 100 ng/paw), bradykinin (BK; 500 ng/paw) or prostaglandin E2 (PGE2; 0.1 nmol/paw) or epinephrine (100 ng/paw), and the mechanical withdrawal thresholds were evaluated using von Frey filament (0.6 g) at different time points. The effect of the compounds against inflammatory and neuropathic pain was also evaluated using complete Freund’s adjuvant (CFA), or by performing partial sciatic nerve ligation (PSNL).Results
Animals pre-treated with AA and OA reduced hypersensitivity induced by carrageenan, LPS and BK, and modest inhibition of PGE2-induced hypersensitivity and carrageenan-induced paw oedema were observed in mice treated with OA. Though the partial effect presented by AA and OA, when dosed once a day, both compounds were able to significantly reduce the persistent inflammatory and neuropathic pain induced by CFA and PSNL, respectively.Conclusion
These results demonstrate that the sphingosine derivatives AA and OA present important anti-hypersensitive effects, suggesting a possible interaction with the kinin signalling pathway. This may represent an interesting tool for the management of acute and chronic pain, with good bioavailability and safety. 相似文献997.
Relationship between Optimum Mini‐doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes – A Simulation Study 下载免费PDF全文
Ajenthen Ranjan Sabrina L. Wendt Signe Schmidt Sten Madsbad Jens J. Holst Henrik Madsen Carsten B. Knudsen John B. Jørgensen Kirsten Nørgaard 《Basic & clinical pharmacology & toxicology》2018,122(3):322-330
Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin‐dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose–insulin–glucagon model was used to describe seven virtual patients with insulin pump‐treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba‐insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre‐defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125‐μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba‐insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model‐based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin‐dependent glucagon dosing regimen for treatment of insulin‐induced mild hypoglycaemia in patients with type 1 diabetes. 相似文献
998.
A validated,sensitive electrophoretic method for the detection of activin receptor type II‐Fc fusion proteins in human blood 下载免费PDF全文
New therapeutic proteins that trap circulating members of the transforming growth factor (TGF) beta superfamily (activins and growth differentiation factors) show promising effects on erythropoiesis and muscular growth. They are dimeric recombinant fusion proteins composed of the extracellular domain of a human activin receptor (ActRIIA or IIB) linked to the Fc part of human IgG1. Sotatercept (ActRIIA‐Fc) and Luspatercept (a modified ActRIIB‐Fc) in particular are now in phase 2/3 of clinical trials against anemia and included in the prohibited list established by the World Anti‐Doping Agency. To prevent a potential misuse by athletes in the near future, a robust and sensitive method of detection is needed. We validated an approach adapted from an electrophoretic method used for the detection of recombinant erythropoietins that allowed detection of various ActRIIA‐Fc and ActRIIB‐Fc proteins, including variants produced in different cell types, after a single immuno‐extraction step. After separation by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE), an initial testing procedure performed by single‐blotting can indicate the presence of an ActRII‐Fc (indifferently type IIA or IIB). A confirmation performed by double‐blotting using different antibodies for detection allows a more precise identification of the type of ActRII‐Fc (IIA, IIB). Starting from a few hundred microliters of serum or plasma, this method is specific, sensitive, and easy to perform. It could easily be adopted by anti‐doping laboratories. 相似文献
999.
目的 建立白桦茸多糖含量测定方法,比较不同部位多糖含量及抗疲劳作用。方法 采用紫外分光光度法测定比较不同部位多糖含量,小鼠负重力竭游泳实验比较不同部位抗疲劳作用。结果 重复性RSD=1.77%(n=6),加样回收率为99.93%,RSD=1.96%(n=6)。白桦茸菌肉多糖含量3.18%,外壳含量8.57%。与空白组比较,菌肉与外壳组小鼠负重游泳力竭时间显著延长。结论 该方法准确、简便,可用于白桦茸多糖含量测定。外壳多糖含量显著高于菌肉,白桦茸外壳提升正常小鼠抗疲劳能力较菌肉强。 相似文献
1000.
目的 比较了红旱莲药材不同部位(茎、叶、花、果)中金丝桃苷的含量差异。方法 采用高效液相色谱法进行测定,采用C18(4.6 mm×250 mm,5 μm)色谱柱,乙腈-0.1%磷酸为流动相,360 nm为检测波长,流速为1.0 mL·min-1,柱温30 ℃。结果 金丝桃苷的线性范围为2.904~58.08 μg·mL-1,相关系数r=0.999 8,平均回收率为 95.1%,RSD为1.3%;红旱莲药材不同部位(茎、叶、花、果)中金丝桃苷的含量分别为0.405、3.221、2.260、0.371 mg·g-1。结论 红旱莲中不同部位中金丝桃苷含量具有显著差异,叶中含量最高。 相似文献