Using Agent-Based Simulation Models in the Analysis of Market Crashes

In this thesis we propose an agent-based model for a financial market with a single asset. The agents are motivated to trade via their personal beliefs about the future direction of the asset price moves. Additionally, the trades are restricted by the resources available to agents. The constructed model is used to attempt to gain some insight into the origin of large price moves in the market (“market crashes”). Monte Carlo simulations are used to study model behaviour under varying initial conditions. The model is found to be generally capable of reproducing the stylised facts of real financial markets. The ubiquity of relatively high incidence of large price moves in the results of model simulation, together with results from similar models by other authors allow us to conjecture that such moves are inherent in a market model based on a heterogenous population of intelligent agents. Finally, several directions for model improvement are identified

Biomedical Applications of Nano-Sized Polymeric Micelles and Polyion Complexes

The paper provides a high-level overview of the use of polymeric micelles, polyion complexes, cell mediated drug carriers and exosomes in the therapy of cancer and neurodegenerative diseases. The author tries to combine the lessons-learned during over a quarter of century work in the field of nanomedicine and drug delivery along with a vision statement of some trends and future prospective in this field. Several most recent examples from the University of North Carolina and Moscow State University laboratories are presented including high capacity polymeric micelles for single and multiple water-insoluble drugs for cancer therapy. The nanoscale size polyion complexes formed by ionic block copolymers and polypeptides for the delivery of these polypeptides are also discussed. Examples include antioxidant enzymes (e.g. superoxide dismutase, catalase), stoichiometric and catalytic scavengers of organophosphorus toxins (butirylcholine esterase, organophosphate hydrolase) and neurotrophins (brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor). The applications include treatments of obesity, stroke, Parkinson’s disease, RETT syndrome, organophosphorus toxins poisoning, and some other medical conditions that have been demonstrated using animal models. The application of these complexes in the context of the macrophage carriers for drug delivery to the site of inflammation is presented. A concept of the use of genetically modified macrophages as natural gene delivery vectors is stated and illustrated using Parkinson’s disease therapy as an example. The role of exosomes in gene and protein delivery and its potential as a true pharmaceutical modality are also discusse

Entwicklung höchstfester Pipeline-Stähle mit MA-Phase für die Herstellung von Grobblechen

Die vorliegende Dissertation konzentriert sich auf die Untersuchung und Entwicklung hochfester Grobblechstähle mit erhöhtem Gehalt an der MA-Phase (Martensit-Austenit Phase). Dabei wurden Bildungsmechanismen der Mikrostruktur und insbesondere der MA-Phase in Abhängigkeit von der Walztechnologie an vier mikrolegierten Grobblechstählen untersucht. Zu diesem Zweck erfolgten zahlreihe Untersuchungen an verschiedenen Prüf- und Simulationsanlagen zur Charakterisierung des Werkstoffverhaltens sowie zur physikalischen Simulation der Grobblechherstellung mit der Anwendung von bekannten und neu entwickelten Wärmebehandlungstechnologien. Abschließend wurden mehrere Serien von Laborwalzversuchen auf einer Warmwalzpilotanlage durchgeführt, um die gewonnenen Erkenntnisse zu evaluieren, sowie die für Pipelinestähle relevanten mechanischen Eigenschaften zu ermitteln. Somit erstreckt sich die Arbeit über die gesamte Produktionskette zur Erzeugung der Grobblechstähle mit MA-Phase und beschreibt hierfür geeignete Herstellungsbedingungen, die in Betriebsanlagen leicht realisierbar sind

The Promise and Perils of CNS Drug Delivery: A Video Debate

Neurodegenerative and infectious disorders related to host genetics, aging, and environment are rapidly increasing. Drugs, vaccines, or regenerative proteins offer “real” possibilities for positively affecting disease outcomes but are limited by access across the blood-brain barrier. New developments in nanomedicine and cell based drug delivery are becoming available. These discoveries can lead to improved neurological disease outcomes. Such obstacles include the toxicities inherent in the delivery systems de novo such as immuno- and neurological dysfunctions and perturbations of blood-brain barrier function. This debate by leading experts in the field highlights the promise and perils of CNS drug delivery. Click on Supplemental HTML to watch the streaming video

Enhancement of the polycation-mediated DNA uptake and cell transfection with Pluronic P85 block copolymer

AbstractPolyelectrolyte complexes formed between DNA and poly(N-ethyl-4-vinylpyridinium) cations were shown to effectively transfect mammalian cells [7]. This work suggests that the polycation-mediated uptake of the plasmid DNA and cell transfection are significantly enhanced when these complexes are administered simultaneously with a poly(ethylene oxide)block-poly(propylene oxide)-block-poly(ethylene oxide) copolymer, Pluronic P85. The uptake studies were performed using radioactively labeled pRSV CAT plasmid on NIH 3T3, MDCK, and Jurkat cell lines. The transfection was investigated by chloramphenicol acetyltransferase assay using 3T3 cells as a model. The effects reported may be useful for the enhancement of the polycation-mediated cell transfection

Brain delivery of proteins via their fatty acid and block copolymer modifications

