The Fiftieth Anniversary of the Institute of Mathematics and Informatics

In October 1997 we celebrate the fiftieth anniversary of the founding of the Institute for Mathematics and Informatics (IMI) of the Bulgarian Academy of Sciences (BAS)

Statistical Analysis of Data on Linker Histones/DNA Interactions

2000 Mathematics Subject Classification: 62P10, 92C40Linker histones (H1, H1o H5, subtypes and variants) play a pivotal role in formation of higher order chromatin structure and thus - as main regulators of the expression of genetic information kept in DNA. That is why the knowledge of the nature of linker histones/DNA interactions is of a greatest interest in understanding of such important issues as transcription regulation, cell division, and cancerogenesis. As DNA is a main "target" of most anticancer antibiotics, the analysis of competitive reactions between that drugs (in our case actinomycin D and netropsin) and linker histones for binding to certain sites in DNA gives hopeful information concerning the mode of such interactions. In this work we present statistical analysis of some experimental data concerning the influence of some anticancer antibiotics on linker histones/DNA interactions. First, it was investigated the formulated hypothesis of the dependence of H1/DNA interaction on actinomycin D concentration. Such a relation was expected knowing the different mode for binding of the both drugs to DNA double helix. The applied statistical analysis using chi-square test for independence showed that the concentration of Actinomycin D in reaction mixture had no essential effect on linker histone/DNA binding. On the contrary, the same analysis with the second antibiotic - netropsin showed that we could not reject the hypothesis of dependence. Some other statistical models are also proposed, applying chi-square test for homogeneity, test of Willcockson, Smirnov's test and others.This paper is supported by NESI - Bulgaria - Grant K - 1003/2000 Partialy supported by Pro-ENBIS GTC1 -2001-43031. This paper is supported by NESI - Bulgaria - Grant MM - 1101/2001

Adipose tissue: a master in toxicology

Conventional wisdom in the pathogenesis of obesity and related cardiometabolic, malignant and neurodegenerative diseases focuses mainly on genetic predisposition and lifestyle (high caloric foods, sedentary lifestyle, smoking). The human genome project's big promise was that it could improve our understanding of the pathogenesis and therapy of diseases. However, the genes have been found to account for only about 10% of diseases, and the remaining causes appear to be from environmental exposures, hence the exposure science emerges. Note that molecular epidemiology and toxicology may be essential partners of exposure science. Indeed, Homo sapiens recens is exposed to an overwhelming number of chemical contaminants circulating every day in the air, water, food, and general environment. The body is a well-equipped entity with capabilities to excrete water-soluble pollutants, but not as well-equipped to excrete some of the lipid-soluble xenobiotics. In the late 1990's, according to the European Environmental Agency more than 100 000 chemical compounds were registered in the European Catalogue of Commercialized Chemical Substances. Here we present data that adipose tissue may be an important participant in the environmental molecular toxicology. The discovery of adipocyte-secreted leptin in 1994 was a paradigm shift event in the study of adipose tissue. It was applauded by scientific community and thus triggered a new direction in the evaluation of endocrine function of adipose tissue, that is, adipoendocrinology. This is why the today's adipose tissue is viewed not merely as a lipid storage, but also as a dynamic secretory - endocrine and paracrine - organ, synthesizing, storing, and releasing a dazzling number of signaling proteins collectively termed adipokines. Numerous evidence demonstrates that the exposure to persistent organic pollutants (POP) may contribute to the pathogenesis of obesity and its related diseases. Noteworthy, these pollutants accumulate mainly in the adipose tissue. And xenobiotic-metabolizing cytochromes p450 (CYP ) are expressed in adipose tissue, where CYP 1A1 and CYP 1B1 can bioactivate carcinogenic polycyclic aromatic hydrocarbons and xenoestrogens. Altogether, the present review highlights an adipocentric approach in molecular toxicology. It is conceptualized as adipotoxicology, that is, the study of accumulation, metabolism, and release of xenobiotics in adipose tissue in health and disease. In effect, the adipose tissue may be a new bridge between environment and health - let us call it a master in toxicology.Adipobiology 2012; 4: 59-66

Adipotoxicology of obesity and related diseases

The human genome project's big promise was that it could improve our understanding of the pathogenesis and therapy of diseases. However, the genes have been found to account for only about 10% of diseases, and the remaining causes appear to be from environmental exposures, hence the exposure science (exposome concept) emerges. Indeed, Homo sapiens is exposed to an overwhelming number of chemical contaminants circulating every day in the air, water, food, and general environment. The body is a well-equipped entity with capabilities to excrete water-soluble pollutants, but not as well-equipped to excrete some of the lipid-soluble xenobiotics. Here we present data that adipose tissue may be an important participant in the environmental molecular toxicology. Numerous evidence demonstrates that the exposure to persistent organic pollutants may contribute to the pathogenesis of obesity and its related diseases. Noteworthy, these pollutants accumulate mainly in the adipose tissue. And xenobiotic-metabolizing cytochromes p450 (CYP) are expressed in adipose tissue, where CYP1A1 and CYP1B1 can bioactivate carcinogenic polycyclic aromatic hydrocarbons and xenoestrogens. Altogether, the present review highlights an adipocentric approach in molecular toxicology. It is conceptualized as adipotoxicology, that is, the study of accumulation, metabolism, and release of xenobiotics in adipose tissue in health and disease.Biomedical Reviews 2012; 23: 53-60

