全文获取类型
收费全文 | 1670篇 |
免费 | 98篇 |
国内免费 | 76篇 |
出版年
2024年 | 4篇 |
2023年 | 13篇 |
2022年 | 43篇 |
2021年 | 33篇 |
2020年 | 50篇 |
2019年 | 85篇 |
2018年 | 58篇 |
2017年 | 31篇 |
2016年 | 46篇 |
2015年 | 51篇 |
2014年 | 128篇 |
2013年 | 119篇 |
2012年 | 89篇 |
2011年 | 126篇 |
2010年 | 81篇 |
2009年 | 75篇 |
2008年 | 96篇 |
2007年 | 105篇 |
2006年 | 82篇 |
2005年 | 68篇 |
2004年 | 62篇 |
2003年 | 53篇 |
2002年 | 39篇 |
2001年 | 39篇 |
2000年 | 19篇 |
1999年 | 20篇 |
1998年 | 29篇 |
1997年 | 23篇 |
1996年 | 19篇 |
1995年 | 18篇 |
1994年 | 21篇 |
1993年 | 11篇 |
1992年 | 10篇 |
1991年 | 16篇 |
1990年 | 10篇 |
1989年 | 7篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1986年 | 8篇 |
1985年 | 9篇 |
1984年 | 8篇 |
1983年 | 7篇 |
1982年 | 6篇 |
1981年 | 4篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 1篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1974年 | 1篇 |
排序方式: 共有1844条查询结果,搜索用时 140 毫秒
31.
《Bioorganic & medicinal chemistry》2019,27(18):4110-4123
The sulfonamidophenylethylamide analogues were explored for finding novel and potent cardiac myosin activators. Among them, N-(4-(N,N-dimethylsulfamoyl)phenethyl-N-methyl-5-phenylpentanamide (13, CMA at 10 µM = 48.5%; FS = 26.21%; EF = 15.28%) and its isomer, 4-(4-(N,N-dimethylsulfamoyl)phenyl-N-methyl-N-(3-phenylpropyl)butanamide (27, CMA at 10 µM = 55.0%; FS = 24.69%; EF = 14.08%) proved to be efficient cardiac myosin activators both in in vitro and in vivo studies. Compounds 13 (88.2 + 3.1% at 5 µM) and 27 (46.5 + 2.8% at 5 µM) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13 and 27 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, and therefore these potent and selective amide derivatives could be considered a new class of cardiac myosin activators for the treatment of systolic heart failure. 相似文献
32.
Miyuki Kusajima Moeka Fujita Hiromoto Yamakawa Tsukasa Ushiwatari Takamasa Mori Kazuki Tsukamoto 《Bioscience, biotechnology, and biochemistry》2020,84(7):1427-1435
ABSTRACT A newly identified chemical, 4-{3-[(3,5-dichloro-2-hydroxybenzylidene)amino]propyl}-4,5-dihydro-1H-pyrazol-5-one (BAPP) was characterized as a plant immunity activator. BAPP enhanced disease resistance in rice against rice blast disease and expression of a defense-related gene without growth inhibition. Moreover, BAPP was able to enhance disease resistance in dicotyledonous tomato and Arabidopsis plants against bacterial pathogen without growth inhibition, suggesting that BAPP could be a candidate as an effective plant activator. Analysis using Arabidopsis sid2-1 and npr1-2 mutants suggested that BAPP induced systemic acquired resistance (SAR) by stimulating between salicylic acid biosynthesis and NPR1, the SA receptor protein, in the SAR signaling pathway. 相似文献
33.
