TOWARD IMPROVING METALLOENZYME INHIBITOR DESIGN: A THERMODYNAMIC STUDY OF SMALL MOLECULE INTERACTIONS WITH COPPER(II), COBALT(II) AND MANGANESE(II)

This work aimed at understanding the interactions of 1) three physiologically relevant transition metal ions copper(II), cobalt(II) and manganese(II) with five tri- or tetra-dentate metal chelators (ligand or L) and 2) the resulting ML complexes with two known metalloenzyme inhibitors, 8-hydroxyquinoline (8-HQ) and acetohydroxamic acid (AHA). The ultimate goal of the work was to identify ligands that can form enzyme active site M2+ structural mimetics capable of interacting with metalloenzyme active site inhibitors. The ligands studied were N-(2-(1-methylimidazolyl)methyl)iminodiacetic acid (DA2Im), nitrilotriacetic acid (NTA), tris(2-aminoethyl)amine (TREN), tris(2-pyridylmethyl)amine (TPA), and bis(2-picolyl)amine (BPA) and they were chosen to mimic the coordination environment for the common enzyme active site transition metal ions. Isothermal titration calorimetry (ITC), UV-Vis absorbance spectroscopy and computational chemistry were used for the study. The appropriate ligand to form the copper active site structural mimetic was identified as bis(2-picolyl)amine (BPA) as BPA was found to bind Cu2+ strongly forming a 1:1 Cu(BPA) binary complex. Upon addition of 8-HQ, Cu(BPA) formed a Cu(BPA)(8-HQ) ternary complex. Cu(TREN) and Cu(TPA) however did not form CuL(8-HQ) ternary complex but rather had the TREN or TPA displaced by 8-HQ, yielding the Cu(8-HQ)2 complex. Results from this work helped us better understand the binding reactivity of Cu2+, Co2+ and Mn2+ ions with the small molecule ligands and the enzyme active site inhibitors. The experiments also helped us estimate the energetic contribution of the active site metal ion to enzyme inhibitor binding. Results of this study will be useful to developing new therapeutics targeting metalloenzymes involved in diseases such as cancer

A virtual element formulation for general element shapes

The virtual element method is a lively field of research, in which considerable progress has been made during the last decade and applied to many problems in physics and engineering. The method allows ansatz function of arbitrary polynomial degree. However, one of the prerequisite of the formulation is that the element edges have to be straight. In the literature there are several new formulations that introduce curved element edges. These virtual elements allow for specific geometrical forms of the course of the curve at the edges. In this contribution a new methodology is proposed that allows to use general mappings for virtual elements which can model arbitrary geometries. © 2020, The Author(s)

Računalna mehanika u znanosti i inženjerstvu – Quo vadis

Computational Mechanics has many applications in science and engineering. Its range of application has been enlarged widely in the recent decades. Hence, nowadays areas such as biomechanics and additive manufacturing are among the new research topics, in which computational mechanics helps solve complex problems and processes. In this contribution, these emerging areas will be discussed together with new discretization schemes, e. g. virtual element method and particle methods, whereby the latter need high performance computing facilities in order to solve problems such as mixing in an accurate way. Failure analysis of structures and components is another topic that is developing fast. Here, modern computational approaches rely on the phase field method that simplifies discretizations schemes. All these approaches and methods are discussed and evaluated by means of examples.Računalna mehanika ima široku primjenu u znanosti i inženjerstvu. Njeno područje primjene se znatno povećalo u zadnjim desetljećima. Danas polja kao biomehanika i aditivna proizvodnja nova su područja istraživanja u kojima računalna mehanika pomaže rješavati složene probleme i procese. U radu se razmatraju ova granična područja zajedno s novim diskretizacijskim postupcima kao što su metoda virtualnih elemenata i metoda čestica, gdje potonja zahtijeva moćnu računalnu opremu da bi se mogli točno riješiti problemi kao što je miješanje. Analiza oštećenja konstrukcija i njenih komponenata je drugo područje koje se brzo razvija, pa se ovdje moderni računalni postupci odnose na metodu faznih polja koja pojednostavljuje diskretizacijske sheme. Svi navedeni postupci i metode su razmatrani i vrednovani u numeričkim primjerima

