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111.
Characterization of a selective and potent antagonist of human P2X(7) receptors, AZ11645373
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Stokes L Jiang LH Alcaraz L Bent J Bowers K Fagura M Furber M Mortimore M Lawson M Theaker J Laurent C Braddock M Surprenant A 《British journal of pharmacology》2006,149(7):880-887
BACKGROUND AND PURPOSE: The ATP-gated P2X(7) receptor has been shown to play a role in several inflammatory processes, making it an attractive target for anti-inflammatory drug discovery. We have recently identified a novel set of cyclic imide compounds that inhibited P2X(7) receptor-mediated dye uptake in human macrophage THP-1 cells. In this study the actions and selectivity of one of these compounds, AZ11645373, were characterized. EXPERIMENTAL APPROACH: We measured membrane currents, calcium influx, and YOPRO-1 uptake from HEK cells expressing individual P2X receptors, and YOPRO1 uptake and interleukin-1beta release from THP-1 cells in response to ATP and the ATP analogue benzoylbenzoyl ATP (BzATP). KEY RESULTS: AZ11645373 up to 10 microM, had no agonist or antagonist actions on membrane currents due to P2X receptor activation at human P2X(1), rat P2X(2), human P2X(3), rat P2X(2/3), human P2X(4), or human P2X(5) receptors expressed in HEK cells. AZ11645373 inhibited human P2X(7) receptor responses in HEK cells in a non-surmountable manner with K (B) values ranging from 5 - 20 nM, with mean values not significantly different between assays. K (B) values were not altered by removing extracellular calcium and magnesium. ATP-evoked IL-1beta release from lipopolysaccharide-activated THP-1 cells was inhibited by AZ11645373, IC(50) = 90 nM. AZ11645373 was > 500-fold less effective at inhibiting rat P2X(7) receptor-mediated currents with less than 50% inhibition occurring at 10 microM. CONCLUSIONS AND IMPLICATIONS: AZ11645373 is a highly selective and potent antagonist at human but not rat P2X(7) receptors and will have much practical value in studies of human cells. 相似文献
112.
Pigs are considered the most likely source of organs and tissues should the barriers to xenotransplantation be overcome. The use of animal blood for transfusion, xenotransfusion, would have advantages over blood from random human donors with respect to supply and infection control. Large animals such as cows would be more suitable than pigs for blood donation because of easier venous access and large volume phlebotomy. Blood from 12 Holstein cows was typed and then tested for hemagglutination assay (HA), complement mediated lysis (CML), human IgM and IgG antibody binding, anti-human globulin augmented clinical cross-match and osmotic fragility with normal human serum. Results were compared with porcine erythrocytes (pRBC) and with human type O controls (hRBC). The frequency of ultra-low xenoantigen expressors was tested in a larger herd of various breeds using HA and CML. Median HA and CML titers were one of six (no HA-one of 64) and one of 26 (no CML-one of 64), respectively for bovine erythrocytes (bRBC). Hemagglutination titer was significantly higher for pRBC at one of 170 (one of four-one of 1024). HA and CML were lowest with bovine blood group J. Repeated HA and CML were negative with bRBC from one cow that also tested negative by anti-human globulin augmented cross-match with seven of nine random human sera representing the different blood groups. However, flow cytometry showed that bRBC from all cows bound human IgM and IgG. IgM mean channel fluorescence (MCF) was positively correlated with HA titer. The mean corpuscular fragility of pRBC, bRBC, and hRBC was 0.56, 0.48 and 0.41%, respectively. The frequency of HA-negative and CML-negative cows were 20 and 35%, respectively in herds of 49 animals. Bovine RBC elicit variable in vitro responses from human serum but these are uniformly much less than those seen with pRBC. Bovine RBC is more robust than pRBC. These characteristics including the potential ease and volume of blood collection make the cow a more suitable blood donor than the pig. 相似文献
113.
