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151.
FBXL20 promotes breast cancer malignancy by inhibiting apoptosis through degradation of PUMA and BAX
Rajesh Kumar Manne Yashika Agrawal Sunil K. Malonia Shahid Banday Sarathkumar Edachery Asha Patel Avinash Kumar Praveenkumar Shetty Manas Kumar Santra 《The Journal of biological chemistry》2021,297(4)
Apoptosis is a programmed cell death that efficiently removes damaged cells to maintain tissue homeostasis. Defect in apoptotic machinery can lead to tumor development, progression, and resistance to chemotherapy. PUMA (p53 upregulated modulator of apoptosis) and BAX (BCL2-associated X protein) are among the most well-known inducers of apoptosis. It has been reported that expression levels of BAX and PUMA are controlled at the posttranslational level by phosphorylation. However, the posttranslational regulation of these proapoptotic proteins remains largely unexplored. In this study, using biochemical, molecular biology, flow cytometric, and immunohistochemistry techniques, we show that PUMA and BAX are the direct target of the F-box protein FBXL20, which restricts their cellular levels. FBXL20 directs the proteasomal degradation of PUMA and BAX in a protein kinase AKT1-dependent manner to promote cancer cell proliferation and tumor growth. Interestingly, inactivation of AKT1 results in activation of another protein kinase GSK3α/β, which facilitates the proteasomal degradation of FBXL20 by another F-box protein, FBXO31. Thus, a switch between two signaling kinases AKT1 and GSK3α/β modulates the functional activity of these proapoptotic regulators, thereby determining cell survival or death. RNAi-mediated ablation of FBXL20 results in increased levels of PUMA as well as BAX, which further enhances the sensitivity of cancer cells to chemotherapeutic drugs. We showed that high level expression of FBXL20 in cancer cells reduces therapeutic drug-induced apoptosis and promotes chemoresistance. Overall, this study highlights the importance of targeting FBXL20 in cancers in conjunction with chemotherapy and may represent a promising anticancer strategy to overcome chemoresistance. 相似文献
152.
Santosh Kumar Srivastava V. Rajesh Iyer Tamoghna Ghosh Paramesh Ramulu Lambadi Ranjana Pathania Naveen Kumar Navani 《Nucleic acids research》2016,44(5):2451-2461
Advances in chemical biology have led to selection of synthetic functional nucleic acids for in vivo applications. Discovery of synthetic nucleic acid regulatory elements has been a long-standing goal of chemical biologists. Availability of vast genome level genetic resources has motivated efforts for discovery and understanding of inducible synthetic genetic regulatory elements. Such elements can lead to custom-design of switches and sensors, oscillators, digital logic evaluators and cell–cell communicators. Here, we describe a simple, robust and universally applicable module for discovery of inducible gene regulatory elements. The distinguishing feature is the use of a toxic peptide as a reporter to suppress the background of unwanted bacterial recombinants. Using this strategy, we show that it is possible to isolate genetic elements of non-genomic origin which specifically get activated in the presence of DNA gyrase A inhibitors belonging to fluoroquinolone (FQ) group of chemicals. Further, using a system level genetic resource, we prove that the genetic regulation is exerted through histone-like nucleoid structuring (H-NS) repressor protein. Till date, there are no reports of in vivo selection of non-genomic origin inducible regulatory promoter like elements. Our strategy opens an uncharted route to discover inducible synthetic regulatory elements from biologically-inspired nucleic acid sequences. 相似文献
153.
Genetic rescue of chondrodysplasia and the perinatal lethal effect of cartilage link protein deficiency 总被引:1,自引:0,他引:1
Czipri M Otto JM Cs-Szabó G Kamath RV Vermes C Firneisz G Kolman KJ Watanabe H Li Y Roughley PJ Yamada Y Olsen BR Glant TT 《The Journal of biological chemistry》2003,278(40):39214-39223
154.
Preliminary results on the photoluminescence and optically stimulated luminescence in Cu‐doped and Ag‐doped ZnB2X4 (B = Li,Na, K: X = Cl,Br) compounds 下载免费PDF全文
Photoluminescence, and optically stimulated luminescence in ZnB2X4 (B; Li,Na,K: X; Cl,Br) compounds doped with Cu+ or Ag+ were studied. Double humped emission bands attributable to the activators were observed in all the samples. The observed photoluminescence of Cu+ and Ag+ could be identified with 3d94s1?3d10 and 4d95s1?5d10 transitions respectively. The longer wavelength band (400–500 nm range) could be attributed to the Cu+ or Ag+ ion replacing alkali ion at the octahedral alkali site whereas short wavelength band (340–400 nm range) is attributed to a Cu or Ag ion at tetrahedral zinc site. The short wavelength band was found to be intense compared with long wavelength and gave an indication that most of the Cu or Ag ions prefered a tetrahedral Zn site compared with the octahedral alkali site. All the samples exhibit optically stimulated luminescence (OSL). The sensitivity was found to be lattice dependent. The lowest sensitivity of about 1% compared with Al2O3:C was observed in lithium lattices whereas highest the sensitivity of about 290% was observed in the case of Cu‐doped ZnNa2Br4. 相似文献
155.
