全文获取类型
收费全文 | 599篇 |
免费 | 24篇 |
专业分类
623篇 |
出版年
2022年 | 3篇 |
2021年 | 8篇 |
2020年 | 6篇 |
2019年 | 4篇 |
2018年 | 14篇 |
2017年 | 11篇 |
2016年 | 13篇 |
2015年 | 15篇 |
2014年 | 20篇 |
2013年 | 38篇 |
2012年 | 50篇 |
2011年 | 46篇 |
2010年 | 28篇 |
2009年 | 24篇 |
2008年 | 39篇 |
2007年 | 48篇 |
2006年 | 19篇 |
2005年 | 26篇 |
2004年 | 27篇 |
2003年 | 30篇 |
2002年 | 34篇 |
2001年 | 8篇 |
2000年 | 4篇 |
1999年 | 6篇 |
1998年 | 12篇 |
1997年 | 8篇 |
1996年 | 5篇 |
1995年 | 6篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 4篇 |
1991年 | 6篇 |
1990年 | 7篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 7篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1977年 | 4篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1969年 | 1篇 |
1967年 | 1篇 |
1966年 | 2篇 |
1964年 | 1篇 |
1963年 | 2篇 |
排序方式: 共有623条查询结果,搜索用时 0 毫秒
501.
502.
Smriti Khanna Sandeep Burudkar Komal Bajaj Pranay Shah Ashish Keche Usha Ghosh Avani Desai Ankita Srivastava Asha Kulkarni-Almeida Nitin J. Deshmukh Amol Dixit Manoja K. Brahma Umakant Bahirat Lalit Doshi Kumar V.S. Nemmani Prashant Tannu Anagha Damre Chandrika B-Rao Rajiv Sharma H. Sivaramakrishnan 《Bioorganic & medicinal chemistry letters》2012,22(24):7543-7546
Structure–activity relationship studies were carried out for lead generation following structure-guided design approach from an isocytosine scaffold identified earlier for xanthine oxidase inhibition. A 470-fold improvement in in vitro IC50 was obtained in the process. Five most potent compounds with nanomolar IC50 values were selected for pharmacokinetics and in vivo experiments. The best compound showed good in vivo activity when administered intraperitoneally but was not active by oral route. The results suggest that improvement in oral exposure could improve the in vivo efficacy of this series. 相似文献
503.
Kamal A Shaik AB Kumar CG Mongolla P Rani PU Krishna KV Mamidyala SK Joseph J 《Journal of microbiology and biotechnology》2012,22(1):69-79
In an ongoing survey of the bioactive potential of microorganisms from Ladakh, India, the culture medium of a bacterial strain of a new Pseudomonas sp., strain ICTB-745, isolated from an alkaline soil sample collected from Leh, Ladakh, India, was found to contain metabolites that exhibited broad-spectrum antimicrobial and biosurfactant activities. Bioactivity-guided purification resulted in the isolation of four bioactive compounds. Their chemical structures were elucidated by (1)H and (13)C NMR, 2D-NMR (HMBC, HSQC, (1)H,(1)H-COSY, and DEPT- 135), FT-IR, and mass spectroscopic methods, and were identified as 1-hydroxyphenazine, phenazine-1-carboxylic acid (PCA), rhamnolipid-1 (RL-1), and rhamnolipid-2 (RL-2). These metabolites exhibited various biological activities like antimicrobial and efficient cytotoxic potencies against different human tumor cell lines such as HeLa, HepG2, A549, and MDA MB 231. RL-1 and RL-2 exhibited a dose-dependent antifeedant activity against Spodoptera litura, producing about 82.06% and 73.66% antifeedant activity, whereas PCA showed a moderate antifeedant activity (63.67%) at 60 microgram/cm2 area of castor leaf. Furthermore, PCA, RL-1, and RL-2 exhibited about 65%, 52%, and 47% mortality, respectively, against Rhyzopertha dominica at 20 microgram/ml. This is the first report of rhamnolipids as antifeedant metabolites against Spodoptera litura and as insecticidal metabolites against Rhyzopertha dominica. The metabolites from Pseudomonas sp. strain ICTB-745 have interesting potential for use as a biopesticide in pest control programs. 相似文献
504.
