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排序方式: 共有1473条查询结果,搜索用时 15 毫秒
61.
《Bioorganic & medicinal chemistry》2016,24(21):5462-5480
Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson’s disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure–activity-relationships. Several compounds blocked human and rat A1 and A2AARs at similar concentrations representing dual A1/A2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Ki human A1: 65.5 nM, A2A: 230 nM; Ki rat A1: 352 nM, A2A: 316 nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Ki human A1: 642 nM, A2A: 203 nM; Ki rat A1: 166 nM, A2A: 121 nM). Compound 57 was found to be well water-soluble (0.7 mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1 and A2AARs and at MAO-B (Ki human A1: 393 nM, human A2A: 595 nM, IC50 human MAO-B: 210 nM) thus allowing future in vivo explorations of the intended multi-target approach. 相似文献
62.
刘永莹 《基因组学与应用生物学》2019,38(5):2307-2311
为了探讨磁共振成像(magnetic resonance imaging, MRI)在胎盘植入介入治疗中的诊断作用和为临床治疗提供依据,本研究选取30例于2012年6月至2015年12月间在我院进行介入治疗的胎盘植入患者作为研究对象,根据病理诊断标准,分析患者胎盘植入介入治疗前后的MRI检查结果。结果显示,粘连性胎盘的敏感性和特异性分别为77.5%和90.2%,植入性胎盘的敏感性和特异性分别为75.5%和87.7%,穿透性胎盘的敏感性和特异性分别为85%和100%。最好的预测胎盘植入的MRI特征是在T2W磁共振成像(T2W-MRI)序列上存在暗色的胎盘内条带。介入治疗1年后复查时,发现患者子宫恢复为正常大小,宫腔内的胎盘组织基本消失,宫壁与植入胎盘融合、宫腔内膜线和子宫结合带的信号完整。综上结果,说明MRI可作为检测胎盘植入可靠性和可重复性的工具,并且能够显示胎盘植入部位及子宫肌层受侵程度,可用于评价胎盘植入介入治疗的疗效。 相似文献
63.
John F. Bateman Lisa Sampurno Antonio Maurizi Shireen R. Lamand Natalie A. Sims Tegan L. Cheng Aaron Schindeler David G. Little 《Journal of cellular and molecular medicine》2019,23(3):1735-1745
Osteogenesis imperfecta (OI) is commonly caused by heterozygous type I collagen structural mutations that disturb triple helix folding and integrity. This mutant‐containing misfolded collagen accumulates in the endoplasmic reticulum (ER) and induces a form of ER stress associated with negative effects on osteoblast differentiation and maturation. Therapeutic induction of autophagy to degrade the mutant collagens could therefore be useful in ameliorating the ER stress and deleterious downstream consequences. To test this, we treated a mouse model of mild to moderate OI (α2(I) G610C) with dietary rapamycin from 3 to 8 weeks of age and effects on bone mass and mechanical properties were determined. OI bone mass and mechanics were, as previously reported, compromised compared to WT. While rapamycin treatment improved the trabecular parameters of WT and OI bones, the biomechanical deficits of OI bones were not rescued. Importantly, we show that rapamycin treatment suppressed the longitudinal and transverse growth of OI, but not WT, long bones. Our work demonstrates that dietary rapamycin offers no clinical benefit in this OI model and furthermore, the impact of rapamycin on OI bone growth could exacerbate the clinical consequences during periods of active bone growth in patients with OI caused by collagen misfolding mutations. 相似文献
64.
