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   1420篇
  免费   181篇
  国内免费   67篇
耳鼻咽喉   1篇
儿科学   35篇
妇产科学   12篇
基础医学   192篇
口腔科学   27篇
临床医学   53篇
内科学   225篇
皮肤病学   45篇
神经病学   71篇
特种医学   9篇
外科学   243篇
综合类   182篇
预防医学   30篇
眼科学   27篇
药学   249篇
中国医学   52篇
肿瘤学   215篇
  2024年   1篇
  2023年   34篇
  2022年   60篇
  2021年   90篇
  2020年   70篇
  2019年   87篇
  2018年   79篇
  2017年   59篇
  2016年   89篇
  2015年   115篇
  2014年   168篇
  2013年   163篇
  2012年   107篇
  2011年   105篇
  2010年   83篇
  2009年   73篇
  2008年   76篇
  2007年   50篇
  2006年   48篇
  2005年   37篇
  2004年   22篇
  2003年   12篇
  2002年   5篇
  2001年   5篇
  2000年   2篇
  1999年   4篇
  1998年   6篇
  1997年   7篇
  1996年   2篇
  1995年   3篇
  1994年   3篇
  1993年   1篇
  1992年   1篇
  1989年   1篇
排序方式: 共有1668条查询结果,搜索用时 156 毫秒
1.
2.
目的 探讨沙格列汀干预非酒精性脂肪性肝病(NAFLD)合并2型糖尿病(T2DM)大鼠对肝组织腺苷酸活化蛋白激酶(AMPK)/哺乳动物雷帕霉素靶蛋白(mTOR)-转录因子EB(TFEB)自噬信号通路蛋白表达的影响。方法 将42只大鼠随机分为对照组、模型组和沙格列汀干预组,每组14只。采用高脂饲料喂养和链脲佐菌素腹腔注射构建NAFLD合并T2DM模型。在建模成功后,分别给予沙格列汀或生理盐水灌胃8 w。采用放射免疫法检测空腹胰岛素(INS,使用全自动生化分析仪检测空腹血糖(FPG),计算胰岛素抵抗指数(HOMA-IR)。采用Western bloting法检测肝组织p-AMPK、mTOR、TFEB和自噬标记物LC3B-II蛋白表达。结果 沙格列汀处理组大鼠体质量、肝质量和肝脏指数分别为(341.53±5.15)g、(11.06±0.49)g和(3.32±0.25)%,显著低于模型组【分别为(353.27±8.74)g、(12.77±0.84)g和(3.67±0.18)%,P<0.05】;FPG、INS和HOMA-IR水平分别为(9.45±0.71)mmol/L、(7.92±0.34)mIU/L和(3.44±0.36),显著低于模型组【分别为(13.97±0.92)mmol/L、(14.57±0.84)mIU/L和(9.03±0.91),P<0.05】;TC、TG、ALT和AST水平分别为(3.79±0.17)mmol/L、(0.81±0.13)mmol/L、(68.76±4.11)IU/L和(54.49±5.21)IU/L,均显著低于模型组【分别为(4.05±0.20)mmol/L、(2.04±0.15)mmol/L、(119.73±3.94)IU/L和(83.27±7.68)IU/L,P<0.05】;肝组织p-AMPK、TFEB和LC3B-II表达分别为(1.13±0.11)、(1.23±0.13)和(1.17±0.12),显著强于模型组【分别为(0.62±0.07)、(0.48±0.05)和(0.37±0.04)】,而mTOR表达为(0.89±0.08),显著弱于模型组【(1.53±0.16),P<0.05】。结论 沙格列汀可能通过调控AMPK/mTOR-TFEB自噬信号通路显著降低NAFLD合并T2DM大鼠血糖和血脂水平,改善肝脂肪变。  相似文献   
3.
目的:研究Rheb1基因在小鼠巨核-红系多能性干细胞发育成熟中的作用及相关的机制。方法:利用Vav-Cre在造血系统中特异性敲除小鼠Rheb1(Vav1-Cre;Rheb1fl/fl,Rheb1Δ/Δ小鼠),采用流式细胞术检测Rheb1敲除组和对照组小鼠骨髓和外周血中红系细胞的比例;CFC克隆形成实验检测敲除组和对照组小鼠骨髓中巨核-红系多能性干细胞体外克隆形成能力;利用实时荧光定量PCR检测敲除组和对照组小鼠巨核-红系多能性干细胞中PU.1、GATA-1、GATA-2、CEBPα和CEBPβ的相对表达量;在培养基中加入雷帕霉素,检测野生型小鼠巨核-红系多能性干细胞体外克隆形成能力的变化。结果:Rheb1敲除后,小鼠骨髓中红系细胞发育受抑且应激能力减弱,小鼠骨髓中巨核-红系多能性干细胞体外克隆形成能力减弱,GATA-1的表达水平降低;雷帕霉素可以抑制野生型小鼠骨髓中巨核-红系多能性干细胞体外克隆的形成。结论:Rheb1基因在小鼠巨核-红系多能性干细胞发育中具有重要的调控作用,Rheb1可能通过mTOR信号通路调控小鼠巨核-红系多能性干细胞发育。  相似文献   
4.
ObjectiveTo study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC).Patients and MethodsThe Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML).ResultsA total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm.ConclusionThe identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.  相似文献   
5.
