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331.
Kohli N Hassler BL Parthasarathy L Richardson RJ Ofoli RY Worden RM Lee I 《Biomacromolecules》2006,7(12):3327-3335
This paper presents the formation of a novel biomimetic interface consisting of an electrolessly deposited gold film overlaid with a tethered bilayer lipid membrane (tBLM). Self-assembly of colloidal gold particles was used to create an electrolessly deposited gold film on a glass slide. The properties of the film were characterized using field-effect scanning electron microscopy, energy dispersive spectroscopy, and atomic force microscopy. Bilayer lipid membranes were then tethered to the gold film by first depositing an inner molecular leaflet using a mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate], 1,2-di-O-phytanyl-sn-glycero-3-phosphoethanolamine (DPGP), and cystamine in ethanol onto a freshly prepared electrolessly deposited gold surface. The outer leaflet was then formed by the fusion of liposomes made from DPGP or 1,2-dioleoyl-sn-glycero-3-phosphocholine on the inner leaflet. To provide functionality, two membrane biomolecules were also incorporated into the tBLMs: the ionophore valinomycin and a segment of neuropathy target esterase containing the esterase domain. Electrochemical impedance spectroscopy, UV/visible spectroscopy, and fluorescence recovery after pattern photobleaching were used to characterize the resulting biomimetic interfaces and confirm the biomolecule activity of the membrane. Microcontact printing was used to form arrays of electrolessly deposited gold patterns on glass slides. Subsequent deposition of lipids yielded arrays of tBLMs. This approach can be extended to form functional biomimetic interfaces on a wide range of inexpensive materials, including plastics. Potential applications include high-throughput screening of drugs and chemicals that interact with cell membranes and for probing, and possibly controlling, interactions between living cells and synthetic membranes. In addition, the gold electrode provides the possibility of electrochemical applications, including biocatalysis, bio-fuel cells, and biosensors. 相似文献
332.
Saravanan Parthasarathy Kenneth Henry Huaxing Pei Josh Clayton Mark Rempala Deidre Johns Oscar De Frutos Pablo Garcia Carlos Mateos Sehila Pleite Yong Wang Stephanie Stout Bradley Condon Sheela Ashok Zhohai Lu William Ehlhardt Tom Raub Mei Lai Timothy P. Burkholder 《Bioorganic & medicinal chemistry letters》2018,28(10):1887-1891
During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model. 相似文献
333.
Thomas Ibanez Cláudia Baider Chris Birkinshaw Heike Culmsee Susan Cordell F. B. Vincent Florens Janet Franklin Christian P. Giardina Thomas W. Gillespie Melinda Laidlaw Creighton M. Litton Tara G. Martin Rebecca Ostertag Narayanaswamy Parthasarathy Richard Randrianaivo Miramasoandro Randrianjanahary Muthu Rajkumar Ladan Rasingam Fidy Ratovoson Ludovic Reza Lawren Sack Shin‐ichiro Aiba Edward Webb Timothy J. S. Whitfeld Runguo Zang Philippe Birnbaum 《Global Ecology and Biogeography》2018,27(4):474-486
334.
Bagavathy Shanmugam Karthikeyan Suvaiyarasan Suvaithenamudhan Mohammad Abdulkader Akbarsha Subbiah Parthasarathy 《Cell biochemistry and biophysics》2018,76(1-2):91-110
Cytochrome P450 (CYP) 1A and 2B subfamily enzymes are important drug metabolizing enzymes, and are highly conserved across species in terms of sequence homology. However, there are major to minor structural and macromolecular differences which provide for species-selectivity and substrate-selectivity. Therefore, species-selectivity of CYP1A and CYP2B subfamily proteins across human, mouse and rat was analyzed using molecular modeling, docking and dynamics simulations when the chiral molecules quinine and quinidine were used as ligands. The three-dimensional structures of 17 proteins belonging to CYP1A and CYP2B subfamilies of mouse and rat were predicted by adopting homology modeling using the available structures of human CYP1A and CYP2B proteins as templates. Molecular docking and dynamics simulations of quinine and quinidine with CYP1A subfamily proteins revealed the existence of species-selectivity across the three species. On the other hand, in the case of CYP2B subfamily proteins, no role for chirality of quinine and quinidine in forming complexes with CYP2B subfamily proteins of the three species was indicated. Our findings reveal the roles of active site amino acid residues of CYP1A and CYP2B subfamily proteins and provide insights into species-selectivity of these enzymes across human, mouse, and rat. 相似文献
335.