Prostaglandin E2 (PGE2) is an endogenous lipid molecule involved in normal brain development. Cyclooxygenase‐2 (COX2) is the main regulator of PGE2 synthesis. Emerging clinical and molecular research provides compelling evidence that abnormal COX2/PGE2 signaling is associated with autism spectrum disorder (ASD). We previously found that COX2 knockout mice had dysregulated expression of many ASD genes belonging to important biological pathways for neurodevelopment. The present study is the first to show the connection between irregular COX2/PGE2 signaling and autism‐related behaviors in male and female COX2‐deficient knockin, (COX)‐2?, mice at young (4‐6 weeks) or adult (8‐11 weeks) ages. Autism‐related behaviors were prominent in male (COX)‐2? mice for most behavioral tests. In the open field test, (COX)‐2? mice traveled more than controls and adult male (COX)‐2? mice spent less time in the center indicating elevated hyperactive and anxiety‐linked behaviors. (COX)‐2? mice also buried more marbles, with males burying more than females, suggesting increased anxiety and repetitive behaviors. Young male (COX)‐2? mice fell more frequently in the inverted screen test revealing motor deficits. The three‐chamber sociability test found that adult female (COX)‐2? mice spent less time in the novel mouse chamber indicative of social abnormalities. In addition, male (COX)‐2? mice showed altered expression of several autism‐linked genes: Wnt2, Glo1, Grm5 and Mmp9. Overall, our findings offer new insight into the involvement of disrupted COX2/PGE2 signaling in ASD pathology with age‐related differences and greater impact on males. We propose that (COX)‐2? mice might serve as a novel model system to study specific types of autism. 相似文献
65.
66.
《Molecular & cellular proteomics : MCP》2019,18(6):1227-1241
Highlights
- •Quantitative microproteomics to study the CNS and PNS of the Twitcher mouse.
- •10plex TMT experiments on corpus callosum, motor cortex and sciatic nerves extracts.
- •More than 400 proteins groups deregulated between Twitcher and wildtype mice.
- •New insights into the molecular mechanisms of Krabbe disease.
67.
Jamal S.M. Sabir Abdelfatteh El Omri Noor A. Shaik Babajan Banaganapalli Nahid H. Hajrah Houda Zrelli Leila Arfaoui Zuhier A. Awan Abdulkader M. Shaikh Omar Arif Mohammed Mona G. Alharbi Alawiah M. Alhebshi Robert K. Jansen Muhummadh Khan 《Saudi Journal of Biological Sciences》2019,26(7):1338-1343
Obesity is a multifactorial metabolic disorder characterized by low grade chronic inflammation. Rare and novel mutations in genes which are vital in several key pathways have been reported to alter the energy expenditure which regulates body weight. The TP53 or p53 gene plays a prominent role in regulating various metabolic activities such as glycolysis, lipolysis, and glycogen synthesis. Recent genome-wide association studies reported that tumor suppressor gene p53 variants play a critical role in the predisposition of type 2 diabetes and obesity. Till date, no reports are available from the Arabian population; hence the present study was intended to assess the association between p53 variants with risk of obesity development in the Saudi population. We have selected three p53 polymorphisms, rs1642785 (C > G), and rs9894946 (A > G), and rs1042522 (Pro72Arg; C > G) and assessed their association with obesity risk in the Saudi population. Phenotypic and biochemical parameters were also evaluated to check their association with p53 genotypes and obesity. Genotyping was carried out on 136 obese and 122 normal samples. We observed that there is significantly increased prevalence p52 Pro72Arg (rs1042522) polymorphism in obese persons when compared to controls at GG genotype in overall comparison (OR: 2.169, 95% CI: 1.086-4.334, p = 0.02716). Male obese subjects showed three-fold higher risk at GG genotype (OR: 3.275, 95% CI: 1.230-8.716, p = 0.01560) and two-fold risk at G allele (OR: 1.827, 95% CI: 1.128-2.958, p = 0.01388) of p53 variant Pro72Arg respectively. This variant has also shown significant influence on cholesterol, LDL level, and random insulin levels in obese subjects (p ≤ 0.05). In conclusion, p53 Pro72Arg variant is highly prevalent among obese individuals and may act as a genetic modifier for obesity development among Saudis. 相似文献
68.
Progranulin (PGRN), a widely expressed glycoprotein with pleiotropic function, has been linked to a host of physiological processes and diverse pathological states. A series of contemporary preclinical disease models and clinical trials have evaluated various therapeutic strategies targeting PGRN, highlighting PGRN as a promising therapeutic target. Herein we summarize available knowledge of PGRN targeting in various kinds of diseases, including common neurological diseases, inflammatory autoimmune diseases, cancer, tissue repair, and rare lysosomal storage diseases, with a focus on the functional domain-oriented drug development strategies. In particular, we emphasize the role of extracellular PGRN as a non-conventional, extracellular matrix bound, growth factor-like conductor orchestrating multiple membrane receptors and intracellular PGRN as a chaperone/co-chaperone that mediates the folding and traffic of its various binding partners. 相似文献
69.
70.