摘要 目的:观察天麻素对小鼠抑郁症模型异常行为的改善以及Janus激酶2-信号转导和转录激活因子3(JAK2 -STAT3)信号通路的表达变化。方法:40只雄性昆明小鼠,随机分为正常组和模型组。模型组小鼠经过4周CUMS刺激建模,第6周检测小鼠行为学变化以验证建模效果。随后将模型组分为CUMS+生理盐水、CUMS+氟西汀以及CUMS+天麻素3个亚组,第7-8周继续进行CUMS刺激,同时对3个亚组小鼠腹腔注射给药。第9周再次进行行为学检测。取小鼠脑组织进行HE染色(hematoxylin-eosin staining)和蛋白免疫印迹(western blot)检测。结果:第6周检测结果显示:与对照组比较,模型组小鼠体重增幅显著降低(P<0.001),悬尾和强迫游泳不动时间显著增加(P<0.001、P<0.001),糖水消耗率显著降低(P<0.001)。第9周检测结果显示:与CUMS+生理盐水组相比,CUMS+氟西汀组和CUMS+天麻素组小鼠体重增幅显著增加(P<0.001,P<0.001),强迫游泳不动时间显著降低(P<0.001,P<0.001),悬尾不动时间显著降低(P<0.01,P<0.01),糖水消耗率显著增加(P<0.001、P<0.001)。与CUMS+生理盐水组比较,CUMS+天麻素组小鼠JAK2、STAT3、IL-1β蛋白表达显著降低(P<0.01、P<0.01、P<0.05);HE染色结果提示,CUMS+生理盐水组小鼠神经元形态发生改变,细胞结构不清晰,细胞核固缩、深染;与CUMS+生理盐水组相比,CUMS+天麻素组小鼠神经元形态得到改善。结论:天麻素可以有效改善CUMS诱导的小鼠抑郁样行为,其作用可能与JAK2-STAT3信号通路关键蛋白的表达有关。 相似文献
34.
Viviana De Luca Andrea Petreni Vincenzo Carginale Andrea Scaloni Claudiu T. Supuran Clemente Capasso 《Journal of enzyme inhibition and medicinal chemistry》2021,36(1):1000
We here report a study on the activation of the ι-class bacterial CA from Burkholderia territorii (BteCAι). This protein was recently characterised as a zinc-dependent enzyme that shows a significant catalytic activity (kcat 3.0 × 105 s−1) for the physiological reaction of CO2 hydration to bicarbonate and protons. Some amino acids and amines, among which some proteinogenic derivatives as well as histamine, dopamine and serotonin, showed efficient activating properties towards BteCAι, with activation constants in the range 3.9–13.3 µM. L-Phe, L-Asn, L-Glu, and some pyridyl-alkylamines, showed a weaker activating effect towards BteCAι, with KA values ranging between 18.4 µM and 45.6 µM. Nowadays, no information is available on active site architecture, metal ion coordination and catalytic mechanism of members of the ι-group of CAs, and this study represents another contribution towards a better understanding of this still uncharacterised class of enzymes. 相似文献
35.
PurposeRadiation therapy plans are assessed using dose volume metrics derived from clinical toxicity and outcome data. In this study, plans for patients with locally advanced non-small cell lung cancer (LA-NSCLC) are examined in the context of the implementation of the Acuros XB (AXB) dose calculation algorithm focussing on the impact on common metrics. Methods: Volumetric modulated arc therapy (VMAT) plans were generated for twenty patients, using the Analytical Anisotropic Algorithm (AAA) and recalculated with AXB for both dose to water (Dw) and dose to medium (Dm). Standard dose volume histogram (DVH) metrics for both targets and organs-at-risk (OARs) were extracted, in addition to tumour control probability (TCP) for targets. Results: Mean dose to the planning target volume (PTV) was not clinically different between the algorithms (within ±1.1 Gy) but differences were seen in the minimum dose, D99% and D98% as well as for conformity and homogeneity metrics. A difference in TCP was seen for AXBDm plans versus both AXBDw and AAA plans. No clinically relevant differences were seen in the lung metrics. For point doses to spinal cord and oesophagus, the AXBDm values were lower than AXBDw, by up to 1.0 Gy. Conclusion: Normalisation of plans to the mean/median dose to the target does not need to be adjusted when moving from AAA to AXB. OAR point doses may decrease by up to 1 Gy with AXBDm, which can be accounted for in clinical planning. Other OAR metrics do not need to be adjusted. 相似文献
36.
