Structure-Based Design and Synthesis of Benzothiazole Phosphonate Analogues with Inhibitors of Human ABAD-Aβ for Treatment of Alzheimer’s disease

This is the peer reviewed version of the following article: Valasani, K. R., Hu, G., Chaney, M. O. and Yan, S. S. (2013), Structure-Based Design and Synthesis of Benzothiazole Phosphonate Analogues with Inhibitors of Human ABAD-Aβ for Treatment of Alzheimer’s Disease. Chemical Biology & Drug Design, 81: 238–249. doi:10.1111/cbdd.12068, which has been published in final form at http://doi.org/10.1111/cbdd.12068. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Amyloid binding alcohol dehydrogenase (ABAD), a mitochondrial protein, is a cofactor facilitating amyloid-β peptide (Aβ) induced cell stress. Antagonizing Aβ-ABAD interaction protects against aberrant mitochondrial and neuronal function and improves learning memory in the Alzheimer’s disease (AD) mouse model. Therefore, it offers a potential target for Alzheimer’s drug design, by identifying potential inhibitors of Aβ-ABAD interaction. 2D QSAR methods were applied to novel compounds with known IC50 values, which formed a training set. A correlation analysis was carried out comparing the statistics of the measured IC50 with predicted values. These selectivity-determining descriptors were interpreted graphically in terms of principle component analyses, which are highly informative for the lead optimization process with respect to activity enhancement. A 3D pharmacophore model also was created. The 2D QSAR and 3D pharmacophore models will assist in hi-throughput screening. In addition, ADME descriptors were also determined to study their pharmacokinetic properties. Finally, ABAD molecular docking study of these novel molecules was undertaken to determine whether these compounds exhibit significant binding affinity with the binding site. We have synthesized only the compounds that have shown the best drug like properties as candidates for further studies

Criteria for Selection of Frequency of Electromagnetic Radiation for Underwater proximity Fuzes

Electromagnetic proximity fuzes play important role in underwater weapons. The characteristics of the electromagnetic field, i.e., the wavelength, penetration, propagation constant, velocity, etc in sea water are different from those in air. The conducting properties of the medium are strongly dependent on the frequency of the electromagnetic waves. This paper highlights the basis for selection of frequency of electromagnetic propagation for such applications as proximity fuze for underwater weapons

Maximum Likelihood Estimator for Bearings-only Passive Target Tracking in Electronic Surveillance Measure and Electronic Warfare Systems

Maximum likelihood estimator is a suitable algorithm for passive target tracking applications. Nardone, Lindgren and Gong introduced this approach using batch processing. In this paper, the batch processing is converted into sequential processing for real-time applications like passive target tracking using bearings-only measurements. Adaptively, the variance of each measurement is computed and is used along with the measurement in such a way that the effect of false bearings can be reduced. The transmissions made by radar on a target ship are assumed to be intercepted by an electronic warfare (EW) system of own ship. The generated bearings in intercept mode are processed through maximum likelihood estimator (MLE) to find out target motion parameters. Instead of assuming some arbitrary values, pseudo linear estimator outputs are used for the initialisation of MLE. The algorithm is tested in Monte-Carlo simulation and its results are presented for two typical scenarios.Defence Science Journal, 2010, 60(2), pp.197-203, DOI:http://dx.doi.org/10.14429/dsj.60.34