RME-based pharmacology: The inhibition of viral entry as therapeutic perspective in viral diseases including AIDS. Hypothesis updated and enlarged

In 1990, one of us (GNC) for the first time reported a hypothesis of receptor-mediated endocytosis (RME)-based pharmacology relevant to the possible antiviral therapy including in acquired immunodeficiency syndrome (AIDS). Then, RME using clathrin-coated pits/vesicles was the best-characterized endocytic pathway. Since then now, intensive research on the mechanisms of both RME and receptor-mediated virus-cell fusion (receptor-mediated fusion - RMF) helped to expand the list of chemical compounds with potential clinical application as antiviral agents, the so-called entry inhibitors, e.g. (i) inhibitors of clathrin-, dynamin-2-, caveolin- and/or lipid rafts-dependent RME, and (ii) inhibitors of RMF. Accordingly, in the present Dance Round we update and enlarge our hypothesis of RME-based antiviral pharmacology

Simulation and Robust Modifications of Estimates in Branching Processes

This study is focused on the comparison and modification of different estimates arising in the branching processes. Simulations of models with or without migration are put through. Due to the complexity of the computations the algorithms are designed with the language of technical computing MATLAB. Using the simulations, estimates of the o spring mean of the generated processes are calculated. It is well known in the literature that under certain conditions the asymptotic distribution of the estimates is proved to be normal. Using the asymptotic normality a modified method of maximum likelihood is proposed. The aim is to obtain trimmed maximum likelihood estimates based on several sample paths with the same number of generations. Thus in a natural way the observations, inconsistent with the aprior information about the asymptotic normality are excluded from the model. The computation of the standard error allows the comparison of different types of estimates.This paper is supported by National Foundation for Scienti c Investigation - Bulgaria, grant MM-1101/2001 and PRO-ENBIS: GTC1-2001-43031

Branching Populations of Cells Bearing a Continuous Label

2000 Mathematics Subject Classification: 60J80.This paper is concerned with an age-dependent branching process with particles (cells) bearing a label, the latter being treated as a continuous parameter. The proposed stochastic model is motivated by applications in cell biology. It is assumed that the mitotic division results in a random distribution of the label among daughter cells in accordance with some bivariate probability distribution. In the event of cell death the label borne by that cell disappears. The main focus is on the label distribution as a function of the time elapsed from the moment of label administration. Explicit expressions for this distribution are derived in some particular cases which are of practical interest in the analysis of cell cycle. The Markov branching process with the same evolution of a continuously distributed label is considered as well.This research is supported in part by NIH/NINDS grant NS39511 (Yakovlev), ECO-NET-06 action 12634TJ funded by French Foreign Office (Yanev) and grant VU-MI-105/2005 by NSF

Integer Programming Approach to HP Folding

One of the most widely studied protein structure prediction models is the hydrophobic-hydrophilic (HP) model, which explains the hydrophobic interaction and tries to maximize the number of contacts among hydrophobic amino-acids. In order to find a lower bound for the number of contacts, a number of heuristics have been proposed, but finding the optimal solution is still a challenge. In this research, we focus on creating a new integer programming model which is capable to provide tractable input for mixed-integer programming solvers, is general enough and allows relaxation with provable good upper bounds. Computational experiments using benchmark problems show that our formulation achieves these goals.This work was supported by NFSR of Bulgaria, projects DOO2-162/16.12.2008, DOO2-135/31.07.2009 and DO 02-35

The fibrous cap: a promising target in the pharmacotherapy of atherosclerosis

Recent advances have shed light on the relationship between smooth muscle cell (SMC) phenotypic modulation, resolution of inflammation and atherosclerotic plaque stability. The thick fibrous cap covering the lipid core of plaques is composed of bundles of SMC and collagen fibers and few macrophages and lymphocytes, all of which make the plaque resistant to rupture. The thin fibrous cap contains many macrophages and lymphocytes, few SMC and less collagen fibers, all of which may weaken the cap, leaving the plaque vulnerable to rupture. In the present Dance Round, we, at a pharmacotherapeutic level, address the possibility of how the control over the activity of the essential cellular components of the plaque, particularly its fibrous cap, could be implicated in plaque stabilization, focusing on (i) the modulation of SMC from contractile to secretory (fibrogenic) phenotype, (ii) the control on plaque inflammation-resolution processes, and (iii) the reduction of plaque lipid content. Further studies on both unstable plaque and aortic aneurysm, which share a similar, matrix-based vulnerability, may bring new insights for pharmacotherapy of vascular injuries

Is there a common therapeutical strategy for bone joints and blood vessels?

Growing evidence demonstrated recently a rationale for the use of orally administered collagen hydrolysate (collagen peptides) in the therapy of patients with osteoarthritis or other arthrodegenerative disorders. At the same time, there is a need for an effective treatment for millions of people in the world with atherosclerosis and its complications mainly due to the rupture of fibrous (collagenous-muscle) cap of the atherosclerotic plaque. Aortic aneurysm dissection in the heritable connective tissue disorders like Marfan, Ehlers-Danlos and Loeys-Dietz syndromes should also be considered herein. This Dance round article argues that the clinical data of collagen hydrolysate and matrix metalloproteinases (e.g., MMP-2, -9) inhibitors might be translated from osteoarthritis to the therapy of atherosclerosis as fibrous plaque stabilizers – this would be a joint of bone joints and blood vessels in action