Xi Huang Jisen Dai Chuanshu Huang Qi Zhang Opinder Bhanot Edward Pelle 《Free radical research》2013,47(10):1135-1142
Deferoxamine (DFO) is a drug widely used for iron overload treatment to reduce body iron burden. In the present study, it was shown in mouse epidermal JB6 cells that all iron compounds transiently induced extracellular signal-regulated kinases (ERK) phosphorylation, whereas DFO further enhanced ERK phosphorylation over long periods. The ERK phosphorylation by DFO treatment appears to be due to the inhibition of MAPK phosphatases (MKP) by DFO. The combined effects of iron-initiated MAPK activation and DFO-mediated MKP inhibition resulted in a synergistic enhancement on AP-1 activities. The results indicate that the interplay between MAPK and MKP is important in regulating the extent of AP-1 activation. It is known that administration of DFO in iron overload patients often results in allergic responses at the injection sites. The results suggest that this synergistic AP-1 activation might play a role in DFO-induced skin immune responses of iron overload patients. 相似文献
37.
S. S. Nerurkar A. R. Olzinski K. S. Frazier R. C. Mirabile S. P. O'Brien J. Jing 《Biomarkers》2013,18(1):87-112
The assessment of target organ damage is important in defining the optimal treatment of hypertension and blood pressure-related cardiovascular disease. The aims of the present study were (1) to investigate candidate biomarkers of target organ damage, osteopontin (OPN) and plasminogen activator inhibitor-1 (PAI-1), in models of malignant hypertension with well characterized end-organ pathology; and (2) to evaluate the effects of chronic treatment with a p38 MAPK inhibitor. Gene expression, plasma concentrations, and renal immunohistochemical localization of OPN and PAI-1 were measured in stroke-prone spontaneously hypertensive rats on a salt–fat diet (SFD SHR-SP) and in spontaneously hypertensive rats receiving Nω-nitro-L-arginine methyl ester (L-NAME SHR). Plasma concentrations of OPN and PAI-1 increased significantly in SFD SHR-SP and L-NAME SHR as compared with controls, (2.5–4.5-fold for OPN and 2.0–9.0-fold for PAI-1). The plasma levels of OPN and PAI-1 were significantly correlated with the urinary excretion of albumin (p<0.0001). Elevations in urinary albumin, plasma OPN and PAI-1 were abolished by chronic treatment (4–8 weeks) with a specific p38 MAPK inhibitor, SB-239063AN. OPN immunoreactivity was localized predominantly in the apical portion of tubule epithelium, while PAI-1 immunoreactivity was robust in glomeruli, tubules and renal artery endothelium. Treatment with the p38 MAPK inhibitor significantly reduced OPN and PAI-1 protein expression in target organs. Kidney gene expression was increased for OPN (4.9- and 7.9-fold) and PAI-1 (2.8- and 11.5-fold) in SFD SHR-SP and L-NAME SHR, respectively. In-silico pathway analysis revealed that activation of p38 MAPK was linked to OPN and PAI-1 via SP1, c-fos and c-jun; suggesting that these pathways may play an important role in p38 MAPK-dependent hypertensive renal dysfunction. The results suggest that enhanced OPN and PAI-1 expression reflects end-organ damage in hypertension and that suppression correlates with end-organ protection regardless of overt antihypertensive action. 相似文献
38.
