Efficient synthesis of CCR5 antagonist, 2,3-dihydro-1-benzothiepine derivatives by improved intramolecular Claisen type reaction using dialkylcarbonate

The efficient synthesis of 2,3-dihydro-1-benzothiepine derivatives 4 has been developed. The intramolecular Claisen type reaction of the new products, 4-(o-formylphenylthio)butyrate 9, with alcoholate in dialkylcarbonate as a solvent afforded 4 in good yields. According to this new procedure, we have accomplished the practical preparation of CCR5 antagonist 1 as a candidate for oral HIV-1 therapy.     

Design and Synthesis of Tri-substituted Chiral Pyrrolidin-2-one Derivatives as CCR4 Antagonists

A series of tri-substituted chiral pyrrolidin-2-one derivatives have been designed and synthesized as CC chemokine receptor 4 （CCR4） antagonists. The structure of CCR4 was built by homology modeling. Asymmetric synthesis was applied to synthesize the R,R configuration chiral pyrrolidin-2-one scaffold. The stereoisomeric con- figurations of the compounds were identified by 2D I H-~H COSY spectroscopy and 1D NOESY spectroscopy. This method was more economical and convenient than traditional X-ray single crystal diffraction. In addition, the inter- actions between these compounds and the N-terminal extracellular tail of CCR4 were studied using capillary zone electrophoresis. The CCR4 chemotaxis inhibition effect was tested in CCR4-transfected HEK293 cells. Several compounds showed potent activities as CCR4 antagonists. Among these compounds, lc is the most active one. Its apparent binding constant of CZE experiment result is （1.569±0.11）× 10s L·mol ^-1, and its percentage inhibition of the HEK293/CCR4 cells migration with the concentration of I gmol·L ^-1 in DMSO is 59%. And compound If has slightly higher affinity to N-terminal of CCR4 according to its apparent binding constant than lb because of the in- troduced ester linkage. Further studies on the mechanism of these compounds are in progress.     

An epsilon-based measure of efficiency in DEA – A third pole of technical efficiency

In DEA, we have two measures of technical efficiency with different characteristics: radial and non-radial. In this paper we compile them into a composite model called “epsilon-based measure (EBM).” For this purpose we introduce two parameters which connect radial and non-radial models. These two parameters are obtained from the newly defined affinity index between inputs or outputs along with principal component analysis on the affinity matrix. Thus, EBM takes into account diversity of input/output data and their relative importance for measuring technical efficiency.     

On the classification and modular extendability of E0-semigroups on factors

In this paper we study modular extendability and equimodularity of endomorphisms and E₀-semigroups on factors, when these definitions are recast to the context of faithful normal semifinite weights and this dependency is analyzed. We show that modular extendability is a property that does not depend on the choice of weights, it is a cocycle conjugacy invariant and it is preserved under tensoring. Furthermore, we prove a necessary and sufficient condition for equimodularity of endomorphisms in the context of weights. This extends previously known results regarding the necessity of this condition in the case of states. The classification of E₀-semigroups on factors is considered: a modularly extendable E₀-semigroup is said to be of type EI, EII or EIII if its modular extension is of type I, II or III, respectively. We prove that all types exist on properly infinite factors. We show that q-CCR flows are not extendable, and we extend previous results by the first author regarding the non-extendability of CAR flow to a larger class of quasi-free states. We also compute the coupling index and the relative commutant index for the CAR flows and q-CCR flows. As an application, by considering repeated tensors of the CAR flows we show that there are infinitely many non cocycle conjugate non-extendable E₀-semigroups on the hyperfinite factors of types II₁ and III_λ, for $\text{◂+▸}\lambda \in (0,1)$.     

Thermal Ionization

In the context of an idealized model describing an atom coupled to black-body radiation at a sufficiently high positive temperature, we show that the atom will end up being ionized in the limit of large times. Mathematically, this is translated into the statement that the coupled system does not have any time-translation invariant state of positive (asymptotic) temperature, and that the expectation value of an arbitrary finite-dimensional projection in an arbitrary initial state of positive (asymptotic) temperature tends to zero, as time tends to infinity. These results are formulated within the general framework of W ^*-dynamical systems, and the proofs are based on Mourre's theory of positive commutators and a new virial theorem. Results on the so-called standard form of a von Neumann algebra play an important role in our analysis.     

Wick products of the CCR algebra

The purpose of this paper is to put in a precise mathematical (algebraic) form the Wick products of the CCR algebra. We state in detail the reduction of ordinary product of Bose fields in terms of a finite sum of monomials in the creation and annihilation operators in which all creation operators occur to the left of all annihilation operators (Wick‐ordered) and the Fock (vacuum) state of the former. © 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim     

Selective addition of CXCR3+CCR4-CD4+ Th1 cells enhances generation of cytotoxic T cells by dendritic cells in vitro

Increasing importance is being given to the stimulation of Th1 response in cancer immunotherapy because its presence can shift the direction of adaptive immune responses toward protective immunity. Based on chemokine receptor expression, CXCR3⁺CCR4^-CD4⁺ T cells as Th1-type cells were investigated its capacity in monocyte-derived dendritic cell (DC) maturation and polarization, and induction of antigen specific cytotoxic T lymphocytes (CTL) in vitro. The levels of IL-4, IL-5 and IL-10 were decreased to the basal level compared with high production of IFN-γ, TNF-α, and IL-2 in CXCR3⁺CCR4^-CD4⁺ T cells stimulated with anti-CD3 and anti-CD28 antibodies. Co-incubation of activated CD4⁺ or CXCR3⁺CCR4^-CD4⁺ T cells with DC (CD4⁺/DC or CXCR3⁺CD4⁺/DC, respectively) particularly up-regulated IL-12 and CD80 expression compared with DC matured with TNF-α and LPS (mDC). Although there was no significant difference between the effects of the CXCR3⁺CCR4^-CD4⁺ and CD4⁺ T cells on DC phenotype expression, CXCR3⁺CD4⁺/DC in CTL culture were able to expand number of CD8⁺ T cells and increased frequencies of IFN-γ secreting cells and overall cytolytic activity against tumor antigen WT-1. These results demonstrated that the selective addition of CXCR3⁺CCR4^-CD4⁺ T cells to CTL cultures could enhance the induction of CTLs by DC in vitro, and implicated on a novel strategy for adoptive T cell therapy.     

Target setting in the general combined-oriented CCR model using an interactive MOLP method

The traditional data envelopment analysis (DEA) model does not include a decision maker’s (DM) preference structure while measuring relative efficiency, with no or minimal input from the DM. To incorporate DM’s preference information in DEA, various techniques have been proposed. An interesting method to incorporate preference information, without necessary prior judgment, is the use of an interactive decision making technique that encompasses both DEA and multi-objective linear programming (MOLP). In this paper, we will use Zionts-Wallenius (Z-W) method to reflecting the DM’s preferences in the process of assessing efficiency in the general combined-oriented CCR model. A case study will conducted to illustrate how combined-oriented efficiency analysis can be conducted using the MOLP method.