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1.
Feng He Yuanjun Ma Shi Li Haozhe Ren Qian Liu Xiaohua Chen Hui Miao Tao Ye Qian Lu Zuge Yang Tianle Li Xin Tong Hongxu Yang Mian Zhang Helin Wang Yazhou Wang Shibin Yu 《Journal of bone and mineral research》2022,37(5):1044-1055
Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage-associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain-like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra-articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria-derived activator of caspases (SMAC) mimetics and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (z-VAD-fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα-SDC4-TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR). 相似文献
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目的:探讨活性氧(ROS)对人类精子线粒体tRNALeuUUR基因的氧化损伤。方法:采用Percoll梯度离心法筛选具有正常生理功能的精子,作为正常精子模型,并分为损伤组20例和对照组20例,分别加入次黄嘌呤-黄嘌呤氧化酶体系或不予处理,37℃有氧环境中孵育60min。分别提取精子DNA,以Fpg酶切损伤碱基并采用接头介导PCR(LM-PCR)检测线粒体tRNALeuUUR基因的氧化损伤。采用Rhodamine(Rh123)荧光探针标记精子,通过流式细胞仪检测线粒体膜电位,观察精子的功能。结果:与对照组相比,损伤组精子孵育后线粒体膜电位明显降低[(116.27±11.72)%vs(64.00±4.88)%,P<0.05]。Fpg酶切和LM-PCR显示精子线粒体tRNALeuUUR基因损伤。结论:ROS可能通过对精子线粒体tRNALeuUUR基因氧化损伤而影响精子功能(线粒体膜电位明显降低),从而引起不育。 相似文献
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川芎嗪对大鼠局灶性脑缺血后侧脑室室下区细胞增殖的作用 总被引:5,自引:0,他引:5
目的 观察川芎嗪对大鼠局灶性脑缺血后侧脑室室下区(SVZ)细胞增殖的作用。方法 SD雄性大鼠随机分为假手术组、缺血模型组和川芎嗪组。线栓法制作大鼠大脑中动脉阻塞模型,川芎嗪组术后2h腹腔注射川芎嗪(80mg/kg,1次/d),各组术后4h腹腔注射5-溴脱氧尿核苷(BrdU,50mg/kg,1次/d)。术后7、14、21d取材,采用免疫组织化学染色观察SVZ BrdU阳性细胞数和Doublecortin(DCX)的表达。结果 缺血模型组术后7d时SVZBrdU阳性细胞较假手术组明显增加(P〈0.01),并持续至14d,21d减少;川芎嗪组14dSVZ BrdU阳性细胞达峰值,21d有所减少,与缺血模型组比较,7、14dBrdU阳性细胞均明显增加(P〈0.01)。缺血模型组7d时SVZ有DCX阳性表达,14d达最多,21d表达减少,与假手术组相应时间点比较均明显增加(P〈0.01);川芎嗪组随缺血时间延长SVZDCX表达明显增强,21d仍处于高水平,与缺血模型组比较,14、21dDCX表达明显增强(P〈0.01)。结论 川芎嗪对成年大鼠局灶性脑缺血诱导的SVZ神经干细胞/祖细胞增殖可能有促进作用。 相似文献
4.
目的研究中国人胃癌6号染色体长臂微卫星不稳定性(microsatellite instability,MSI)和杂合性缺失(loss of heterozygosity,LOH)状况及与临床病理特征之间的联系。方法采用PCR-SSLP-银染方法对27例胃癌组织及其相应正常组织6号染色体长臂(6q)不同位置的4个位点进行MSI和LOH检测。结果27例信息个体中16例检测到一个或多个位点MSI,平均MSI频率59.2%;11例不具MSI的信息个体中7例存在1个或更多位点LOH,平均频率63.6%。MSI和LOH频发位点均为D6S434(6q16.3-q21)和D6S404(6q16.3-q23)。MSI和LOH在高分化胃癌和低分化胃癌各个时期均有发生.但高分化胃癌中高水平MSI(MSI-H)发生有增高趋势。结论MSI和LOH发生率与年龄、性别、组织分化程度、病理分期及发病部位等临床指标虽然无明显相关,但6q等位基因缺失关键区域与其它国家、地区相似,进一步证实6q上该区可能存在与胃癌相关的肿瘤抑制基因。 相似文献
5.
建立糖尿病心肌病动物模型方法的实验研究 总被引:10,自引:0,他引:10
目的研究建立糖尿病心肌病动物模型的科学、实用的方法。方法应用链脲佐菌素对SD大鼠进行一次性腹腔注射,通过观察大鼠的一般状况、进食量、进水量、尿量、体重的变化,监测血糖、尿糖、心肌酶含量、胰岛素水平、心肌超微结构、心脏大血管内膜情况及心电图情况来评估糖尿病心肌病的发病情况。结果腹腔注射STZ 3周后,模型组大鼠出现病态表现,进食量、饮水量、尿量增加,体重下降。血糖值、尿糖值及肌酸激酶、乳酸脱氢酶值均较对照组大鼠升高。胰岛素水平较对照组明显降低,心肌超微结构符合糖尿病心肌病表现,心脏大血管未见纤维斑块和粥样斑块。结论对SD大鼠进行一次性腹腔注射链脲佐菌素(55mg/kg),大鼠于注射后第3周可出现稳定的糖尿病心肌病状态。这是一种可靠且实用性强的糖尿病心肌病动物模型的制备方法。 相似文献
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Timing of disease occurrence and hepatic resection on long‐term outcome of patients with neuroendocrine liver metastasis 下载免费PDF全文
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The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer 下载免费PDF全文
Muyang Ding Hang Zhang Zhen Li Cuili Wang Jasmine Chen Liyun Shi Dakang Xu Yane Gao 《Clinical and experimental pharmacology & physiology》2015,42(5):458-464
Enhancer of zeste 2 (EZH2), a polycomb histone methyltransferase, is overexpressed in various cancers, including cervical cancer. Gene expression analysis revealed that increased expression of EZH2 is associated with cervical cancer progression, particularly the progression to invasive squamous cell carcinoma. Enhancer of zeste 2 is known to trimethylate lysine 27 on histone H3, leading to gene silencing that contributes to the progression of tumours into a more aggressive form of cancer. However, the specific molecular mechanisms by which EZH2 contributes to the development of cervical cancer remain largely unknown. Recently, an EZH2 inhibitor was reported to selectively inhibit trimethylated lysine 27 on histone H3 and to reactivate silenced genes in cancer cells. In this study, we found that GSK343 (a specific inhibitor of EZH2 methyltransferase) induces phenotypic reprogramming of cancer cells from mesenchymal to epithelial cells, reducing proliferation and cell motility and blocking the invasion of cervical cancer cell lines both in vitro and in vivo. Treatment with the EZH2 inhibitor led to increased levels of the epithelial marker E‐cadherin and decreased levels of mesenchymal markers such as N‐cadherin and vimentin. The observed reprogramming is associated with restrained cervical cancer progression and provides direct evidence in support of EZH2 as a therapeutic target. 相似文献