Bo Tan Debra A. Young Zhao-Hai Lu Tao Wang Timothy I. Meier Robert L. Shepard Kenneth Roth Yan Zhai Karen Huss Ming-Shang Kuo James Gillig Saravanan Parthasarathy Timothy P. Burkholder Michele C. Smith Sandaruwan Geeganage Genshi Zhao 《The Journal of biological chemistry》2013,288(5):3500-3511
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD+, essential for cellular metabolism, energy production, and DNA repair. NAMPT has been extensively studied because of its critical role in these cellular processes and the prospect of developing therapeutics against the target, yet how it regulates cellular metabolism is not fully understood. In this study we utilized liquid chromatography-mass spectrometry to examine the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and serine biosynthesis in cancer cells and tumor xenografts. We show for the first time that NAMPT inhibition leads to the attenuation of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step due to the reduced availability of NAD+ for the enzyme. The attenuation of glycolysis results in the accumulation of glycolytic intermediates before and at the glyceraldehyde 3-phosphate dehydrogenase step, promoting carbon overflow into the pentose phosphate pathway as evidenced by the increased intermediate levels. The attenuation of glycolysis also causes decreased glycolytic intermediates after the glyceraldehyde 3-phosphate dehydrogenase step, thereby reducing carbon flow into serine biosynthesis and the TCA cycle. Labeling studies establish that the carbon overflow into the pentose phosphate pathway is mainly through its non-oxidative branch. Together, these studies establish the blockade of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step as the central metabolic basis of NAMPT inhibition responsible for ATP depletion, metabolic perturbation, and subsequent tumor growth inhibition. These studies also suggest that altered metabolite levels in tumors can be used as robust pharmacodynamic markers for evaluating NAMPT inhibitors in the clinic. 相似文献
336.
Structure,Dynamics, Evolution,and Function of a Major Scaffold Component in the Nuclear Pore Complex
Parthasarathy Sampathkumar Seung Joong Kim Paula Upla William J. Rice Jeremy Phillips Benjamin L. Timney Ursula Pieper Jeffrey B. Bonanno Javier Fernandez-Martinez Zhanna Hakhverdyan Natalia E. Ketaren Tsutomu Matsui Thomas M. Weiss David L. Stokes J. Michael Sauder Stephen K. Burley Andrej Sali Michael P. Rout Steven C. Almo 《Structure (London, England : 1993)》2013,21(4):560-571
337.
Parthasarathy Chandrakesan Laxmi Uma Maheswar Rao Jakkula Ishfaq Ahmed Badal Roy Shrikant Anant Shahid Umar 《PloS one》2013,8(11)
Both β-catenin and NF-κB have been implicated in our laboratory as candidate factors in driving proliferation in an in vivo model of Citrobacter rodentium (CR)-induced colonic crypt hyper-proliferation and hyperplasia. Herein, we test the hypothesis that β-catenin and not necessarily NF-κB regulates colonic crypt hyperplasia or tumorigenesis in response to CR infection. When C57Bl/6 wild type (WT) mice were infected with CR, sequential increases in proliferation at days 9 and 12 plateaued off at day 19 and paralleled increases in NF-κB signaling. In Tlr4−/− (KO) mice, a sequential but sustained proliferation which tapered off only marginally at day 19, was associated with TLR4-dependent and independent increases in NF-κB signaling. Similarly, increases in either activated or total β-catenin in the colonic crypts of WT mice as early as day 3 post-infection coincided with cyclinD1 and c-myc expression and associated crypt hyperplasia. In KO mice, a delayed kinetics associated predominantly with increases in non-phosphorylated (active) β-catenin coincided with increases in cyclinD1, c-myc and crypt hyperplasia. Interestingly, PKCζ-catalyzed Ser-9 phosphorylation and inactivation of GSK-3β and not loss of wild type APC protein accounted for β-catenin accumulation and nuclear translocation in either strain. In vitro studies with Wnt2b and Wnt5a further validated the interplay between the Wnt/β-catenin and NF-κB pathways, respectively. When WT or KO mice were treated with nanoparticle-encapsulated siRNA to β-catenin (si- β-Cat), almost complete loss of nuclear β-catenin coincided with concomitant decreases in CD44 and crypt hyperplasia without defects in NF-κB signaling. si-β-Cat treatment to Apc
Min/+ mice attenuated CR-induced increases in β-catenin and CD44 that halted the growth of mutated crypts without affecting NF-κB signaling. The predominant β-catenin-induced crypt proliferation was further validated in a Castaneus strain (B6.CAST.11M) that exhibited significant crypt hyperplasia despite an attenuated NF-κB signaling. Thus, β-catenin and not necessarily NF-κB regulates crypt hyperplasia in response to bacterial infection. 相似文献
338.
