Dynamic interaction among the platform domain and two membrane-proximal immunoglobulin-like domains of class I major histocompatibility complex: normal mode analysis

Class I major histocompatibility complex (MHC) molecules have three domains, a platform domain and two membrane-proximal immunoglobulin-like domains, an alpha3 domain and a beta2-immunoglobulin (beta2m). To understand the dynamic interactions among the three domains, we simulated the behavior of a partial model deficient in beta2m and another model deficient in the alpha3 domain, by normal mode analysis. As a result, the partial model deficient in beta2m was more flexible in interdomain conformation than the other model. The lowest frequency modes (<2 cm(-1)) observed for the simulations of the partial model deficient in beta2m showed clear interdomain motions as if each domain moved like a rigid body. Such low frequencies and clear interdomain motions were not observed for the simulations of the other model, therefore the interdomain flexibility of the partial model deficient in beta2m may be due to the lowest frequency modes (<2 cm(-1)). These results suggest that beta2m contributes to maintaining the interdomain conformation of class I MHC molecules more than the alpha3 domain does, and may offer convincing evidence to support the notion that the alpha3 domain and beta2m do not have an equal influence on the structural stability of class I MHC molecules.     

Synthesis of N-functionalized oleamide derivatives

Oleamide is an interesting compound, which shows various pharmacological activities including the inhibitory effect of gap junction formation. Recently, the studies of the gap junction have been some of the hot topics in biology and its inhibitors have become more useful tools [Cravatt, B. F.; Garcia, O. P.; Siuzdak, G.; Gilula, N. B.; Henriksen, S. J.; Boger, D. L.; Lerner, R. A. Science1995, 268, 1506-1509; Cravatt, B. F.; Lerner, R. A.; Boger, D. L. J. Am. Chem. Soc.1996, 118, 580-590; Guan, X; Cravatt, B. F.; Ehring, G. R.; Hall, J. E.; Boger, D. L.; Lerner, R. A.; Gilula, N. B. J. Cell Biol.1997, 139, 1785-1792; Boger, D. L.; Patterson, J. E.; Guan, X.; Cravatt, B. F.; Lerner, R. A.; Gilula, N. B. Proc. Natl. Acad. Sci. U.S.A.1998, 95, 4810-4815; Ito, A.; Morita, N.; Miura, D.; Koma, Y.; Kataoka, T. R.; Yamasaki, H.; Kitamura, Y.; Kita, Y.; Nojima, H. Carcinogenesis2004, 25, 2015-2022]. However, many reports suggest that the functionalizations of oleamide to retain its biological activity were difficult [Boger, D. L.; Patterson, J. E.; Guan, X.; Cravatt, B. F.; Lerner, R. A.; Gilula, N. B. Proc. Natl. Acad. Sci. U.S.A.1998, 95, 4810-4815; Ito, A.; Morita, N.; Miura, D.; Koma, Y.; Kataoka, T. R.; Yamasaki, H.; Kitamura, Y.; Kita, Y.; Nojima, H. Carcinogenesis2004, 25, 2015-2022]. The synthesis of the functionalized oleamide derivatives, whose biological activity is not blocked, has become attractive in both the biological and chemical fields.Herein, by linking the fluorophore to the oleamide by alkyl chains, we synthesized the fluorescently tagged oleamide whose biological feature is similar to that of oleamide. Moreover, we also synthesized other bioactive derivatives tagged by other groups such as the sugars and biotin via alkyl chain linkers.     

Protein-templated organic/inorganic hybrid materials prepared by liquid-phase deposition

Organic/inorganic hybrid thin films for protein recognition have been prepared by the liquid-phase deposition (LPD) coupled with template synthesis, i.e., molecular imprinting, where pepsin (Pep) was used as a model protein and titanium oxide was deposited on gold substrates in the presence of Pep-poly-L-lysine (PL) complexes. The complexes remained in the templated film after the deposition, and the binding sites for Pep were constructured after Pep was removed from the film. Surface plasmon resonance signals on the deposited films were measured to examine the binding behaviors toward proteins. The binding of Pep on the templated film was reversible, and the binding isotherm of Pep depicted a saturation curve with a binding constant of 7.3 x 105 M(-1), which was 10 times higher than that of albumin. In contrast, titanium oxide films prepared without PL did not show any selectivity; therefore, the hybridization of PL as the organic binder with the inorganic material is necessary to obtain selective binding sites for Pep. It was also shown that the hybridization process should proceed without denaturing the template protein, in order to obtain selective binding sites for the template. The procedure for preparation of the films was simple to perform, and the process for hybridization of the thin films with nanometer-order thickness was easily controlled by changing the LPD reaction time period. Consequently, the proposed LPD coupled with template synthesis is among the most appropriate methods to prepare hybrid materials with protein recognition ability, which proceeds under mild conditions in aqueous solution.     