Kumar A Sushama A Manral S Sinha R Joshi R Singh U Rohil V Prasad AK Parmar VS Raj HG 《Nitric oxide》2012,26(1):9-19
Polyphenols have attracted immense interest because of their diverse biological and pharmacological activities. Surprisingly, not much is documented about the biological activities of acetoxy derivatives of polyphenol called polyphenolic acetates (PA). In our previous reports, we have conclusively established the Calreticulin Transacetylase (CRTAase) catalyzed activation of neuronal nitric oxide synthase (nNOS) and tumor necrosis factor-α (TNF-α) induced nitric oxide synthase (iNOS) by PA. In the present work, specificity of CRTAase to various classes of PA was characterized in human platelet. The effect of PA, on platelet NOS and intracellular cyclic guanosine monophosphate (cGMP), and adenosine diphosphate (ADP)-induced platelet aggregation were studied in an elaborated manner. Platelet CRTAase exhibited differential specificities to polyphenolic acetates upon incubation with l-arginine leading to activation of NOS. The intraplatelet generation of NO was studied by flowcytometry using DCFH-DA. The differential specificities of CRTAase to PA were found to positively correlate with increased production of NO upon incubation of PRP with PA and l-arginine. Further, the inhibitory effect of l-NAME on PA induced NO formation in platelets substantiated the CRTAase catalyzed activation of NOS. The real-time RT-PCR profile of NOS isoforms confirmed the preponderance of eNOS over iNOS in human platelets on treatment with PA. Western blot analysis also reiterated the differential pattern of acetylation of eNOS by PA. PA were also found effective in increasing the intraplatelet cGMP levels and inhibiting ADP-induced platelet aggregation. It is worth mentioning that the effects of PA were found to be in tune with the specificities of platelet CRTAase to PA as the substrates. 相似文献
505.
Adila?Alkindy Nadia?Chuzhanova Usha?Kini David?N?Cooper Meena?UpadhyayaEmail author 《Human genomics》2012,6(1):12
Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder with an increased susceptibility to develop both benign and malignant tumors but with a wide spectrum of inter and intrafamilial clinical variability. The establishment of genotype-phenotype associations in NF1 is potentially useful for targeted therapeutic intervention but has generally been unsuccessful, apart from small subsets of molecularly defined patients. The objective of this study was to evaluate the clinical phenotype associated with the specific types of NF1 mutation in a retrospectively recorded clinical dataset comprising 149 NF1 mutation-known individuals from unrelated families. Each patient was assessed for ten NF1-related clinical features, including the number of café-au-lait spots, cutaneous and subcutaneous neurofibromas and the presence/absence of intertriginous skin freckling, Lisch nodules, plexiform and spinal neurofibromas, optic gliomas, other neoplasms (in particular CNS gliomas, malignant peripheral nerve sheath tumors (MPNSTs), juvenile myelomonocytic leukemia, rhabdomyosarcoma, phaechromocytoma, gastrointestinal stromal tumors, juvenile xanthogranuloma, and lipoma) and evidence of learning difficulties. Gender and age at examination were also recorded. Patients were subcategorized according to their associated NF1 germ line mutations: frame shift deletions (52), splice-site mutations (23), nonsense mutations (36), missense mutations (32) and other types of mutation (6). A significant association was apparent between possession of a splice-site mutation and the presence of brain gliomas and MPNSTs (p?=?0.006). If confirmed, these findings are likely to be clinically important since up to a third of NF1 patients harbor splice-site mutations. A significant influence of gender was also observed on the number of subcutaneous neurofibromas (females, p?=?0.009) and preschool learning difficulties (females, p?=?0.022). 相似文献
506.
507.
Prosenjit Sen Sanghamitra Sahoo Usha R. Pendurthi L. Vijaya Mohan Rao 《The Journal of biological chemistry》2010,285(26):20410-20420
Zinc is an essential trace element for human nutrition and is critical to the structure, stability, and function of many proteins. Zinc ions were shown to enhance activation of the intrinsic pathway of coagulation but down-regulate the extrinsic pathway of coagulation. The protein C pathway plays a key role in blood coagulation and inflammation. At present there is no information on whether zinc modulates the protein C pathway. In the present study we found that Zn2+ enhanced the binding of protein C/activated protein C (APC) to endothelial cell protein C receptor (EPCR) on endothelial cells. Binding kinetics revealed that Zn2+ increased the binding affinities of protein C/APC to EPCR. Equilibrium dialysis with 65Zn2+ revealed that Zn2+ bound to the Gla domain as well as sites outside of the Gla domain of protein C/APC. Intrinsic fluorescence measurements suggested that Zn2+ binding induces conformational changes in protein C/APC. Zn2+ binding to APC inhibited the amidolytic activity of APC, but the inhibition was reversed by Ca2+. Zn2+ increased the rate of APC generation on endothelial cells in the presence of physiological concentrations of Ca2+ but did not further enhance increased APC generation obtained in the presence of physiological concentrations of Mg2+ with Ca2+. Zn2+ had no effect on the anticoagulant activity of APC. Zn2+ enhanced APC-mediated activation of protease activated receptor 1 and p44/42 MAPK. Overall, our data show that Zn2+ binds to protein C/APC, which results in conformational changes in protein C/APC that favor their binding to EPCR. 相似文献
508.