Anthocyanins in chronic inflammatory bowel disease in rats

Inflammatory Bowel Disease (IBD), including Crohn’s disease and ulcerative colitis, is an uncontrolled inflammation of the gastrointestinal tract with unclear aetiology affecting over 85,000 Australians and 5 million globally. IBD produces symptoms such as weight loss, bloody diarrhoea and severe abdominal pain. Multiple factors are involved in IBD pathogenesis including genetic predisposition, gut microbial imbalance, mucosal barrier malfunction, immune system dysfunction and environmental factors. Current drug therapy for IBD includes sulphasalazine, aminosalicylates, corticosteroids, tumour necrosis factor blockers, immunomodulators (azathioprinemercaptopurine/ methotrexate), anti-integrins alpha4beta2 (vedolizumab), antiinterleukin-12 (ustekinumab), and small molecules including janus kinase inhibitor (tofacitinib). As nutrition can influence some of the causative factors, dietary modulation in IBD patients may be a preventive and therapeutic approach. In particular, anthocyanins such as cyanidin 3-glucoside (C3G) present in common foods such as Queen Garnet plum and purple carrots and pelargonidin 3-glucoside (P3G) in strawberry have anti-inflammatory activities that may be effective in IBD. The aim of my thesis is to understand whether these anthocyanin-containing functional foods improve the structure and function of the gastrointestinal tract, and improve gut bacteria in a rat model of chronic IBD. The first objective of my thesis was to mimic chronic human IBD in rats. I developed a model of reversible chronic IBD in young male Wistar rats using 0.5% dextran sodium sulphate (DSS) in drinking water for 12 weeks. DSS induced IBD with increased diarrhoea, haematochezia (passage of fresh blood through the anus, usually with stools), infiltration of inflammatory cells in ileum and colon, depletion of mucosal epithelial layer including villi, crypts, goblet cells, and gut microbiota imbalance with increased Proteobacteria phylum and decreased commensal bacteria. IBD symptoms were reversed with replacement of 0.5% DSS with water or the standard IBD drug treatment, sulphasalazine (300 mg/kg body weight/day) for the final 6 weeks. The second objective was to investigate the effects of functional foods to attenuate IBD in the rat model. For the last 6 weeks of the protocol, either Queen Garnet plum juice, purple carrot juice or pure C3G at 8mg/kg/day, or strawberry powder at 8mg P3G/kg/day was added in the food to the rats fed with either 0% or 0.5% DSS water. Queen Garnet plum, purple carrot and C3G improved IBD symptoms with reduced diarrhoea and haematochezia. The ileum and colon showed reduced infiltration of inflammatory cells and increased villi length and crypt depth. C3G improved the gut bacteria homeostasis. Similarly, P3G-containing strawberry mitigated the signs of IBD with reduced stool bleeding and diarrhoea, improved ileum and colon structure, suppressed infiltration of inflammatory cells and restored goblet cells. C3G and P3G were as effective as the standard drug sulphasalazine in this model suggesting their promising role in human IBD therapy. My PhD thesis concludes that functional foods containing anthocyanins may be an alternate or complementary treatment for IBD patients owing to their anti-inflammatory activity, and the ability to balance gut bacteria. Further mechanistic studies and clinical trials are warranted for their inclusion in complementary therapy of human IBD

Free A*-algebras

In this paper we studied the free A*-algebras, the sub A*-algebra generated by a subset and its characterization, an A*-algebra freely generated by a subset and introduced the concept of A*-field of sets. Also we established some theorems on making A*-field of sets into A*-algebras

Simulation of mirror inversion of quantum states in an XY spin chain using NMR

We report an experimental quantum simulation of unitary dynamics of an XY spin chain with pre-engineered couplings. Using this simulation, we demonstrate the mirror inversion of quantum states, proposed by Albanese et al. [Phys. Rev. Lett. 93, 230502 (2004)]. The experiment is performed with a 5-qubit dipolar coupled spin system using nuclear magnetic resonance techniques. To perform quantum simulation we make use of the recently proposed unitary operator decomposition algorithm of Ajoy et al. [Phys. Rev. A 85, 030303 (2012)] along with numerical pulse optimization techniques. Further, using mirror inversion, we demonstrate that entangled states can be transferred from one end of the chain to the other end. The simulations are implemented with high experimental fidelity, which implies that these kind of simulations may be possible in larger systems.Comment: 9 pages, 6 figure

Violation of Entropic Leggett-Garg Inequality in Nuclear Spins

We report an experimental study of recently formulated entropic Leggett-Garg inequality (ELGI) by Usha Devi et al. (arXiv: 1208.4491v2 (2012)). This inequality places a bound on the statistical measurement outcomes of dynamical observables describing a macrorealistic system. Such a bound is not necessarily obeyed by quantum systems, and therefore provides an important way to distinguish quantumness from classical behavior. Here we study ELGI using a two-qubit nuclear magnetic resonance system. To perform the noninvasive measurements required for the ELGI study, we prepare the system qubit in a maximally mixed state as well as use the `ideal negative result measurement' procedure with the help of an ancilla qubit. The experimental results show a clear violation of ELGI by over four standard deviations. These results agree with the predictions of quantum theory. The violation of ELGI is attributed to the fact that certain joint probabilities are not legitimate in the quantum scenario, in the sense they do not reproduce all the marginal probabilities. Using a three-qubit system, we experimentally demonstrate that three-time joint probabilities do not reproduce certain two-time marginal probabilities.Comment: 5 pages, 5 figures, 1 page supplementar