3D mixed virtual element formulation for dynamic elasto-plastic analysis

The virtual element method (VEM) for dynamic analyses of nonlinear elasto-plastic problems undergoing large deformations is outlined within this work. VEM has been applied to various problems in engineering, considering elasto-plasticity, multiphysics, damage, elastodynamics, contact- and fracture mechanics. This work focuses on the extension of VEM formulations towards dynamic elasto-plastic applications. Hereby low-order ansatz functions are employed in three dimensions with elements having arbitrary convex or concave polygonal shapes. The formulations presented in this study are based on minimization of potential function for both the static as well as the dynamic behavior. Additionally, to overcome the volumetric locking phenomena due to elastic and plastic incompressibility conditions, a mixed formulation based on a Hu-Washizu functional is adopted. For the implicit time integration scheme, Newmark method is used. To show the model performance, various numerical examples in 3D are presented

Development of Awareness: The Power of Society and Men in the Saudi Women's Novel

This thesis investigates two of the most important themes concerning women’s problems that have been tackled by Saudi female novelists between 1958-2011 with special attention to the development of their thoughts about the issues from stage to stage. To investigate the two powers over women explored in Saudi women’s novels, the works have been divided into four separate and important stages and each stage has its own thematic and stylistic charactersics. The thesis consists of seven chapters starting with an Introduction, in which the importance of studying the subject is detailed; the theortical framework and the methodology of this study is also discussed. A section is devoted to reviewing previous studies of the Saudi novel in general, as well as studies published on the women’s novel. The status of women in Saudi society is discussed in Chapter Two which covers the structure of Saudi society, women’s education, women’s employment and the effects on the status of women in Saudi Arabia of the events of September 11th, 2001. The other four chapters are divided according to the stages of development of Saudi women’s novels. In each chapter, two novels are analysed: the first novel represents the first theme examined in the thesis, which is the authority of society over women. The second novel represents the second theme, which is the Saudi novelists’ vision regarding the relationships between the sexes in Saudi society. In addition, a section in each chapter is devoted to an examination of the characteristic of the themes in each stage by comparing and contrasting sample novels with the case study novels. The conclusion summarises the most important points of this research with reference to the findings of this study. It also suggests some further research in the field of Saudi literature

Multilevel Global-Local techniques for adaptive ductile phase-field fracture

This paper outlines a rigorous variational-based multilevel Global-Local formulation for ductile fracture. Here, a phase-field formulation is used to resolve failure mechanisms by regularizing the sharp crack topology on the local state. The coupling of plasticity to the crack phase-field is realized by a constitutive work density function, which is characterized through a degraded stored elastic energy and the accumulated dissipated energy due to plasticity and damage. Two different Global-Local approaches based on the idea of multiplicative Schwarz' alternating method are proposed: (i) A global constitutive model with an elastic-plastic behavior is first proposed, while it is enhanced with a single local domain, which, in turn, describes an elastic-plastic fracturing response. (ii) The main objective of the second model is to introduce an adoption of the Global-Local approach toward the multilevel local setting. To this end, an elastic-plastic global constitutive model is augmented with two distinct local domains; in which, the first local domain behaves as an elastic-plastic material and the next local domain is modeled due to the fracture state. To further reduce the computational cost, predictor-corrector adaptivity within Global-Local concept is introduced. An adaptive scheme is devised through the evolution of the effective global plastic flow (for only elastic-plastic adaptivity), and through the evolution of the local crack phase-field state (for only fracture adaptivity). Thus, two local domains are dynamically updated during the computation, resulting with two-way adaptivity procedure. The overall response of the Global-Local approach in terms of accuracy/robustness and efficiency is verified using single-scale problems. The resulting framework is algorithmically described in detail and substantiated with numerical examples.Comment: 50 pages, 24 Figures, 4 Table