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91.
Alex Madrahimov Tomáš Helikar Bryan Kowal Guoqing Lu Jim Rogers 《Bulletin of mathematical biology》2013,75(6):988-1011
The replication and life cycle of the influenza virus is governed by an intricate network of intracellular regulatory events during infection, including interactions with an even more complex system of biochemical interactions of the host cell. Computational modeling and systems biology have been successfully employed to further the understanding of various biological systems, however, computational studies of the complexity of intracellular interactions during influenza infection is lacking. In this work, we present the first large-scale dynamical model of the infection and replication cycle of influenza, as well as some of its interactions with the host’s signaling machinery. Specifically, we focus on and visualize the dynamics of the internalization and endocytosis of the virus, replication and translation of its genomic components, as well as the assembly of progeny virions. Simulations and analyses of the models dynamics qualitatively reproduced numerous biological phenomena discovered in the laboratory. Finally, comparisons of the dynamics of existing and proposed drugs, our results suggest that a drug targeting PB1:PA would be more efficient than existing Amantadin/Rimantaine or Zanamivir/Oseltamivir. 相似文献
92.
The genetic stability of transgenes is a critical characteristic used to assess constructed cell lines used for vaccine production. The evaluation of gene copy numbers by a qPCR method, is one of the most common approaches used to assess the consistency of transgenes in a constructed cell line. The cell line AV529-19 is a Vero-based cell line specifically engineered to express the HSV-1 UL5 and UL29 open reading frames. AV529-19 is used to support the replication of a defective HSV-2 viral candidate vaccine called HSV529. To assess the genetic stability of the UL5 and UL29 transgenes in AV529-19 cells, a digital PCR-based approach was developed. During characterization of the test method, the specificity, accuracy, and intermediate precision of the assay was investigated based on regulatory guidelines. The developed assay was used to monitor the stability of the transgenes in the manufactured AV529-19 cell lines by comparison of transgene copy numbers in the master cell bank (MCB) with their copy numbers in the extended cell bank (ECB). Results showed that the UL29 and UL5 transgenes are stable in that there are one and three copies of the UL29 and UL5 genes, respectively, per cell in both the AV529-19 MCB and ECB. 相似文献
93.
Margaret Doherty Jonathan Bones Niaobh McLoughlin Jayne E. Telford Bryan Harmon Michael R. DeFelippis Pauline M. Rudd 《Analytical biochemistry》2013
Oligosaccharides attached to Asn297 in each of the CH2 domains of monoclonal antibodies play an important role in antibody effector functions by modulating the affinity of interaction with Fc receptors displayed on cells of the innate immune system. Rapid, detailed, and quantitative N-glycan analysis is required at all stages of bioprocess development to ensure the safety and efficacy of the therapeutic. The high sample numbers generated during quality by design (QbD) and process analytical technology (PAT) create a demand for high-performance, high-throughput analytical technologies for comprehensive oligosaccharide analysis. We have developed an automated 96-well plate-based sample preparation platform for high-throughput N-glycan analysis using a liquid handling robotic system. Complete process automation includes monoclonal antibody (mAb) purification directly from bioreactor media, glycan release, fluorescent labeling, purification, and subsequent ultra-performance liquid chromatography (UPLC) analysis. The entire sample preparation and commencement of analysis is achieved within a 5-h timeframe. The automated sample preparation platform can easily be interfaced with other downstream analytical technologies, including mass spectrometry (MS) and capillary electrophoresis (CE), for rapid characterization of oligosaccharides present on therapeutic antibodies. 相似文献
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96.
Leslie W. Tari Michael Trzoss Daniel C. Bensen Xiaoming Li Zhiyong Chen Thanh Lam Junhu Zhang Christopher J. Creighton Mark L. Cunningham Bryan Kwan Mark Stidham Karen J. Shaw Felice C. Lightstone Sergio E. Wong Toan B. Nguyen Jay Nix John Finn 《Bioorganic & medicinal chemistry letters》2013,23(5):1529-1536
The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity. 相似文献
97.
