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BK. Binukumar Varsha Shukla Niranjana D. Amin Philip Grant M. Bhaskar Susan Skuntz Joseph Steiner Harish C. Pant 《Molecular biology of the cell》2015,26(24):4478-4491
Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease. 相似文献
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Summary Enhancing Factor (EF) is a 14 kDa protein isolated from mouse small intestines, which enhances the binding of 125I-EGF to A431 cells. This observation as well as our earlier in vitro studies have indicated that EF is a modulator of EGF. In adult mice, localization of EF by immunohistochemistry shows it is present pre-dominantly in the Paneth cells of the small intestines and to a lesser extent in the stomach and colon. This study of the ontogeny of EF shows that the appearance of the protein coincides with the appearance of mature Paneth cells. In new born mouse skin EF is localized in the hair follicles in the first hair cycle from day 2 to day 8. It is however absent in the adult skin. Thus EF is associated with tissues which have a high growth rate. 相似文献
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Barley plants (Hordeum vulgare L.) received foliar applications of 10–4 M gibberellic acid (GA3) and Kinetin (KN) individually and in combination at one or more of three growth stages: flag leaf appearance (I), ear emergence (II), and the first stage of senescence initiation in the flag leaf (III). Both plant growth regulators (PGR) hastened onset of senescence when sprayed at Stage I and/or Stage II. Treatment at Stage III, either alone or in combination with treatments at the other stages, tended to postpone senescence. Yield components also showed stage-dependent response: Stage I treatment increased the formation of total and bearing tillers, and Stage III treatment improved grain number and weight. However, while GA3 proved more effective than KN, the two together acted antagonistically. 相似文献
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Rahul C Deo Gabriel Musso Murat Tasan Paul Tang Annie Poon Christiana Yuan Janine F Felix Ramachandran S Vasan Rameen Beroukhim Teresa De Marco Pui-Yan Kwok Calum A MacRae Frederick P Roth 《Genome biology》2014,15(12)
Background
Cardiovascular disease (CVD) is the leading cause of death in the developed world. Human genetic studies, including genome-wide sequencing and SNP-array approaches, promise to reveal disease genes and mechanisms representing new therapeutic targets. In practice, however, identification of the actual genes contributing to disease pathogenesis has lagged behind identification of associated loci, thus limiting the clinical benefits.Results
To aid in localizing causal genes, we develop a machine learning approach, Objective Prioritization for Enhanced Novelty (OPEN), which quantitatively prioritizes gene-disease associations based on a diverse group of genomic features. This approach uses only unbiased predictive features and thus is not hampered by a preference towards previously well-characterized genes. We demonstrate success in identifying genetic determinants for CVD-related traits, including cholesterol levels, blood pressure, and conduction system and cardiomyopathy phenotypes. Using OPEN, we prioritize genes, including FLNC, for association with increased left ventricular diameter, which is a defining feature of a prevalent cardiovascular disorder, dilated cardiomyopathy or DCM. Using a zebrafish model, we experimentally validate FLNC and identify a novel FLNC splice-site mutation in a patient with severe DCM.Conclusion
Our approach stands to assist interpretation of large-scale genetic studies without compromising their fundamentally unbiased nature.Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0534-8) contains supplementary material, which is available to authorized users. 相似文献8.
Manju Shri Arti Rai Pankaj Kumar Verma Prashant Misra Sonali Dubey Smita Kumar Sikha Verma Neelam Gautam Rudra Deo Tripathi Prabodh Kumar Trivedi Debasis Chakrabarty 《Protoplasma》2013,250(2):631-636
Agrobacterium-mediated transformation of indica rice varieties has been quite difficult as these are recalcitrant to in vitro responses. In the present study, we established a high-efficiency Agrobacterium tumefaciens-mediated transformation system of rice (Oryza sativa L. ssp. indica) cv. IR-64, Lalat, and IET-4786. Agrobacterium strain EHA-101 harboring binary vector pIG121-Hm, containing a gene encoding for β-glucuronidase (GUS) and hygromycin resistance, was used in the transformation experiments. Manipulation of different concentrations of acetosyringone, days of co-culture period, bacterial suspension of different optical densities (ODs), and the concentrations of l-cysteine in liquid followed by solid co-culture medium was done for establishing the protocol. Among the different co-culture periods, 5 days of co-culture with bacterial cells (OD600 nm?=?0.5–0.8) promoted the highest frequency of transformation (83.04 %) in medium containing l-cysteine (400 mg l?1). Putative transformed plants were analyzed for the presence of a transgene through genomic PCR and GUS histochemical analyses. Our results also suggest that different cultural conditions and the addition of l-cysteine in the co-culture medium improve the Agrobacterium-mediated transformation frequencies from an average of 12.82 % to 33.33 % in different indica rice cultivars. 相似文献
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Melissa Latigo Mugambi Sarang Deo Adeodata Kekitiinwa Charles Kiyaga Mendel E. Singer 《PloS one》2013,8(11)