John den Engelsman Erik J Bennink Linda Doerwald Carla Onnekink Lisa Wunderink Usha P Andley Kanefusa Kato Wilfried W de Jong Wilbert C Boelens 《European journal of biochemistry》2004,271(21):4195-4203
The mammalian small heat shock protein alphaB-crystallin can be phosphorylated at three different sites, Ser19, Ser45 and Ser59. We compared the intracellular distribution of wild-type, nonphosphorylatable and all possible pseudophosphorylation mutants of alphaB-crystallin by immunoblot and immunocytochemical analyses of stable and transiently transfected cells. We observed that pseudophosphorylation at two (especially S19D/S45D) or all three (S19D/S45D/S59D) sites induced the partial translocation of alphaB-crystallin from the detergent-soluble to the detergent-insoluble fraction. Double immunofluorescence studies showed that the pseudophosphorylation mutants localized in nuclear speckles containing the splicing factor SC35. The alphaB-crystallin mutants in these speckles were resistant to mild detergent treatment, and also to DNase I or RNase A digestion, indicating a stable interaction with one or more speckle proteins, not dependent on intact DNA or RNA. We further found that FBX4, an adaptor protein of the ubiquitin-protein isopeptide ligase SKP1/CUL1/F-box known to interact with pseudophosphorylated alphaB-crystallin, was also recruited to SC35 speckles when cotransfected with the pseudophosphorylation mutants. Because SC35 speckles also react with an antibody against alphaB-crystallin endogenously phosphorylated at Ser45, our findings suggest that alphaB-crystallin has a phosphorylation-dependent role in the ubiquitination of a component of SC35 speckles. 相似文献
509.
All living systems respond to a variety of stress conditions by inducing the synthesis of stress or heat shock proteins (HSPs), which transiently protect cells. HSP synthesis was preceded by an increase in intracellular free calcium concentration [(Ca(2+))i]. In this study, we show that Ca(2+) ionophore, ionomycin, induced an immediate increase in intracellular free Ca(2+) and examined how this increase affects heat shock response in rat hepatoma cell line H4II-E-C3. Results indicate that incubating H4II-E-C3 cells with 0.3 microM ionomycin at 37 degrees C for 15 min results in the induction of HSP 70 in both Ca(2+)-containing and Ca(2+)-free medium. Associated with this increase in free Ca(2+) is an in vivo change in membrane organization and activation of signaling molecules like ERKS and SAPKs/JNK. In Ca(2+) containing medium HSP 70 induction mediated by HSF-HSE interaction was faster upon ionomycin treatment as compared to heat shock. Our results show that ionomycin, at sub lethal concentration, increases intracellular free Ca(2+) concentration, activates SAPK/JNK and HSF-HSE interaction, and induces HSP 70 synthesis. 相似文献
510.
A total of 72 plant extracts were tested in vitro for their ability to inhibit the mycelial growth of Lasiodiplodia theobromae and Colletotrichum musae the causal agents of crown rot disease of banana. The results showed that the leaf extract of Zimmu (an interspecific hybrid of Allium cepa L. × Allium sativum L.) and tuber extract of Zehneria scabra recorded maximum inhibition of mycelial growth and spore germination of both the test pathogens. The dipping of banana fruits in Zimmu leaf extract at 25% conc. exhibited 100% inhibition of crown rot disease in cold storage (14 °C) up to 35 days and increased the shelf life to 64 days. However, at room storage (28 ± 2 °C), the same treatment exhibited 86% inhibition of crown rot disease up to 12 days. It was found that the treatment of banana fruits with Zimmu leaf extract did not alter the organoleptic properties of banana. The biochemical analysis of banana fruits treated with Zimmu leaf extract showed significant increase in phenylalanine ammonia-lyase (PAL), chitinase and β-1,3-glucanase activities and enhanced accumulation of phenolic compounds compared to other treatments. These findings suggest that the effect of Zimmu leaf extract on crown rot disease may be associated with the direct fungi toxic property against the test pathogens and elicitation of defense related compounds in banana fruits. 相似文献