Ojas A. Namjoshi Zhi-jian Wang Sundari K. Rallapalli Edward Merle Johnson Yun-Teng Johnson Hanna Ng Joachim Ramerstorfer Zdravko Varagic Werner Sieghart Samarpan Majumder Bryan L. Roth James K. Rowlett James M. Cook 《Bioorganic & medicinal chemistry》2013,21(1):93-101
Selective modulation of specific benzodiazepine receptor (BzR) gamma amino butyric acid-A (GABAA) receptor ion channels has been identified as an important method for separating out the variety of pharmacological effects elicited by BzR-related drugs. Importantly, it has been demonstrated that both α2β(2/3)γ2 (α2BzR) and α3BzR (and/or α2/α3) BzR subtype selective ligands exhibit anxiolytic effects with little or no sedation. Previously we have identified several such ligands; however, three of our parent ligands exhibited significant metabolic liability in rodents in the form of a labile ester group. Here eight analogs are reported which were designed to circumvent this liability by utilizing a rational replacement of the ester moiety based on medicinal chemistry precedents. In a metabolic stability study using human liver microsomes, four compounds were found to undergo slower metabolic transformation, as compared to their corresponding ester analogs. These compounds were also evaluated in in vitro efficacy assays. Additionally, bioisostere 11 was evaluated in a rodent model of anxiety. It exhibited anxiolytic activity at doses of 10 and 100 mg/kg and was devoid of sedative properties. 相似文献
98.
Youngjae Kim Jeeyeon Kim Jinsung Tae Bryan L. Roth Hyewhon Rhim Gyochang Keum Ghilsoo Nam Hyunah Choo 《Bioorganic & medicinal chemistry》2013,21(9):2568-2576
It has been reported that 5-HT7 receptors are promising targets of depression and neuropathic pain. 5-HT7 receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT7 modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphenyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affinities to the 5-HT7 receptor depending upon the substituents attached to the biphenyl and aryl functionalities. Among those synthesized compounds, the compounds 1–24 and 1–26 showed the best binding affinities to the 5-HT7 receptor with Ki values of 43.0 and 46.0 nM, respectively. Structure–activity relationship study in conjunction with molecular docking study proposed that the 5-HT7 receptor might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH3 substituents within the arylpiperazine and the other for biphenyl methoxy group. 相似文献
99.
Craig S. Charron Beverly A. Clevidence George A. Albaugh Matthew H. Kramer Bryan T. Vinyard John A. Milner Janet A. Novotny 《The Journal of nutritional biochemistry》2013,24(5):894-902
Allyl isothiocyanate (AITC) is a dietary component with possible anticancer effects, though much information about AITC and cancer has been obtained from cell studies. To investigate the effect of AITC on DNA integrity in vivo, a crossover study was conducted. Adults (n= 46) consumed AITC, AITC-rich vegetables [mustard and cabbage (M/C)] or a control treatment with a controlled diet for 10 days each. On day 11, volunteers provided blood and urine before and after consuming treatments. Volunteers were characterized for genotype for GSTM1 and GSTT1 (glutathione S-transferases) and XPD (DNA repair). DNA integrity in peripheral blood mononuclear cells was assessed by single-cell gel electrophoresis. Urine was analyzed for 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) and creatinine. Ten-day intake of neither AITC nor M/C resulted in statistically significant differences in DNA strand breaks [least squares mean (LSmean) % DNA in tail±S.E.M.: 4.8±0.6 for control, 5.7±0.7 for AITC, 5.3±0.6 for M/C] or urinary 8-oxodG (LSmean μg 8-oxodG/g creatinine±S.E.M.: 2.95±0.09 for control, 2.88±0.09 for AITC, 3.06±0.09 for M/C). Both AITC and M/C increased DNA strand breaks 3 h postconsumption (LSmean % DNA in tail±S.E.M.: 3.2±0.7 for control, 8.3±1.7 for AITC, 8.0±1.7 for M/C), and this difference disappeared at 6 h (4.2±0.9 for control, 5.7±1.2 for AITC, 5.5±1.2 for M/C). Genotypes for GSTM1, GSTT1 and XPD were not associated with treatment effects. In summary, DNA damage appeared to be induced in the short term by AITC and AITC-rich products, but that damage disappeared quickly, and neither AITC nor AITC-rich products affected DNA base excision repair. 相似文献
100.
Craig?SaleEmail author Guilherme?G.?Artioli Bruno?Gualano Bryan?Saunders Ruth?M.?Hobson Roger?C.?Harris 《Amino acids》2013,44(6):1477-1491
Carnosine was first discovered in skeletal muscle, where its concentration is higher than in any other tissue. This, along with an understanding of its role as an intracellular pH buffer has made it a dipeptide of interest for the athletic population with its potential to increase high-intensity exercise performance and capacity. The ability to increase muscle carnosine levels via β-alanine supplementation has spawned a new area of research into its use as an ergogenic aid. The current evidence base relating to the use of β-alanine as an ergogenic aid is reviewed here, alongside our current thoughts on the potential mechanism(s) to support any effect. There is also some emerging evidence for a potential therapeutic role for carnosine, with this potential being, at least theoretically, shown in ageing, neurological diseases, diabetes and cancer. The currently available evidence to support this potential therapeutic role is also reviewed here, as are the potential limitations of its use for these purposes, which mainly focusses on issues surrounding carnosine bioavailability. 相似文献