F. Mahboudi F. Barkhordari R.M. Godarzi S. Enayati F. Davami 《Journal of applied microbiology》2013,114(2):364-372
Aims
A novel chimeric‐truncated form of tissue‐type plasminogen activator (t‐PA) with improved fibrin affinity and resistance to PAI was successfully produced in CHO expression system during our previous studies. Considering advantages of prokaryotic expression systems, the aim in this study was to produce the novel protein in Escherichia coli (BL21) strain and compare the protein potency in batch and fed‐batch processes.Methods and Results
The expression cassette for the novel t‐PA was prepared in pET‐28a(+). The E. coli expression procedure was compared in traditional batch and newly developed fed batch, EnBase® Flo system. The protein was purified in soluble format, and potency results were identified using Chromolize t‐PA Assay Kit. The fed‐batch fermentation mode, coupled with a Ni‐NTA affinity purification procedure under native condition, resulted in higher amounts of soluble protein, and about a 30% of improvement in the specific activity of the resulted recombinant protein (46·66 IU mg?1) compared to traditional batch mode (35·8 IU mg?1).Conclusions
Considering the undeniable advantages of expression in the prokaryotic expression systems such as E. coli for recombinant protein production, applying alternative methods of cultivation is a promising approach. In this study, fed‐batch cultivation methods showed the potential to replace miss‐folded formats of protein with proper folded, soluble form with improved potency.Significance and Impact of the Study
Escherichia coli expression of recombinant proteins still counts for nearly 40% of marketed biopharmaceuticals. The major drawback of this system is the lack of appropriate post‐translational modifications, which may cause potency loss/decline. Therefore, applying alternative methods of cultivation as investigated here is a promising approach to overcome potency decrease problem in this protein production system. 相似文献39.
Dejan Cagli? Kristin M. Bompiani Michelle C. Krutein Petr ?apek Tobin J. Dickerson 《Journal of visualized experiments : JoVE》2013,(82)
Botulinum neurotoxin (BoNT) is a potent and potentially lethal bacterial toxin that binds to host motor neurons, is internalized into the cell, and cleaves intracellular proteins that are essential for neurotransmitter release. BoNT is comprised of a heavy chain (HC), which mediates host cell binding and internalization, and a light chain (LC), which cleaves intracellular host proteins essential for acetylcholine release. While therapies that inhibit toxin binding/internalization have a small time window of administration, compounds that target intracellular LC activity have a much larger time window of administrations, particularly relevant given the extremely long half-life of the toxin. In recent years, small molecules have been heavily analyzed as potential LC inhibitors based on their increased cellular permeability relative to larger therapeutics (peptides, aptamers, etc.). Lead identification often involves high-throughput screening (HTS), where large libraries of small molecules are screened based on their ability to modulate therapeutic target function. Here we describe a FRET-based assay with a commercial BoNT/A LC substrate and recombinant LC that can be automated for HTS of potential BoNT inhibitors. Moreover, we describe a manual technique that can be used for follow-up secondary screening, or for comparing the potency of several candidate compounds. 相似文献
40.
Tijjani Salihu Shinkafi Abhinav Kaushik Amena Mahmood Ambrish Kumar Tiwari Mohammad Mumtaz Alam Mymoona Akhter 《Journal of biomolecular structure & dynamics》2020,38(10):2976-2987
AbstractThis study identifies and validates hexokinase type 4 (HK4), an isozyme of hexokinase in the liver and pancreas, as an important target of C2-β-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone (βdGT), a xanthone glucoside suggested to have antidiabetic property. In the study, we applied the computational pipeline of molecular docking followed by the molecular dynamics simulations to shortlist potential βdGT protein targets. The analysis of protein dynamics and the binding free energy (ΔG) led us to the identification of HK4 as a key βdGT target, whereby the binding mode and domain dynamics suggested the activator function of βdGT. βdGT bound to the allosteric site of the isozyme ~13?Å away from the substrate (glucose)-binding site. The binding free energy of the ligand-protein complex was energetically feasible (ΔG, –41.61?kcal/mol) and the cleft angle deviation between the two (small and large) domains of HK4 revealed differential HK4 dynamics in response to βdGT binding. 3D structure analysis of the isozyme-ligand complex highlighted the role of Arg63, Glu67 and Lys458 in ligand stabilization and hydrophobic interactions mediated by Tyr214 and Met235. Experimental validation of the results of computational analysis confirmed the activator function of βdGT on HK4. The study has implication in diabetes as βdGT may be used to lower the blood glucose level by activating hepatic and pancreatic hexokinase without the risk of hypoglycemia.Communicated by Ramaswamy H. Sarma 相似文献