环孢素A血浓度监测在异基因骨髓移植中的意义 总被引:5,自引:0,他引:5
观察69例异基因骨髓移植患者,探讨环孢素A(CsA)谷浓度与急性移植物抗宿主病(aGVHD)和CsA相关毒副作用之间的关系。结果表明,Ⅱ~Ⅳ度aGVHD发生率为36.23%;Ⅱ~Ⅳ度aGVHD的发生与植活时的CsA谷浓度相关(P=0.0318);若谷浓度低于150μg/L,Ⅱ~Ⅳ度aGVHD发生率增加(P<0.05);当CsA谷浓度高于200μg/L时,CsA相关的肝、肾毒副作用发生率明显上升(P<0.05)。认为将CsA谷浓度尤其是植活时的谷浓度维持在150~200μg/L,可以提高CsA的效果,并降低CsA的肝、肾毒副作用发生率。 相似文献
114.
重组合异种骨移植成骨活性及量效关系的实验研究 总被引:7,自引:0,他引:7
观察重组合异种骨的成骨活性及其量效关系。方法采用RBX移植建立BALB/C小鼠股后肌袋模型,术后定期对移植组织进行放射学,病理学及碱性磷酸酶活性检查。结果(1)含不同比例的牛骨形态发生蛋白的RBX组,成活性与bBMP含量呈正相关,存在着剂量依赖关系;(2)RBXI组成骨良好,同样含量的纯bMP组也出现可见的成骨效应,但最终未能成骨;(3)ALP活性以术后7天最高,42例时仍较明显。结论RBX是高效 相似文献
115.
外源基因在巴斯德毕赤酵母中的表达 总被引:1,自引:0,他引:1
酵母是单细胞真核生物 ,既具有类似原核生物的生长特性 ,又具有一般真核生物的细胞生物学特性。巴斯德毕赤酵母是新近发展起来的新型表达系统 ,许多有应用价值的外源基因成功地在其中表达 ,使其日益受到关注。本文就毕赤酵母的生物学特性、表达系统的构建和分泌蛋白的翻译后修饰等方面进行综述 相似文献
116.
117.
新型重组异种骨移植与其同带血循骨膜联合移植治疗兔骨缺损 总被引:3,自引:1,他引:2
目的:探讨新型重组异种骨-复合rhBMP2的异种骨(rhBMP2/BCB)移值及其与带血循骨膜联合移植,修复节段性骨缺损的效果,方法:将基因重组人BMP2(rhBMP2)与去抗原牛松质骨载体(BCB)复合,制成rhBMP2/BCB,并采用桡骨干1.5cm缺损动物模型,通过线,生物力学,骨密度,组织学等检测手段,对单纯rhBMP/2BCB移植方法及其与带血循骨膜联合移植方法进行对比研究,结果:(1)单纯rhBNP2/BCB移植,可在16wk使节段性骨缺损基本修复,其机制与过程与重组合异种相似;(2)rhBMP2/BCB与带血循骨联合移植,双用8wk即可修复骨损损,其修复机制与骨膜联合移植,仅用8wk即可修复骨缺损,其修复机制与骨折修复相仿,包括膜内成骨和软骨成骨两种机制,结论:上述二种方法均可有效地修复节段性骨缺损,但以rhBMP2/BCB与带血循骨膜联合移植较为理想,该方法同时具有良好的骨生成,骨传导和骨诱导作用。 相似文献
118.
H2O2处理大块牛松质骨后成分分析 总被引:2,自引:0,他引:2
目的:研究大块牛松质骨(MBCB)处理后的各种成分及高浓度H2O2消除异种骨抗原性机制,方法:采用干燥失重法及殖渣法检测经过系统去抗原处理后的大块异常骨的有机,无机质及水份含量,将25块大块新鲜牛松质骨均分为5组,分别用高浓度H2O2浸泡0,24,48,72和96h,采用氨基酸分析方法研究不同H2O2处理时间的骨块中羟脯氨酸,脯氨酸含量,结果:经处理后,MBCB为色白,并呈现出多孔样结构,扫描电镜观察,松质骨呈清晰的多孔结构,孔壁光滑,5组检测样品中羟脯氨酸及脯氨酸的含量随有H2O2处理时间的延长均有同步下降的趋势,但各组间无显性差异(P>0.05),5组检测样品中18例氨基酸含量及氨基酸总量随着H2O2处理时间的延长亦有同步下降的趋势,仅0h与96h组间18种氨基酸以及总氨基酸含量有显性差异(P<0.05),其余各组间无显性差异(P>0.05),5组检测样品中羟脯氨酸及脯氨酸在总氨基酸总量所占比例随差H2O2处理时间的延长无明显变化,各组间无显性差异(P>0.05),结论:大块异种骨经系统去抗原处理后,保持了一定的有机及无机质比列,即具有良好的力学特性又消除了其抗原性,提示高氧化剂引起蛋白质变性是消除大块异种骨抗原性的主要原因。 相似文献
119.
