Quantum phases and dynamics of geometric phase in a quantum spin chain system under linear quench

We study the quantum phases of anisotropic XY spin chain system in presence and absence of adiabatic quench. A connection between geometric phase and criticality is established from the dynamical behaviour of the geometric phase for a quench induced quantum phase transition in a quantum spin chain. We predict XX criticality associated with a sequence of non-contractible geometric phases.Comment: 9 pages, 3 figures, one reference added. arXiv admin note: significant text overlap with arXiv:0908.329

Breaking into the conversation: cultural value and the role of the South African National Arts Festival from apartheid to democracy

The paper examines the value of the South African National Arts Festival (NAF) in the transition to democracy using theories of cultural capital. NAF history from 1974 to 2004 is used to argue that the Festival provided an important arena for the expression of political resistance in the 1980s and, to some degree, continues to do so today. It is concluded that an important part of the value of the arts is their ability to provide a forum for debating the goals and values of society and that individualistic utility theory is not always successful in measuring such social value

Identification Of A New Hormone-binding Site On The Surface Of Thyroid Hormone Receptor

Thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many nuclear receptor ligand-binding domains (LBDs) reveal that the ligand binds within the hydrophobic core of the ligand-binding pocket, a few studies suggest the possibility of ligands binding to other sites. Here, we report a new x-ray crystallographic structure of TR-LBD that shows a second binding site for T3 and T4 located between H9, H10, and H11 of the TRα LBD surface. Statistical multiple sequence analysis, site-directed mutagenesis, and cell transactivation assays indicate that residues of the second binding site could be important for the TR function. We also conducted molecular dynamics simulations to investigate ligand mobility and ligand-protein interaction for T3 and T4 bound to this new TR surface-binding site. Extensive molecular dynamics simulations designed to compute ligand-protein dissociation constant indicate that the binding affinities to this surface site are of the order of the plasma and intracellular concentrations of the thyroid hormones, suggesting that ligands may bind to this new binding site under physiological conditions. Therefore, the second binding site could be useful as a new target site for drug design and could modulate selectively TR functions. © 2014 by the Endocrine Society.284534545Yen, P., Physiological and molecular basis of thyroid hormone action (2001) Physiol Rev, 81, pp. 1097-10142Ribeiro, R.C., Kushner, P.J., Baxter, J.D., The nuclear hormone receptor gene superfamily (1995) Annu Rev Med, 46, pp. 443-453Lazar, M.A., Chin, W.W., Nuclear thyroid hormone receptors (1990) J Clin Invest, 86, pp. 1777-1782Wagner, R., Huber, B., Shiau, A., Hormone selectivity in thyroid hormone receptors (2001) Mol Endocrinol, 15, pp. 398-410Sandler, B., Webb, P., Apriletti, J., Thyroxine-thyroid hormone receptor interactions (2004) J Biol Chem, 279, pp. 55801-55808Blange, I., Drvota, V., Yen, P.M., Sylven, C., Species differences in cardiac thyroid hormone receptor isoforms protein abundance (1997) Biol Pharm Bull, 20, pp. 1123-1126Schwartz, H.L., Strait, K.A., Ling, N.C., Oppenheimer, J.H., Quantitation of rat tissue thyroid hormone binding receptor isoforms by immunoprecipitation of nuclear triiodothyronine binding capacity (1992) J Biol Chem, 267, pp. 11794-11799Martínez, L., Nascimento, A.S., Nunes, F.M., Gaining ligand selectivity in thyroid hormone receptors via entropy (2009) Proc Natl Acad Sci USA, 106, pp. 20717-20722Bleicher, L., Aparicio, R., Nunes, F., Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms (2008) BMCStruct Biol, 8, p. 8Gauthier, K., Chassande, O., Plateroti, M., Different functions for the thyroid hormone receptors TRα and TRα in the control of thyroid hormone production and post-natal development (1999) EMBO J, 18, pp. 623-631Johansson, C., Vennström, B., Thorén, P., Evidence that decreased heart rate in thyroid hormone receptor-α1-deficient mice is an intrinsic defect (1998) Am J Physiol, 275, pp. R640-R646Weatherman, R.V., Fletterick, R.J., Scanlan, T.S., Nuclear-receptor ligands and ligand-binding domains (1999) Annu Rev Biochem, 68, pp. 559-5581Webb, P., Nguyen, N.H., Chiellini, G., Design