Ashrafian H Czibik G Bellahcene M Aksentijević D Smith AC Mitchell SJ Dodd MS Kirwan J Byrne JJ Ludwig C Isackson H Yavari A Støttrup NB Contractor H Cahill TJ Sahgal N Ball DR Birkler RI Hargreaves I Tennant DA Land J Lygate CA Johannsen M Kharbanda RK Neubauer S Redwood C de Cabo R Ahmet I Talan M Günther UL Robinson AJ Viant MR Pollard PJ Tyler DJ Watkins H 《Cell metabolism》2012,15(3):361-371
156.
157.
Zaware P Shah SR Pingali H Makadia P Thube B Pola S Patel D Priyadarshini P Suthar D Shah M Jamili J Sairam KV Giri S Patel L Patel H Sudani H Patel H Jain M Patel P Bahekar R 《Bioorganic & medicinal chemistry letters》2011,21(2):628-632
A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders. 相似文献
158.
Rinki Ratnapriya Joseph Vijai Jayaram S. Kadandale Rajesh S. Iyer Kurupath Radhakrishnan Anuranjan Anand 《Human genetics》2010,128(2):123-130
We performed a whole genome linkage analysis in a three-generation south Indian family with multiple members affected with
juvenile myoclonic epilepsy (JME). The maximum two-point LOD score obtained was 3.32 at recombination fraction (θ) = 0 for
D2S2248. The highest multipoint score of 3.59 was observed for the genomic interval between D2S2322 and D2S2228 at the chromosomal
region 2q33–q36. Proximal and distal boundaries of the critical genetic interval were defined by D2S116 and D2S2390, respectively.
A 24-Mb haplotype was found to co-segregate with JME in the family. While any potentially causative variant in the functional
candidate genes, SLC4A3, SLC23A3, SLC11A1 and KCNE4, was not detected, we propose to examine brain-expressed NRP2, MAP2, PAX3, GPR1, TNS1 and DNPEP, and other such positional candidate genes to identify the disease-causing gene for the disorder. 相似文献
159.
Pratap S. Jadon Virendra Gajbhiye Rajesh S. Jadon Kavita R. Gajbhiye Narayanan Ganesh 《AAPS PharmSciTech》2009,10(4):1186-1192
The aim of the present report was to develop nonionic surfactant vesicles (niosomes) to improve poor and variable oral bioavailability
of griseofulvin. Niosomes were prepared by using different nonionic surfactants span 20, span 40, and span 60. The lipid mixture
consisted of surfactant, cholesterol, and dicetyl phosphate in the molar ratio of 125:25:1.5, 100:50:1.5, and 75:75:1.5, respectively.
The niosomal formulations were prepared by thin film method and ether injection method. The influence of different formulation
variables such as surfactant type, surfactant concentration, and cholesterol concentration was optimized for size distribution
and entrapment efficiency for both methods. Result indicated that the niosomes prepared by thin film method with span 60 provided
higher entrapment efficiency. The niosomal formulation exhibited significantly retarded in vitro release as compared with free drug. The in vivo study revealed that the niosomal dispersion significantly improved the oral bioavailability of griseofulvin in albino rats
after a single oral dose. The maximum concentration (C
max) achieved in case of niosomal formulation was approximately double (2.98 μg/ml) as compared to free drug (1.54 μg/ml). Plasma
drug profile also suggested that the developed niosomal system also has the potential of maintaining therapeutic level of
griseofulvin for a longer period of time as compared to free griseofulvin. The niosomal formulation showed significant increase
in area under the curve0-24 (AUC; 41.56 μg/ml h) as compared to free griseofulvin (22.36 μg/ml h) reflecting sustained release characteristics. In conclusion,
the niosomal formulation could be one of the promising delivery system for griseofulvin with improved oral bioavailability
and prolonged drug release profiles. 相似文献
160.
Constitutive expression of Arabidopsis NPR1 confers enhanced resistance to the early instars of Spodoptera litura in transgenic tobacco 总被引:1,自引:0,他引:1
Meur G Budatha M Srinivasan T Rajesh Kumar KR Dutta Gupta A Kirti PB 《Physiologia plantarum》2008,133(4):765-775
In Arabidopsis , NPR1 ( AtNPR1 ) regulates salicylic acid (SA)-mediated activation of PR genes at the onset of systemic acquired resistance. AtNPR1 also modulates SA-induced suppression of jasmonic acid-responsive gene expression, and npr1 mutants manifest enhanced herbivore resistance. We have raised stable transgenic tobacco lines, expressing AtNPR1 constitutively, which showed elevated expression of PR1 and PR2 genes upon SA treatment. Herbivore bioassays with a generalist polyphagous pest, Spodoptera litura , revealed that the transgenic lines exhibited enhanced resistance compared to the wild-type plants, particularly with respect to younger larval populations. Insect-mediated injury induced several protease inhibitors (PIs), more significantly a 40-kDa serine PI in all the tobacco lines, but the induction was higher in the transgenic plants. We show in this communication that heterologous expression of AtNPR1 provides enhanced resistance to early larval populations of the herbivore, Spodoptera in transgenic tobacco plants. 相似文献