6.
Centromere proteins (CENPs) are involved in mitosis, and CENP gene expression levels are associated with chemotherapy responses in patients with breast cancer. The present study aimed to examine the roles and underlying mechanisms of the effects of CENP genes on chemotherapy responses and breast cancer prognosis. Using data obtained from the Gene Expression Omnibus (GEO) database, correlation and Cox multivariate regression analyses were used to determine the CENP genes associated with chemotherapy responses and survival in patients with breast cancer. Weighted gene co-expression network and correlation analyses were used to determine the gene modules co-expressed with the identified genes and the differential expression of gene modules associated with the pathological complete response (PCR) and residual disease (RD) subgroups. CENPA, CENPE, CENPF, CENPI, CENPJ and CENPN were associated with a high nuclear grade and low estrogen and progesterone receptor expression levels. In addition, CENPA, CENPB, CENPC and CENPO were independent factors affecting the distant relapse-free survival (DRFS) rates in patients with breast cancer. Patients with high expression levels of CENPA or CENPO exhibited poor prognoses, whereas those with high expression levels of CENPB or CENPC presented with favorable prognoses. For validation between databases, the Cancer Genome Atlas (TCGA) database analysis also revealed that CENPA, CENPB and CENPO exerted similar effects on overall survival. However, according to the multivariate analyses, only CENPA was an independent risk factor associated with DRFS in GEO database. In addition, in the RD subgroup, patients with higher CENPA expression levels had a worse prognosis compared with those with lower CENPA expression levels. Among patients with high expression levels of CENPA, the PI3K/Akt/mTOR pathway was more likely to be activated in the RD compared with the PCR subgroup. The same trend was observed in TCGA data. These results suggested that high CENPA expression levels plus upregulation of the PI3K/Akt/mTOR signaling pathway may affect DRFS in patients with breast cancer.  相似文献   
7.
Post‐transplant lymphoproliferative disorder (PTLD) is a fatal complication of transplantation. There is no clear consensus on the treatment of PTLD. In most cases, the pathogenetic mechanism of PTLD involves the Epstein‐Barr virus (EBV). We report the case of an elderly kidney transplant recipient who developed EBV‐positive monomorphic T‐cell PTLD 14 years after transplantation. Conversion from conventional immunosuppressants to everolimus induced complete remission of PTLD accompanied by a decrease in blood EBV‐DNA level without chemotherapy.  相似文献   
8.
Objective To investigate the molecular mechanisms of the adverse effects of exposure to sulfamonomethoxin(SMM) in pregnancy on the neurobehavioral development of male offspring. Methods Pregnant mice were randomly divided into four groups: control‐(normal saline), low‐ [10 mg/(kg.day)], middle‐ [50 mg/(kg.day)], and high‐dose [200 mg/(kg.day)] groups, which received SMM by gavage daily during gestational days 1‐18. We measured the levels of short‐chain fatty acids(SCFAs) in feces from dams and male pups. Furthermore, we analyzed the mR NA and protein levels of genes involved in the mammalian target of rapamycin(m TOR) pathway in the hippocampus of male pups by RT‐PCR or Western blotting. Results Fecal SCFA concentrations were significantly decreased in dams. Moreover, the production of individual fecal SCFAs was unbalanced, with a tendency for an increased level of total fecal SCFAs in male pups on postnatal day(PND) 22 and 56. Furthermore, the phosphatidylinositol 3‐kinase(PI3 k)/protein kinase B(AKT)/mTOR or mT OR/ribosomal protein S6 kinase 1(S6 K1)/4 EBP1 signaling pathway was continuously upregulated until PND 56 in male offspring. In addition, the expression of Sepiapterin Reductase(SPR), a potential target of m TOR, was inhibited. Conclusion In utero exposure to SMM, persistent upregulation of the hippocampal mTOR pathway related to dysfunction of the gut(SCFA)‐brain axis may contribute to cognitive deficits in male offspring.  相似文献   
9.
The pituitary tumor-transforming gene 1 (PTTG1), also known as Securin, is considered an oncogene. This study aimed to investigate the role of PTTG1 in clear cell renal cell carcinoma (ccRCC) using in silico bioinformatics approaches. A pan-cancer analysis using The Cancer Genome Atlas (TCGA) data indicated that among all cancer types copy number amplification of PTTG1 gene was most frequently found in ccRCC. However, amplification of PTTG1 gene copy number did not correlate with the increase of mRNA level in ccRCC, and did not predict the patients' overall survival. Instead, ccRCC was correlated with overexpression of PTTG1 mRNA, and its expression level was stage-dependent increased in cancer patients. An outlier analysis using the Oncomine database suggested that PTTG1 mRNA expression served as a good biomarker for ccRCC. Pathway analysis for upregulated genes enriched in PTTG1-high expressing ccRCC patients found that PTTG1 overexpression was associated with mitotic defects. Mining drug sensitivity data using the Cancer Therapeutics Response Portal (CTRP) discovered that PTTG1-high expressing ccRCC cell lines were susceptible to a Rac1 (Ras-related C3 botulinum toxin substrate 1) inhibitor NSC23766. Therefore, this study provides an in silico insight into the role of PTTG1 in ccRCC, and repurposes the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing ccRCC.  相似文献   
10.
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