首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   11423篇
  免费   1076篇
  国内免费   1376篇
  2024年   44篇
  2023年   208篇
  2022年   501篇
  2021年   760篇
  2020年   581篇
  2019年   625篇
  2018年   594篇
  2017年   445篇
  2016年   620篇
  2015年   776篇
  2014年   983篇
  2013年   965篇
  2012年   1153篇
  2011年   974篇
  2010年   549篇
  2009年   541篇
  2008年   580篇
  2007年   518篇
  2006年   393篇
  2005年   338篇
  2004年   337篇
  2003年   232篇
  2002年   241篇
  2001年   131篇
  2000年   127篇
  1999年   95篇
  1998年   69篇
  1997年   61篇
  1996年   47篇
  1995年   50篇
  1994年   47篇
  1993年   28篇
  1992年   32篇
  1991年   39篇
  1990年   34篇
  1989年   37篇
  1988年   18篇
  1987年   21篇
  1986年   13篇
  1985年   11篇
  1983年   11篇
  1982年   8篇
  1981年   4篇
  1980年   3篇
  1979年   3篇
  1977年   5篇
  1973年   3篇
  1962年   2篇
  1950年   2篇
  1940年   2篇
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
81.
目的 探究miR-186-5p对小鼠3T3-L1前脂肪细胞增殖,分化的影响及其潜在的分子机制.方法: qRT-PCR检测miR-186-5p在不同周龄小鼠白色脂肪组织及3T3-L1前脂肪细胞增殖分化过程中的表达变化;通过脂质体将miR-186-5p mimics,inhibitors转染入增殖液或分化液培养的3T3-L1细胞后,利用CCK-8,EdU和qRT-PCR检测3T3-L1前脂肪细胞增殖变化,油红O染色观察其脂滴形态;通过生物信息软件TargetScan和双荧光报告系统分别对miR-186-5p靶基因进行预测和确认.结果: (1)miR-186-5p在1~6周龄小鼠的白色脂肪组织及3T3-L1前脂肪细胞自然分化过程中表达量均逐渐上调.(2)与阴性对照相比,mimics或inhibitors转染分别显著地促进或抑制了miR-186-5p的表达.(3)过表达miR-186-5p后,3T3-L1前脂肪细胞的增殖速率减慢,脂滴增大增多;而抑制miR-186-5p后,3T3-L1前脂肪细胞增殖速率增快,脂滴数量减少,且粒径变小.其中过表达miR-186-5p显著地降低了野生型Wnt5aMapk1 3'-UTR活性,而突变相应的绑定位点可解除该抑制作用.结论: miR-186-5p可抑制3T3-L1前脂肪细胞增殖,且通过直接靶向Wnt5aMapk1以促进其分化为成熟脂肪细胞.  相似文献   
82.
张浩  刘伟 《菌物学报》2020,39(11):2109-2119
近年来,致病性念珠菌感染引起的侵袭性念珠菌病患者人数逐年增多。白念珠菌仍是引起感染的主要致病菌,但是由非白念念珠菌引起的感染比例显著升高。致病性念珠菌对常见抗真菌药物的耐药现象呈上升趋势,这是导致临床治疗其所致的侵袭性感染失败的重要原因之一。本文就致病性念珠菌耐药性的流行病学以及其耐药机制方面的研究进展进行了介绍。  相似文献   
83.
BT2 is a BTB/TAZ domain protein with key roles in multiple stress responses and the plant development of Arabidopsis (Figueroa et al. 2005; Ren et al. 2007; Mandadi et al. 2009). Recent studies have demonstrated that apple MdBT2 functions as a negative regulator in diverse hormonal and environmental signal‐induced anthocyanin biosynthesis, suggesting that MdBT2 integrates stress signals and anthocyanin biosynthesis.  相似文献   
84.