of thyroid hormone receptor antagonists from first principles (2002) J Steroid Biochem Mol Biol, 83, pp. 59-73Cunha Lima, S.T., Nguyen, N.H., Togashi, M., Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways (2009) J Steroid Biochem Mol Biol, 117, pp. 125-131Perakyla, M., Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations (2009) Eur Biophys J, 38, pp. 185-198Sonoda, M.T., Martínez, L., Webb, P., Skaf, M.S., Polikarpov, I., Ligand dissociation from estrogen receptor is mediated by receptor dimerization: Evidence from molecular dynamics simulations (2008) Mol Endocrinol, 22, pp. 1565-1578Martínez, L., Polikarpov, I., Skaf, M.S., Only subtle protein conformational adaptations are required for ligand binding to thyroid hormone receptors: Simulations using a novel multipoint steered mo lecular dynamics approach (2008) J Phys Chem B, 112, pp. 10741-10751Genest, D., Garnier, N., Arrault, A., Marot, C., Morin-Allory, L., Genest, M., Ligand-escape pathways from the ligand-binding domain of PPARγ receptor as probed by molecular dynamics simulations (2008) Eur Biophys J, 37, pp. 369-379Carlsson, P., Burendahl, S., Nilsson, L., Unbinding of retinoic acid from the retinoic acid receptor by random expulsion molecular dynamics (2006) Biophys J, 91, pp. 3151-3161Martínez, L., Webb, P., Polikarpov, I., Skaf, M.S., Molecular dynamics simulations of ligand dissociation from thyroid hormone receptors: Evidence of the likeliest escape pathway and its implications for the design of novel ligands (2006) J Med Chem, 49, pp. 23-26Martínez, L., Sonoda, M.T., Webb, P., Baxter, J.D., Skaf, M.S., Polikarpov, I., Molecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors (2005) Biophys J, 89, pp. 2011-2023Moras, D., Gronemeyer, H., The nuclear receptor ligand-binding domain: Structure and function (1998) Curr Opin Cell Biol, 10, pp. 384-391Glass, C.K., Rosenfeld, M.G., The coregulator exchange in transcriptional functions of nuclear receptors (2000) Genes Dev, 14, pp. 121-141Nichols, M., Rientjes, J.M., Stewart, A.F., Different positioning of the ligand-binding domain helix 12 and the F domain of the estrogen receptor accounts for functional differences between agonists and antagonists (1998) EMBO J, 17, pp. 765-773Brzozowski, A.M., Pike, A.C., Dauter, Z., Molecular basis of agonism and antagonism in the oestrogen receptor (1997) Nature, 389, pp. 753-758Figueira, A.C., Saidemberg, D.M., Souza, P.C., Analysis of agonist and antagonist effects on thyroid hormone receptor conformation by hydrogen/deuterium exchange (2011) Mol Endocrinol, 25, pp. 15-31Wang, Y., Chirgadze, N.Y., Briggs, S.L., Khan, S., Jensen, E.V., Burris, T.P., A second binding site for hydroxytamoxifen within the coactivatorbinding groove of estrogen receptor beta (2006) Proc Natl Acad Sci U S A, 103, pp. 9908-9911Hedden, A., Müller, V., Jensen, E., A new interpretation of antiestrogen action (1995) Ann NY Acad Sci, 761, pp. 109-120Jensen, E.V., Khan, S.A., A two-site model for antiestrogen action (2004) Mech Ageing Dev, 125, pp. 679-682Estébanez-Perpiñá, E., Arnold, L.A., Nguyen, P., A surface on the androgen receptor that allosterically regulates coactivator binding (2007) Proc Natl Acad Sci USA, 104, pp. 16074-16079Lack, N.A., Axerio-Cilies, P., Tavassoli, P., Targeting the binding function 3 (BF3) site of the human androgen receptor through virtual screening (2011) J Med Chem, 54, pp. 8563-8573Munuganti, R.S., Leblanc, E., Axerio-Cilies, P., Targeting the binding function 3 (BF3) site of the androgen receptor through virtual screening. 2. Development of 2-(2-phenoxyethyl) thio)-1Hbenzimidazole derivatives (2013) J Med Chem, 56, pp. 1136-1148Mizwicki, M.T., Keidel, D., Bula, C.M., Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1alpha, 25(OH)2-vitamin D3 signaling (2004) Proc Natl Acad Sci U S A, 101, pp. 12876-12881Bernardes, A., Souza, P.C., Muniz, J.R., Molecular mechanism of peroxisome proliferator-activated receptor α activation by WY14643: A new mode of ligand recognition and receptor stabilization (2013) J Mol Biol, 425, pp. 2878-2893Puhl, A.C., Bernardes, A., Silveira, R.L., Mode of peroxisome proliferator-activated receptor γ activation by luteolin (2012) Mol Pharmacol, 81, pp. 788-799Liberato, M.V., Nascimento, A.S., Ayers, S.D., Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) activators and Pan-PPAR partial agonists (2012) Plos One, 7, pp. e36297Itoh, T., Fairall, L., Amin, K., Structural basis for the activation of PPAR by oxidized fatty acids (2008) Nat Struct Mol Biol, 15, pp. 