It is well known that hydrophobic small molecules penetrate cell membranes better than hydrophilic molecules. Amphiphilic molecules that dissolve both in lipid and aqueous phases are best suited for membrane transport. Transport of biomacromolecules across physiological barriers, e.g. the blood-brain barrier, is greatly complicated by the unique structure and function of such barriers. Two decades ago we adopted a simple philosophy that to increase protein delivery to the brain one needs to modify this protein with hydrophobic moieties. With this general idea we began modifying proteins (antibodies, enzymes, hormones, etc.) with either hydrophobic fatty acid residues or amphiphilic block copolymer moieties, such as poy(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (pluronics or poloxamers) and more recently, poly(2-oxasolines). This simple approach has resulted in impressive successes in CNS drug delivery. We present a retrospective overview of these works initiated in the Soviet Union in 1980s, and then continued in the United States and other countries. Notably some of the early findings were later corroborated by brain pharmacokinetic data. Industrial development of several drug candidates employing these strategies has followed. Overall modification by hydrophobic fatty acids residues or amphiphilic block copolymers represents a promising and relatively safe strategy to deliver proteins to the brain

Fatty acid acylated Fab-fragments of antibodies to neurospecific proteins as carriers for neuroleptic targeted delivery in brain

AbstractA method for targeted delivery of neuroleptics from blood in brain based on using Fab-fragments of antibodies to antigens of brain glia cells (acid gliofibrillar antigen and α2-glycoprotein) is suggested. The essence of the technique is that the molecule of neuroleptic (trifluoperazine) is conjugated with Fab-fragments of these antibodies. The conjugate thus obtained is modified by stearoylchloride in the system of Aerosol OT reversed micelles in octane. The study of the distribution of 125I-labelled conjugates in the rat organism after intracordial introduction is performed. On the contrary to the nonmodified conjugates and conjugate, containing fatty acylated Fab-fragments of antibodies, nonspecific to the rat brain, the conjugate of trifluoperazine with stearoylated Fab-fragments of antibodies to neurospecific antigens accumulate in brain tissues. The drastic increase of the neuroleptic activity of trifluoperazine resulting from its coupling with stearoylated Fab-fragments of antiglial antibodies is observed

Pluronics and MDR Reversal: An Update

Multidrug resistance (MDR) remains one of the biggest obstacles for effective cancer therapy. Currently there are only few methods that are available clinically that are used to bypass MDR with very limited success. In this review we describe how MDR can be overcome by a simple yet effective approach of using amphiphilic block copolymers. Triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), arranged in a triblock structure PEO-PPO-PEO, Pluronics or “poloxamers”, raised a considerable interest in the drug delivery field. Previous studies demonstrated that Pluronics sensitize MDR cancer cells resulting in increased cytotoxic activity of Dox, paclitaxel, and other drugs by 2–3 orders of magnitude. Pluronics can also prevent the development of MDR in vitro and in vivo. Additionally, promising results of clinical studies of Dox/Pluronic formulation reinforced the need to ascertain a thorough understanding of Pluronic effects in tumors. These effects are extremely comprehensive and appear on the level of plasma membranes, mitochondria, and regulation of gene expression selectively in MDR cancer cells. Moreover, it has been demonstrated recently that Pluronics can effectively deplete tumorigenic intrinsically drug-resistant cancer stem cells (CSC). Interestingly, sensitization of MDR and inhibition of drug efflux transporters is not specific or selective to Pluronics. Other amphiphilic polymers have shown similar activities in various experimental models. This review summarizes recent advances of understanding the Pluronic effects in sensitization and prevention of MDR

Evaluation of polyplexes as gene transfer agents

Non-viral transfection systems based on the complexes of DNA and polycations (‘polyplexes’) were evaluated with respect to their effectiveness, toxicity and cell type dependence in a variety of in vitro models. The panel of polycations examined included branched and linear polyethyleneimines, poly[N-ethyl-4-vinyl pyridinium bromide], polyamidoamine dendrimer (Superfect™), poly(propyleneimine) dendrimer (Astramol™) and a conjugate of Pluronic® P123 and polyethyleneimine (P123-g-PEI(2K)), having a graft-block copolymer architecture. Using a panel of cell lines the linear polyethyleneimine ExGen™ 500, Superfect™, branched polyethyleneimine 25 kDa, and P123-g-PEI(2K) were determined as systems displaying highest transfection activity while exhibiting relatively low cytotoxicity. These systems had activity higher than or comparable to lipid transfection reagents (Lipofectin®, LipofectAMINE™, CeLLFECTIN® and DMRIE-C) but did not reveal serum dependence and were less toxic than the lipids. Overall, this study demonstrates good potential of structurally diverse polyplex systems as transfection reagents with relatively low cytotoxicity

Soluble Stoichiometric Complexes from Poly(N-ethyl-4-vinylpyridinium) Cations and Poly(ethylene oxide)-block-polymethacrylate Anions

Block ionomer complexes formed between the block copolymers containing poly(sodium methacrylate) (PMANa) and poly(ethylene oxide) (PEO) segments and poly(N-ethyl-4-vinylpyridinium bromide) (PEVP) were investigated. The data obtained suggest that (i) these systems form water-soluble stoichiometric complexes; (ii) these complexes are stable in a much broader pH range compared to the polyelectrolyte complexes prepared from homopolymers; (iii) they self-assemble to form the core of a micelle comprised of neutralized polyions, surrounded by the PEO corona; (iv) they are salt sensitive since they fall apart as the salt concentration increases beyond a critical value; and (v) they can participate in the cooperative polyion substitution reactions. Therefore, these complexes represent a new class of hybrid materials which combine properties of polyelectrolyte complexes and block copolymer micelles