Bone loss (osteopenia) is a common complication in human solid tumour. In addition, after surgical treatment of gynaecological tumour, osteoporosis often occurs due to the withdrawal of oestrogen. The major characteristic of osteoporosis is the low bone mass with micro-architectural deteriorated bone tissue. And the main cause is the overactivation of osteoclastogenesis, which is one of the most important therapeutic targets. Inflammation could induce the interaction of RANKL/RANK, which is the promoter of osteoclastogenesis. Triptolide is derived from the traditional Chinese herb lei gong teng, presented multiple biological effects, including anti-cancer, anti-inflammation and immunosuppression. We hypothesized that triptolide could inhibits osteoclastogenesis by suppressing inflammation activation. In this study, we confirmed that triptolide could suppress RANKL-induced osteoclastogenesis in bone marrow mononuclear cells (BMMCs) and RAW264.7 cells and inhibited the osteoclast bone resorption functions. PI3K-AKT-NFATc1 pathway is one of the most important downstream pathways of RANKL-induced osteogenesis. The experiments in vitro indicated that triptolide suppresses the activation of PI3K-AKT-NFATc1 pathway and the target point located at the upstream of AKT because both NFATc1 overexpression and AKT phosphorylation could ameliorate the triptolide suppression effects. The expression of MDM2 was elevated, which demonstrated the MDM-p53-induced cell death might contribute to the osteoclastogenesis suppression. Ovariectomy-induced bone loss and inflammation activation were also found to be ameliorated in the experiments in vivo. In summary, the new effect of anti-cancer drug triptolide was demonstrated to be anti-osteoclastogenesis, and we demonstrated triptolide might be a promising therapy for bone loss caused by tumour.  相似文献   
85.
Cancer stem cells (CSCs) are a source of tumour recurrence in patients with nasopharyngeal carcinoma (NPC); however, the function of microRNA‐124 (miR‐124) in NPC CSCs has not been clearly defined. In this study, we investigated the role of miR‐124 in NPC CSCs. qRT‐PCR was performed to measure miR‐124 expression in NPC tissues and cell lines and the effects of miR‐124 on stem‐like properties and radiosensitivity of NPC cells measured. Luciferase reporter assays and rescue experiments were used to investigate the interaction of miR‐124 with the 3′UTR of junctional adhesion molecule A (JAMA). Finally, we examined the effects of miR‐124 in an animal model and clinical samples. Down‐regulation of miR‐124 was detected in cancer tissues and was inversely associated with tumour stage and lymph node metastasis. Overexpression of miR‐124 inhibited stemness properties and enhanced radiosensitivity of NPC cells in vitro and in vivo via targeting JAMA. Up‐regulation of miR‐124 was correlated with superior overall survival of patients with NPC. Our study demonstrates that miR‐124 can inhibit stem‐like properties and enhance radiosensitivity by directly targeting JAMA in NPC. These findings provide novel insights into the molecular mechanisms underlying therapy failure in NPC.  相似文献   
86.
Ovarian carcinoma has the highest mortality among the malignant tumours in gynaecology, and new treatment strategies are urgently needed to improve the clinical status of ovarian carcinoma patients. The Cancer Genome Atlas (TCGA) cohort were performed to explore the immune function of the internal environment of tumours and its clinical correlation with ovarian carcinoma. Finally, four molecular subtypes were obtained based on the global immune-related genes. The correlation analysis and clinical characteristics showed that four subtypes were all significantly related to clinical stage; the immune scoring results indicated that most immune signatures were upregulated in C3 subtype, and the majority of tumour-infiltrating immune cells were upregulated in both C3 and C4 subtypes. Compared with other subtypes, C3 subtype had a higher BRCA1 mutation, higher expression of immune checkpoints, and optimal survival prognosis. These findings of the immunological microenvironment in tumours may provide new ideas for developing immunotherapeutic strategies for ovarian carcinoma.  相似文献   
87.
Glioblastoma (GBM) is a malignant intracranial tumour with the highest proportion and lethality. It is characterized by invasiveness and heterogeneity. However, the currently available therapies are not curative. As an essential environmental cue that maintains glioma stem cells, hypoxia is considered the cause of tumour resistance to chemotherapy and radiation. Growing evidence shows that immunotherapy focusing on the tumour microenvironment is an effective treatment for GBM; however, the current clinicopathological features cannot predict the response to immunotherapy and provide accurate guidance for immunotherapy. Based on the ESTIMATE algorithm, GBM cases of The Cancer Genome Atlas (TCGA) data set were classified into high‐ and low‐immune/stromal score groups, and a four‐gene tumour environment‐related model was constructed. This model exhibited good efficiency at forecasting short‐ and long‐term prognosis and could also act as an independent prognostic biomarker. Additionally, this model and four of its genes (CLECL5A, SERPING1, CHI3L1 and C1R) were found to be associated with immune cell infiltration, and further study demonstrated that these four genes might drive the hypoxic phenotype of perinecrotic GBM, which affects hypoxia‐induced glioma stemness. Therefore, these might be important candidates for immunotherapy of GBM and deserve further exploration.  相似文献   
88.
