Tail asymptotics for the fundamental period in the MAP/G/1 queue

This paper studies the tail behavior of the fundamental period in the MAP/G/1 queue. We prove that if the service time distribution has a regularly varying tail, then the fundamental period distribution in the MAP/G/1 queue has also regularly varying tail, and vice versa, by finding an explicit expression for the asymptotics of the tail of the fundamental period in terms of the tail of the service time distribution. Our main result with the matrix analytic proof is a natural extension of the result in (de Meyer and Teugels, J. Appl. Probab. 17: 802–813, 1980) on the M/G/1 queue where techniques rely heavily on analytic expressions of relevant functions. I.-S. Wee’s research was supported by the Korea Research Foundation Grant KRF 2003-070-00008.     

Asymmetry in the Multiprotein Systems of Molecular Biology

Signaling in living systems needs to achieve high specificity, to be reversible, and to achieve high signal to noise. Signaling mediated by multiprotein systems has evolved that avoids the requirement for high-affinity binary complexes that would be difficult to reverse and which, in the overcrowded cell, would lead to excessive noise in the system. Symmetrical structures are only occasionally formed. When they are, it is principally to colocate components, for example, the tyrosyl kinases of growth factors, where dimers form. Symmetry is, however, often broken, presumably to create more sensitivity and specificity in the signaling system by assembling other components, into higher-order multiprotein systems. The binding of a single heparin to two 1:1 FGF:FGFR complexes is an example, as is the binding of a single ligase to the Xrcc4 dimer, perhaps so creating a further DNA-binding site.     

The Interference of Oxygen on Diaphorase from Clostridium kluveri in the Mediated Electrocatalytic Oxidation of Reduced Dihydronicotinamide Adenine Dinucleotide

The effect of oxygen on the mediated electrocatalytic oxidation of nicotinamide adenine dinucleotide (NADH) by diaphorase from Clostridium kluveri (DI) was studied using cyclic voltammetry, UV‐vis spectrophotometry and NMR spectrometry. The enzyme was found to be able to use molecular oxygen as an electron acceptor. NADH could therefore be oxidized by two competitive electron acceptors: a redox mediator, for istance p‐methylamino‐phenolsulfate (MAP) or ferrocene monocarboxylic acid (FMCA) properly added to the solution, and molecular oxygen. Some considerations on the consequence of the use of diaphorase from Clostridium kluveri in amperometric biosensors were also reported.     

Small molecules as inhibitors of cyclin-dependent kinases

Cell division (mitosis) is one of the basic requirements for multicellular oranisms. The capability of a cell to replicate enables a complex assembly to be created. Faulty regulation of the control mechanism in the cell cycle leads to an excessive cell proliferation and is the cause of cancer. The key position of the cyclin-dependent kinases (CDKs) and their direct partners, as well as the fact that the majority of malign illnesses show defects in at least one of these key players of the cell cycle, is of great interest for the development of low-molecular-weight CDK inhibitors. In this Review an overview of the different structural classes of ATP-competitive inhibitors of CDKs are given, whose devlopment was aimed at battling cancer. The Review shows how far the development of selective CDK inhibitors has progressed and to what extent the expectations for such drugs have so far been fulfilled.     

The MAP/PH/N retrial queue in a random environment

We consider the MAP/PH/N retrial queue with a finite number of sources operating in a finite state Markovian random environment. Two different types of multi-dimensional Markov chains are investigated describing the behavior of the system based on state space arrangements. The special features of the two formulations are discussed. The algorithms for calculating the stationary state probabilities are elaborated, based on which the main performance measures are obtained, and numerical examples are presented as well.     

Improvements in the Synthesis of the Third-Generation EGFR Inhibitor Osimertinib

Osimertinib, a third generation potent and specific EGFR inhibitor is an important drug against many forms of cancer. It was synthesized by an improved and highly efficient protocol, revisiting the classical synthetic process and modifying parameters, such as solvents, temperature, reagents, and reaction time. A cost-effective, environmentally friendly methodology for the synthesis of osimertinib was established, which gave shorter reaction times, saved labor by eliminating purification steps through column chromatography, and enhanced yields. Four of the seven steps in total, were proceeded quantitatively or almost quantitatively (ca. 98 %). This synthetic protocol provides a very high overall yield, up to 68 %. In addition, the entire approach enables the preparation of osimertinib analogues and could be extended in the synthesis of other structurally similar bioactive compounds.     

Anti-atherosclerotic activity of Betulinic acid loaded polyvinyl alcohol/methylacrylate grafted Lignin polymer in high fat diet induced atherosclerosis model rats

Betulinic acid is one such natural pentacyclic triterpenoid compound, holding various pharmacological properties but its poor bioavailability is the only limitation. One of the biological macromolecules such as Lignin is a plant-derived aromatic, eco-friendly and low-cost polymer that certainly self-assembles into nano-sized colloids. Therefore, onto the current investigation, we increased the bioavailability of betulinic acid by coating on to a nanopolymer prepared with poly vinyl alcohol, lignins and methyl acrylate. Betulinic acid loaded polyvinyl alcohol/ethylacrylate grafted Lignin polymer (PVA/Lig-g-MA) nanoformulation was characterized using FTIR, XRD, SEM and TEM analysis and also the drug entrapment, in vitro drug releasing capacity was done to examine the efficiency of the nanoformulation of a drug. The MTT assay was evaluated the cytotoxicity of synthesized nanoformulation against normal endothelial cells HUVEC and HAPEC to confirm the side effects of the drug. The anti-atherosclerotic property of the nanoformulation was ascertained in both in vitro condition (with HUVEC and HPAEC) and in vivo studies (with Wistar rats). As a result, the characterization studies and in vitro studies clearly confirmed the Betulinic acid loaded PVA/Lig-g-MA nanoformulation is an ideal nanopolymer and it doesn’t cause any cytotoxic effect in normal endothelial cells. It also decreased the lipopolysaccharides induced inflammation through the down-regulation of NFκB and MAP/JNK signaling molecule expressions. Following in vivo results confirmed the synthesized nanoformulation effectively decreased the hyperchlostremia, inflammation and vasoconstriction, which induced over high fat diet. The results of histopathological analysis of cardiac tissues also confirmed the cardioprotective role of synthesized nanoformulation. Overall, both the in vitro and in vivo studies authentically proven the Betulinic acid loaded PVA/Lig-g-MA nanoformulation would be a potent cost effective anti-atherosclerotic nanodrug.     

New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design,Synthesis and Biological Evaluation

Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure–activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.