Sudhakar Parthasarathy Brian Yoo Dan McElheny William Tay Yoshitaka Ishii 《The Journal of biological chemistry》2014,289(14):9998-10010
The interaction of redox-active copper ions with misfolded amyloid β (Aβ) is linked to production of reactive oxygen species (ROS), which has been associated with oxidative stress and neuronal damages in Alzheimer disease. Despite intensive studies, it is still not conclusive how the interaction of Cu+/Cu2+ with Aβ aggregates leads to ROS production even at the in vitro level. In this study, we examined the interaction between Cu+/Cu2+ and Aβ fibrils by solid-state NMR (SSNMR) and other spectroscopic methods. Our photometric studies confirmed the production of ∼60 μm hydrogen peroxide (H2O2) from a solution of 20 μm Cu2+ ions in complex with Aβ(1–40) in fibrils ([Cu2+]/[Aβ] = 0.4) within 2 h of incubation after addition of biological reducing agent ascorbate at the physiological concentration (∼1 mm). Furthermore, SSNMR 1H T1 measurements demonstrated that during ROS production the conversion of paramagnetic Cu2+ into diamagnetic Cu+ occurs while the reactive Cu+ ions remain bound to the amyloid fibrils. The results also suggest that O2 is required for rapid recycling of Cu+ bound to Aβ back to Cu2+, which allows for continuous production of H2O2. Both 13C and 15N SSNMR results show that Cu+ coordinates to Aβ(1–40) fibrils primarily through the side chain Nδ of both His-13 and His-14, suggesting major rearrangements from the Cu2+ coordination via Nϵ in the redox cycle. 13C SSNMR chemical shift analysis suggests that the overall Aβ conformations are largely unaffected by Cu+ binding. These results present crucial site-specific evidence of how the full-length Aβ in amyloid fibrils offers catalytic Cu+ centers. 相似文献
339.
The crystal structure of 6-azathymine hemihydrate (6AzTH) exhibits a novel intercalation of water molecules interposed half-way between the modified bases 6.3 to 6.7 A apart. The crystal contains four molecules of 6-azathymine (6AzT) and two water molecules as the independent repeating unit. These two water molecules together with the four bases form two separate water sandwiches. In the crystal structure these sandwiches form two sets of local clusters. The anhydrous crystalline form of 6AzT, on the other hand, is stabilized by base stacking interactions. Both the water molecules in 6AzTH that are involved in sandwich formation have trigonal coordination around them. A reexamination of the crystal structure of 5-amino-2-thiocytosine (5A2TC) revealed that one of the water molecules in this structure also forms a water sandwich and has trigonal coordination whereas the other water molecule with tetrahedral coordination does not form a sandwich. The environment and the characteristics of the intercalated water molecule in these structures suggest a possible role for such water intercalations in the dynamics of DNA. Crystals of 6AzTH are monoclinic, space group P21/n, with unit cell parameters a = 8.861 (1), b = 13.177 (3), c = 20.662 (2) A, beta = 93.35 (1) degrees, and Z = 16. From diffractometer data (2503 reflections, greater than or equal to 3 sigma), the crystal structure was solved and refined to an R of 0.056. 相似文献
340.
S. Muthuramkumar N. Ayyappan N. Parthasarathy Divya Mudappa T. R. Shankar Raman M. Arthur Selwyn L. Arul Pragasan 《Biotropica》2006,38(2):143-160
Changes in tree, liana, and understory plant diversity and community composition in five tropical rain forest fragments varying in area (18–2600 ha) and disturbance levels were studied on the Valparai plateau, Western Ghats. Systematic sampling using small quadrats (totaling 4 ha for trees and lianas, 0.16 ha for understory plants) enumerated 312 species in 103 families: 1968 trees (144 species), 2250 lianas (60 species), and 6123 understory plants (108 species). Tree species density, stem density, and basal area were higher in the three larger (> 100 ha) rain forest fragments but were negatively correlated with disturbance scores rather than area per se. Liana species density, stem density, and basal area were higher in moderately disturbed and lower in heavily disturbed fragments than in the three larger fragments. Understory species density was highest in the highly disturbed 18‐ha fragment, due to weedy invasive species occurring with rain forest plants. Nonmetric multidimensional scaling and Mantel tests revealed significant and similar patterns of floristic variation suggesting similar effects of disturbance on community compositional change for the three life‐forms. The five fragments encompassed substantial plant diversity in the regional landscape, harbored at least 70 endemic species (3.21% of the endemic flora of the Western Ghats–Sri Lanka biodiversity hotspot), and supported many endemic and threatened animals. The study indicates the significant conservation value of rain forest fragments in the Western Ghats, signals the need to protect them from further disturbances, and provides useful benchmarks for restoration and monitoring efforts. 相似文献