924-931Ambrosio, A.L., Dias, S.M., Polikarpov, I., Zurier, R.B., Burstein, S.H., Garratt, R.C., Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor γ (2007) J Biol Chem, 282, pp. 18625-18633Estébanez-Perpiñá, E., Arnold, L.A., Jouravel, N., Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor (2007) Mol Endocrinol, 21, pp. 2919-2928Hwang, J.Y., Arnold, L.A., Zhu, F., Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors (2009) J Med Chem, 52, pp. 3892-3901Hwang, J.Y., Attia, R.R., Carrillo, A.K., Connelly, M.C., Guy, R.K., Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor-coactivator interaction (2013) Bioorg Med Chem Lett, 23, pp. 1891-1895Nunes, F.M., Aparício, R., Santos, M.A., Crystallization and preliminary X-ray diffraction studies of isoform α1 of the human thyroid hormone receptor ligand-binding domain (2004) Acta Crystallogr D Biol Crystallogr, 60, pp. 1867-1870Otwinowski, Z., Minor, W., Processing of x-ray diffraction data collected in oscillation mode (1997) Methods Enzymol, 276, pp. 307-326Navaza, J., Implementation of molecular replacement in AMoRe (2001) Acta Crystallogr D Biol Crystallogr, 57, pp. 1367-1372Adams, P.D., Afonine, P.V., Bunkóczi, G., PHENIX: A comprehensive Python-based system for macromolecular structure solution (2010) Acta Crystallogr D, 66, pp. 213-221Murshudov, G., Vagin, A., Dodson, E., Refinement of macromolecular structures by the maximum-likelihood method (1997) Acta Crystallogr D Biol. Crystallogr, 53, pp. 240-255Emsley, P., Cowtan, K., Coot: Model-building tools for molecular graphics (2004) Acta Crystallogr D Biol Crystallogr, 60, pp. 2126-2132Waterhouse, A.M., Procter, J.B., Martin, D.M., Clamp, M., Barton, G.J., Jalview Version 2-a multiple sequence alignment editor and analysis workbench (2009) Bioinformatics, 25, pp. 1189-1191Lockless, S.W., Ranganathan, R., Evolutionarily conserved pathways of energetic connectivity in protein families (1999) Science, 286, pp. 295-299Süel, G.M., Lockless, S.W., Wall, M.A., Ranganathan, R., Evolutionarily conserved networks of residues mediate allosteric communication in proteins (2003) Nature Struct Biol, 10, pp. 59-69Feng, W., Ribeiro, R.C., Wagner, R.L., Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors (1998) Science, 280, pp. 1747-1749Martínez, L., Andrade, R., Birgin, E.G., Martínez, J.M., PACKMOL: A package for building initial configurations for molecular dynamics simulations (2009) J Comput Chem, 30, pp. 2157-2164Martínez, J.M., Martínez, L., Packing optimization for automated generation of complex system's initial configurations for molecular dynamics and docking (2003) J Comput Chem, 24, pp. 819-825Verlet, L., Computer experiments on classical fluids. I Thermodinamical properties of Lennard-Jones molecules (1967) Phys Rev, 159, pp. 98-103Darden, T., York, D., Pedersen, L., Particle Mesh Ewald: An Nlog(N) method for Ewald sums in large systems (1993) J Chem Phys, 98, pp. 10089-10092Phillips, J.C., Braun, R., Wang, W., Scalable molecular dynamics with NAMD (2005) J Comput Chem, 26, pp. 1781-1802McKerell Jr., A.D., Bashford, D., Bellott, M., All-atom empirical potential for molecular modeling and dynamics studies of proteins (1998) J Phys Chem B, 102, pp. 3586-3616Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W., Klein, M.L., Comparison of simple potential functions for simulating liquid water (1983) J Chem Phys, 79, pp. 926-935Duggan, B.M., Craik, D.J., Conformational dynamics of thyroid hormones by variable temperature nuclear magnetic resonance: The role of side chain rotations and cisoid/transoid interconversions (1997) J Med Chem, 40, pp. 2259-2265Duggan, B.M., Craik, D.J., 1H and 13C NMR relaxation studies of molecular dynamics of the thyroid hormones thyroxine, 3, 5, 3-triiodothyronine, and 3, 5-diiodothyronine (1996) J Med Chem, 39, pp. 4007-4016Hansson, A.O., Souza, P.C.T., Silveira, R.L., Martínez, L., Skaf, M.S., CHARMM force field parameterization of rosiglitazone (2011) Int J Quantum Chem, 111, pp. 1346-1354Prates, E.T., Souza, P.C.T., Pickholz, M., Skaf, M.S., CHARMM based parameterization of neutral articaine-a widely used local anesthesic (2011) Intern J Quantum Chem, 111, pp. 1339-1345Hénin, J., Fiorin, J., Chipot, C., Klein, M.L., Exploring multidimensional free energy landscapes using time-dependent biases on collective variables (2010) J Chem Theory Comput, 6, pp. 35-47Hénin, J., Chipot, C., Overcoming free energy barriers using unconstrained molecular dynamics simulations (2004) J Chem Phys, 121, pp. 2904-2914Chipot, C., Hénin, J., Exploring