Lack of antibody production against Hanganutziu-Deicher (H-D) antigens with N-glycolylneuraminic acid in patients with porcine exposure history 总被引:3,自引:2,他引:1
Kobayashi T Yokoyama I Suzuki A Abe M Hayashi S Matsuda H Morozumi K Breimer ME Rydberg L Groth CG Tibell A Korsgren O Takagi H Nakao A 《Xenotransplantation》2000,7(3):177-180
The significance of non-alphagalactosyl antigens remains unclear in pig-to-primate xenotransplantation. Hanganutziu-Deicher (H-D) antigens with terminal N-glycolylneuraminic acid (NeuGc) are widely expressed on endothelial cells of mammalian species, with the exception of humans. As baboons and monkeys also express H-D antigens, a pig-to-non-human primate experimental model cannot resolve the question of whether H-D antigens can elicit a potent humoral response in human recipients. The purpose of this study was to elucidate the clinical significance of H-D antigens by examining the sera from patients who have been previously exposed to porcine tissue. After the digestion of porcine aortic endothelial cells (PAEC) by neuraminidase, NeuGc and N-acetylneuraminic acid (NeuAc) were quantitated by HPLC. IgG and IgM antibody levels against H-D antigens were measured by NeuGc-GM3-coated ELISA plates in the sera of patients who had undergone ex vivo kidney perfusion 1 to 3 weeks and 2 years previously (n=2) or had been injected with fetal porcine islets 2 months previously (n= 10). HPLC determined that 9.7x 10(7) NeuAc and 6.3x 10(7) NeuGc residues per cell were released from PAEC by neuraminidase, while 25.7x 10(7) NeuAc and an undetectable level of NeuGc were released from human aortic endothelial cells (HAEC). No significant elevation of IgG or IgM antibody levels against NeuGc-GM3 was observed in sera from patients with a history of porcine exposure. Considering the active production of antibody against the foreign galactosyl antigens after pig-to-human xenotransplantation, some production of antibodies against the equally foreign H-D antigens would be expected, because large amounts of NeuGc terminated saccharides are present in the pig endothelial cell surface. However, no production of antibodies directed to H-D antigens could be found in patients exposed to porcine tissue. Further studies are warranted to explain why H-D antigens do not elicit a significant antibody production. 相似文献
120.
微囊化兔坐骨神经组织移植对大鼠脊髓损伤神经元的影响 总被引:2,自引:0,他引:2
目的:观察大鼠脊髓半横断损伤后植入微囊化兔坐骨神经组织对一氧化氮合酶(NOS)表达的影响。方法:尼氏染色和NADPH-d组织化学染色。利用图像分析系统检测染色标记细胞数和阳性细胞平均面积、平均光密度。结果:脊髓损伤后神经元数量减少,尼氏体脱失、溶解。术后3d,微囊组NOS阳性细胞数、阳性细胞平均面积及平均光密度均明显高于单损组;术后7d微囊组NOS阳性细胞数和阳性细胞平均面积较细胞组高;术后14d,细胞组NOS阳性细胞数急剧增高超过微囊组,但微囊组仍平稳上升。结论:微囊化兔坐骨神经组织移植能诱导早期NOS表达增加及抑制后期NO过量产生,减轻脊髓继发性损伤,有利于损伤脊髓的修复和再生。 相似文献