Liganded T3 receptor ß2 inhibits the positive feedback autoregulation of the gene for GATA2, a transcription factor critical for thyrotropin production.

The serum concentration of thyrotropin (thyroid stimulating hormone, TSH) is drastically reduced by small increase in the levels of thyroid hormones (T3 and its prohormone, T4); however, the mechanism underlying this relationship is unknown. TSH consists of the chorionic gonadotropin α (CGA) and the ß chain (TSHß). The expression of both peptides is induced by the transcription factor GATA2, a determinant of the thyrotroph and gonadotroph differentiation in the pituitary. We previously reported that the liganded T3 receptor (TR) inhibits transactivation activity of GATA2 via a tethering mechanism and proposed that this mechanism, but not binding of TR with a negative T3-responsive element, is the basis for the T3-dependent inhibition of the TSHß and CGA genes. Multiple GATA-responsive elements (GATA-REs) also exist within the GATA2 gene itself and mediate the positive feedback autoregulation of this gene. To elucidate the effect of T3 on this non-linear regulation, we fused the GATA-REs at -3.9 kb or +9.5 kb of the GATA2 gene with the chloramphenicol acetyltransferase reporter gene harbored in its 1S-promoter. These constructs were co-transfected with the expression plasmids for GATA2 and the pituitary specific TR, TRß2, into kidney-derived CV1 cells. We found that liganded TRß2 represses the GATA2-induced transactivation of these reporter genes. Multi-dimensional input function theory revealed that liganded TRß2 functions as a classical transcriptional repressor. Then, we investigated the effect of T3 on the endogenous expression of GATA2 protein and mRNA in the gonadotroph-derived LßT2 cells. In this cell line, T3 reduced GATA2 protein independently of the ubiquitin proteasome system. GATA2 mRNA was drastically suppressed by T3, the concentration of which corresponds to moderate hypothyroidism and euthyroidism. These results suggest that liganded TRß2 inhibits the positive feedback autoregulation of the GATA2 gene; moreover this mechanism plays an important role in the potent reduction of TSH production by T3.

[Personalized medicine for epilepsy based on the pharmacogenomic testing].

Currently a trial-and-error approach is employed to determine the most effective antiepileptic drug (AED) and dosage for a patient, and almost 30% of all patients are resistant to AED therapy. Introduction of personalized medicine for epilepsy based on pharmacogenomic testing is a new avenue for optimizing AED therapy. However, several crucial issues remain to be resolved before this initiative can be fully pursued. This article provides a critical review of the status and perspectives in the development of personalized medicine for epilepsy based on pharmacogenetic variations that may affect efficacy, tolerability, and safety of AEDs, such as variations in the genes encoding drug-metabolizing enzymes (e.g., cytochrome P450), or drug transporters (e.g., MDR1, MRP2).

Effect of salts on the electrical conductance of a fluorine-containing poly(carboxylic acid), PPFNA.

Electrical conductance and other solution properties of aqueous solutions of a fluorine-containing poly(carboxylic acid), (poly(9H,9H-perfluoro-2,5-dimethyl-3,6-dioxa-8-nonenoic acid), PPFNA) were studied with special attention to the salt effect. This polymer dissociated strongly resulting in a low pH value in unneutralized state (beta=0, beta: degree of neutralization). The specific conductance was the highest at beta=0 and decreased as beta increased. A considerable increase in conductance was observed by titrating NaCl at low beta, because large amounts of bound protons were released by addition of NaCl. The amounts of released protons exceeded those originally dissociated at beta=0. Such an anomalous proton liberation suggests that this polymer is a fairly strong polyacid but not a typical one such as poly(styrene sulfonic acid). Under fully neutralized state (beta=1), however, the solution conductance was lower than the sum of the polymer and NaCl added, due to polyion-salt ion interaction.

Model analysis of surfactant--polymer interaction as cooperative ligand binding to linear lattice.

An improved model of the cooperative binding of monomeric ligands to a linear lattice is proposed for the analysis of surfactant association on the polymer. The interaction between bound ligands across an unoccupied site as well as the steric hindrance effect in consecutive bindings is taken into account here. Typical results of the model calculations are represented, and several least squares fittings of the binding isotherms of the ionic surfactant-polyelectrolyte systems are attempted. The characteristic binding behavior in those systems is interpretable by the feasible model of the interactions between surfactant molecules. The advantages and limitations of the analysis using this model also are discussed.

The cooperative binding of large ligands to a one-dimensional lattice: the steric hindrance effect.

The cooperative binding of monomeric ligands to a long lattice of a linear polymer with complete or partial steric hindrance is treated using a matrix method. Results and typical calculations of the model are represented. Non-saturated cooperative binding as well as two-step (biphasic) binding isotherms can be interpreted by the steric hindrance model. This is applicable to the analysis of the binding of surfactants to polymer. The usefulness and the limitation also are discussed.