the free-energy landscape of a short peptide using an average force (2005) J Chem Phys, 123, p. 244906Nascimento, A.S., Dias, S.M., Nunes, F.M., Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function (2006) J Mol Biol, 360, pp. 586-598Wagner, R.L., Apriletti, J.W., McGrath, M.E., West, B.L., Baxter, J.D., Fletterick, R.J., A structural role for hormone in the thyroid hormone receptor (1995) Nature, 378, pp. 690-697Borngraeber, S., Budny, M.J., Chiellini, G., Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor (2003) Proc Natl Acad Sci USA, 100, pp. 15358-15363Escobar-Morreale, H.F., Obregón, M.J., Escobar del Rey, F., Morreale de Escobar, G., Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats (1995) J Clin Invest, 96, pp. 2828-2838Trost, S.U., Swanson, E., Gloss, B., The thyroid hormone receptor-β-selective agonist GC-1 differentially affects plasma lipids and cardiac activity (2000) Endocrinology, 141, pp. 3057-3064Oppenheimer, J.H., Schwartz, H.L., Stereospecific transport of triiodothyronine from plasma to cytosol and from cytosol to nucleus in rat liver, kidney, brain, and heart (1985) J Clin Invest, 75, pp. 147-154Shahrara, S., Drvota, V., Sylvén, C., Organ specific expression of thyroid hormone receptor mRNA and protein in different human tissues (1999) Biol Pharm Bull, 22, pp. 1027-1033Souza, P.C., Barra, G.B., Velasco, L.F., Helix 12 dynamics and thyroid hormone receptor activity: Experimental and molecular dynamics studies of Ile280 mutants (2011) J Mol Biol, 412, pp. 882-893Marimuthu, A., Feng, W., Tagami, T., TR surfaces and conformations required to bind nuclear receptor corepressor (2002) Mol Endocrinol, 16, pp. 271-286Togashi, M., Nguyen, P., Fletterick, R., Baxter, J.D., Webb, P., Rearrangements in thyroid hormone receptor charge clusters that stabilize bound 3, 5, 5-triiodo-L-thyronine and inhibit homodimer formation (2005) J Biol Chem, 280, pp. 25665-25673Ribeiro, R.C., Feng, W., Wagner, R.L., Definition of the surface in the thyroid hormone receptor ligand binding domain for association as homodimers and heterodimers with retinoid X receptor (2001) J Biol Chem, 276, pp. 14987-14995de Araujo, A.S., Martínez, L., de Paula Nicoluci, R., Skaf, M.S., Polikarpov, I., Structural modeling of high-affinity thyroid receptor-ligand complexes (2010) Eur Biophys J, 39, pp. 1523-1536Takayama, S., Hostick, U., Haendel, M., Eisen, J., Darimont, B., An F-domain introduced by alternative splicing regulates activity of the zebrafish thyroid hormone receptor α (2008) Gen Comp Endocrinol, 155, pp. 176-18

Discovering diverse association rules from multidimensional schema

The integration of data mining techniques with data warehousing is gaining popularity due to the fact that both disciplines complement each other in extracting knowledge from large datasets. However, the majority of approaches focus on applying data mining as a front end technology to mine data warehouses. Surprisingly, little progress has been made in incorporating mining techniques in the design of data warehouses. While methods such as data clustering applied on multidimensional data have been shown to enhance the knowledge discovery process, a number of fundamental issues remain unresolved with respect to the design of multidimensional schema. These relate to automated support for the selection of informative dimension and fact variables in high dimensional and data intensive environments, an activity which may challenge the capabilities of human designers on account of the sheer scale of data volume and variables involved. In this research, we propose a methodology that selects a subset of informative dimension and fact variables from an initial set of candidates. Our experimental results conducted on three real world datasets taken from the UCI machine learning repository show that the knowledge discovered from the schema that we generated was more diverse and informative than the standard approach of mining the original data without the use of our multidimensional structure imposed on it

Gq-16, a novel peroxisome proliferator-activated receptor γ (pparγ) ligand, promotes insulin sensitization without weight gain

The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the β-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPARγ-based therapeutics stabilize the β-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the β-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPARγ-based therapeutics stabilize the β-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects28733281692817