Circular RNAs (circRNAs) represent a newly discovered class of endogenous non‐coding RNAs which are widely expressed and play important roles in disease progression. However, the function of circRNAs in oral squamous cell carcinoma (OSCC) still remains largely unknown. In this research, we found that circ_SEPT9 was highly expressed in OSCC cell lines and tumour tissues. Results showed that circ_SEPT9 promoted OSCC proliferation and tumour growth. And, circ_SEPT9 also enhanced the migration and invasion of OSCC cells. Mechanically, we found that circ_SEPT9 acted as a sponge for miR‐1225 to rescue PKN2 expression in OSCC cells. Inhibition of circ_SEPT9/miR‐1225/PKN2 pathway could effectively block the proliferation and metastasis of OSCC cells. Our study provides strong evidence that circ_SEPT9/miR‐1225/PKN2 axis is a promising target for OSCC treatment.  相似文献   
89.
Psoralea corylifolia (P corylifolia) has been popularly applied in traditional Chinese medicine decoction for treating osteoporosis and promoting fracture healing since centuries ago. However, the bioactive natural components remain unknown. In this study, applying comprehensive two‐dimensional cell membrane chromatographic/C18 column/time‐of‐flight mass spectrometry (2D CMC/C18 column/TOFMS) system, neobavaisoflavone (NBIF), for the first time, was identified for the bioaffinity with RAW 264.7 cells membranes from the extracts of P corylifolia. Here, we revealed that NBIF inhibited RANKL‐mediated osteoclastogenesis in bone marrow monocytes (BMMCs) and RAW264.7 cells dose dependently at the early stage. Moreover, NBIF inhibited osteoclasts function demonstrated by actin ring formation assay and pit‐formation assay. With regard to the underlying molecular mechanism, co‐immunoprecipitation showed that both the interactions of RANK with TRAF6 and with c‐Src were disrupted. In addition, NBIF inhibited the phosphorylation of P50, P65, IκB in NF‐κB pathway, ERK, JNK, P38 in MAPKs pathway, AKT in Akt pathway, accompanied with a blockade of calcium oscillation and inactivation of nuclear translocation of nuclear factor of activated T cells cytoplasmic 1 (NFATc1). In vivo, NBIF inhibited osteoclastogenesis, promoted osteogenesis and ameliorated bone loss in ovariectomized mice. In summary, P corylifolia‐derived NBIF inhibited RANKL‐mediated osteoclastogenesis by suppressing the recruitment of TRAF6 and c‐Src to RANK, inactivating NF‐κB, MAPKs, and Akt signalling pathways and inhibiting calcium oscillation and NFATc1 translocation. NBIF might serve as a promising candidate for the treatment of osteoclast‐associated osteopenic diseases.  相似文献   
90.
The chemical composition and in vitro antioxidant activity of the essential oil of propolis (EOP) collected from 25 locations in China was investigated. Steam‐distillation extraction was used to extract the EOP, and chemical composition was identified by GC/MS. The antioxidant activities of EOP were also measured. The result showed that a total of 406 compounds were detected in EOP. The major compounds of Chinese EOP were cedrol, γ‐eudesmol, benzyl alcohol, phenethyl alcohol, 2‐methoxy‐4‐vinylphenol, 3,4‐dimethoxystyrene and guaiol. Principal component analysis revealed the significant correlation between EOP compositions and their origins, and certain correlation was detected between EOP and their color. Linear discriminant analysis showed that 88 % and 84 % of the propolis samples were predicted correctly as the groupings identified by climatic zone and the color, respectively. Furthermore, the differences of antioxidant activities of EOP were significant. EOP of Shandong had the strongest antioxidant activities, whereas EOP of Guangdong, Yunnan and Hunan showed the poorest.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号