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Amit C Nathwani Cecilia Rosales Jenny McIntosh Ghasem Rastegarlari Devhrut Nathwani Deepak Raj Sushmita Nawathe Simon N Waddington Roderick Bronson Scott Jackson Robert E Donahue Katherine A High Federico Mingozzi Catherine YC Ng Junfang Zhou Yunyu Spence M Beth McCarville Marc Valentine James Allay John Coleman Susan Sleep John T Gray Arthur W Nienhuis Andrew M Davidoff 《Molecular therapy》2011,19(5):876-885
Adeno-associated virus vectors (AAV) show promise for liver-targeted gene therapy. In this study, we examined the long-term consequences of a single intravenous administration of a self-complementary AAV vector (scAAV2/ 8-LP1-hFIXco) encoding a codon optimized human factor IX (hFIX) gene in 24 nonhuman primates (NHPs). A dose–response relationship between vector titer and transgene expression was observed. Peak hFIX expression following the highest dose of vector (2 × 1012 pcr-vector genomes (vg)/kg) was 21 ± 3 µg/ml (~420% of normal). Fluorescent in-situ hybridization demonstrated scAAV provirus in almost 100% of hepatocytes at that dose. No perturbations of clinical or laboratory parameters were noted and vector genomes were cleared from bodily fluids by 10 days. Macaques transduced with 2 × 1011 pcr-vg/kg were followed for the longest period (~5 years), during which time expression of hFIX remained >10% of normal level, despite a gradual decline in transgene copy number and the proportion of transduced hepatocytes. All macaques developed serotype-specific antibodies but no capsid-specific cytotoxic T lymphocytes were detected. The liver was preferentially transduced with 300-fold more proviral copies than extrahepatic tissues. Long-term biochemical, ultrasound imaging, and histologic follow-up of this large cohort of NHP revealed no toxicity. These data support further evaluation of this vector in hemophilia B patients. 相似文献
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目的:观察人胚胎嗅鞘细胞移植治疗额颞叶痴呆的有效性。方法:选择2006-04-04于北京市虹天济神经科学研究院和北京市西山医院暨北京康复中心神经外科就诊患者1例,男性,57岁,因“行为异常,性格及言语改变2年4个月”入院。患者知情同意并签署知情同意书。入院查体双侧Hoffmann征可疑阳性,双侧Babinski征未引出。头颅MRI示双侧额颞叶脑沟、侧裂池增宽,脑实质萎缩明显,诊断为额颞叶痴呆。局麻下对患者进行人胚胎嗅鞘细胞移植术,于双侧额叶放射冠位置分别注射人胚胎嗅鞘细胞约100万个。移植前后使用日常生活活动量表评价患者神经功能。量表包括吃饭、穿衣、购物等20个日常行为活动项目。评分分4级:1级-可由自己完成,无困难;2级-完成有些困难;3级,需要帮助;4级-能力丧失,根本无法完成;如受试者从未做过的项目或无从了解的项目,则记为9,不计入总分。总分20分为正常;>20分为功能低下。结果:术后无任何并发症及不良反应。移植术后3周患者情感、认知方面有所改善。日常生活活动量表与术前比较,分数由43分下降至32分。术后6周电子邮件随访,神经功能继续改善。结论:人胚胎嗅鞘细胞移植后近期可部分改善额颞叶痴呆患者神经系统功能,提高生活质量,其恢复机制和长期效果有待进一步观察。 相似文献
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Purified recombinant human interleukin-11 (rhuIL-11) was assessed for its in vivo effects on the proliferation and differentiation of hematopoietic progenitors as well as its capacity to accelerate the recovery of a drug-suppressed hematopoietic system. Dosage and time sequence studies demonstrated that administration of IL-11 to normal mice resulted in increases in absolute numbers of femoral marrow and splenic myeloid (granulocyte-macrophage colony-forming unit [CFU-GM], burst-forming unit-erythroid [BFU-E], CFU-granulocyte, erythroid, macrophage, megakaryocyte) progenitor cells and in stimulation of these progenitors to a higher cell cycling rate. This was associated with increased numbers of circulating neutrophils. Administration of IL-11 to mice pretreated with cyclophosphamide decreased the time required to regain normal levels of neutrophil and platelet counts in peripheral blood. In addition, IL-11 accelerated reconstitution to normal range of myeloid progenitors from bone marrow and spleen of myelosuppressed mice. These data suggest that IL-11 may play an important role in the regulation of hematopoiesis, and the application of this novel cytokine may have clinical therapeutic benefits. 相似文献
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目的 评价半胱氨酸巯基氧化还原介导剂对人热休克转录因子1(hHSF1)的氧化还原状态、结构和功能的作用,并试图去解释氧化作用在细胞衰老中对hHSF1转录反应的影响。方法 通过改良的Western blot方法检测不同氧化还原介导剂对hHSF1构象的影响;通过凝胶电泳迁移率变动试验检测hHSF1的DNA的结合活性。结果 促进二硫键交联的氧化型介导剂二酰胺(DM)、一氧化氮(NO^ )载体亚硝基谷胱甘肽(GSNO)与含hHSF1的HeLa细胞S100提取液预培育,能在体外形成一个致密的、电泳中移动快速、分子内二硫键交联的氧化型hHSF1(ox-hHSF1)单体构象;在电泳前加入还原型介导剂二硫苏糖醇(DTT)能完全逆转。由于ox-hHSF1形成,使hHSF1在体外不能被热诱导激活形成三体,失去和DNA结合的活性,而且这个作用仅对含半胱氨-酸巯基的转录因子有特异性。结论hHSF1功能反应与其半胱氨酸巯基的氧化还原化学性能相关,氧化作用和hHSF1分子内二硫键交联有可能是衰老细胞热休克转录反应呈渐减性的原因。 相似文献
108.
The genetic sequences encoding the gibbon and human interleukin 3 (IL 3) proteins were molecularly cloned. The amino acid sequence of the mature gibbon IL 3 protein proved to share 93% homology with the corresponding human protein. We examined the effects of biosynthetic (recombinant) gibbon IL 3 on the proliferation and differentiation of an enriched population of human hematopoietic progenitors and compared the results with the effects of recombinant human granulocyte- macrophage colony-stimulating factor (GM-CSF). Gibbon IL 3 supported the formation of various types of single lineage as well as multilineage colonies by My-10+ bone marrow cells in the presence of human erythropoietin (Ep). In contrast, recombinant human GM-CSF supported the formation of single-lineage colonies and only a small number of multilineage colonies. Both IL 3 and GM-CSF had significant erythroid burst-promoting activity (BPA). Delayed addition of gibbon IL 3 to low serum culture of My-10+ marrow cells supported the formation of blast cell colonies with variable but high replating capability. Human GM-CSF was less effective than IL 3 in support of multipotential blast cell colonies. These results are analogous to the effects of murine IL 3 and GM-CSF on murine progenitors and support the notion that the primary factor for multipotential progenitors is IL 3. 相似文献
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