Rates of electronic excitation hopping in anisotropic ionic crystals of [Ru(2,2'-bipyridine)3]X2 (X = ClO4-, PF6-, SbF6-); Monte Carlo simulation of single- and multi-exponential emission decays

Emission decays of triplet metal-to-ligand charge transfer states in anisotropic crystals of [Ru(1 - x)Os(x)(bpy)(3)]X(2) (bpy = 2,2'-bipyridine, X = PF(6)-, ClO(4)-, SbF(6)-, and 0.115 > x > 0.001) at approximately 300 K were measured by means of time-correlated single-photon counting. Rates of excitation hopping calculated on the basis of an interaction between transition dipoles of a donor cation and an acceptor cation are insufficient to simulate the single-exponential decays (x = 0.0099) and the multiexponential decays (x = 0.060 and 0.115) of the PF(6)- salt crystals. A limiting rate of excitation hopping to an imaginary cation at the van der Waals distance via a super-exchange interaction between d orbitals through the bpy ligands was determined to be 0.83 x 10(10) s(-1) on average by means of a step-by-step Monte Carlo simulation, assuming an distance-attenuation factor, beta, of the exchange interaction of 10 nm-1. The total rate of excitation hopping via both a dipole-dipole mechanism and a super-exchange mechanism to the neighboring sites of the cation was calculated to be 5.4 x 10(9) s(-1) for the PF(6)- crystal. Anisotropic diffusion constants estimated from the hopping rates and lengths in the PF(6)- crystal are 9.3 x 10(-6), 9.1 x 10(-6), and 1.4 x 10(-6) cm(2)s(-1) along the a axis, the b axis, and the c axis, respectively, which are compared with an isotropic diffusion constant, 1.3 x 10(-6) cm(2) s(-1), estimated from the pseudo-bimolecular rate constant of excitation transfer to [Os(bpy)(3)](2+), using an isotropic Smoluchowski equation. A multiexponential emission decay of [Ru(0.885)Os(0.115)(bpy)(3)](PF(6))(2) was also simulated to determined the limiting rate of excitation transfer to [Os(bpy)(3)](2+) at the van der Waals distance (2.6 x 10(11) s(-1)). The magnitude of beta determined is 6.5 and 11.5 nm(-1) for the ClO(4)- and the SbF(6)- salt crystals, respectively, on reference to that of beta (10 nm(-1)) for the PF(6)- salt crystal.     

Dynamic assembly of porphyrin wires trapped on a highly oriented pyrolitic graphite surface

Carefully designed porphyrin building blocks assemble through selective imidazole binding in various solvents to form linear multiporphyrin objects. From a dynamic mixture of monomers, dimers, and oligomers, linear objects were observed on a highly oriented pyrolitic graphite (HOPG) surface. On the surface, the objects' morphology clearly depended on the solvent used for deposition and was modified upon heating.     

Copper-mediated and copper-catalyzed cross-coupling of indoles and 1,3-azoles: double C-H activation

A new bronze age: the described copper-mediated cross-coupling with double C-H activation can provide a convergent access to indole-containing biheteroaryls that are of high interest in pharmaceutical and medicinal chemistry. In this strategy an easily attachable and detachable 2-pyrimidyl directing group is used. Moreover, a variant that is catalytic in copper is achieved by using atmospheric oxygen as an ideal co-oxidant.     

Highly cytotoxic vanadium(V) complexes of salan ligands; insights on the role of hydrolysis

Vanadium(V) oxo complexes with tetradentate diamine bis(phenolato) "salan" ligands of the type LVO(OiPr) (L is salan) with different steric and electronic substitutions at the ortho and para positions to the binding phenolato moiety were synthesized and their hydrolytic stability and cytotoxicity were analyzed. With one exception bearing large steric groups, all complexes examined displayed marked cytotoxic activity, comparable to, and often higher than, that of cisplatin. While the hydrolytic stability changed significantly depending on the substituent at the ortho position relative the O-donor with little effect of para substitutions, the cytotoxic activity largely was not affected, and high cytotoxicity was recorded also for relatively unstable complexes. Additional measurements revealed that the cytotoxicity is largely maintained following pre-incubation of up to 18 hours of the complexes in the biological medium prior to cell addition, suggesting that hydrolysis products might serve as the active species. In addition, appreciable cytotoxic activity was measured for an isolated hydrolysis product that was analyzed crystallographically to exhibit a dimeric structure with bridging oxo ligand where both metal centers are bound to the salan ligand, supporting the aforementioned conclusions.     

Advances in zebrafish high content and high throughput technologies

The zebrafish has emerged as an excellent transitional screening model system between cell-based assays, which are rapid and inexpensive but have limited physiological relevance, and higher vertebrate models, which have better physiological relevance, but are more time-consuming and expensive to deploy. As vertebrates, zebrafish maintain significant evolutionary proximity to humans and have been validated as robust models for drug research, studies of mechanism and behavioral genetics. Unlike higher vertebrate models, zebrafish are well-suited to high-throughput applications owing to their high fecundity, rapid extrauterine development and transparency during organogenesis enabling in vivo labeling and imaging. Recent advances have been made in automating high content and high-throughput zebrafish screens, with the goal of developing fully automated drug screening platforms. The application and continued development of these technologies holds potential clinical significance in drug discovery and elucidating disease mechanisms.     

Value theory without symmetry

We investigate quasi-values of finite games – solution concepts that satisfy the axioms of Shapley (1953) with the possible exception of symmetry.  Following Owen (1972), we define “random arrival', or path, values: players are assumed to “enter' the game randomly, according to independently distributed arrival times, between 0 and 1; the payoff of a player is his expected marginal contribution to the set of players that have arrived before him.  The main result of the paper characterizes quasi-values, symmetric with respect to some coalition structure with infinite elements (types), as random path values, with identically distributed random arrival times for all players of the same type.  General quasi-values are shown to be the random order values (as in Weber (1988) for a finite universe of players).  Pseudo-values (non-symmetric generalization of semivalues) are also characterized, under different assumptions of symmetry. Received: April 1998/Revised version: February 2000