Spectroscopic studies on Cyclodextrin and Metal Organic Framework based potential nanovectors for delivery of Anticancer and Antiviral drugs

The aim of this work is to contribute to the development of new multifunctional nanocarriers for improved encapsulation and delivery of anticancer and antiviral drugs. The work focused on water soluble and biocompatible oligosaccharides, the cyclodextrins (CyDs), and a new family of nanostructured, biodegradable carrier materials made of porous metal-organic frameworks (nanoMOFs). The drugs of choice were the anticancer doxorubicin (DOX), azidothymidine (AZT) and its phosphate derivatives and artemisinin (ART). DOX possesses a pharmacological drawback due to its self-aggregation tendency in water. The non covalent binding of DOX to a series of CyD derivatives, such as g-CyD, an epichlorohydrin crosslinked b-CyD polymer (pb-CyD) and a citric acid crosslinked g-CyD polymer (pg-CyD) was studied by UV visible absorption, circular dichroism and fluorescence. Multivariate global analysis of multiwavelength data from spectroscopic titrations allowed identification and characterization of the stable complexes. pg-CyD proved to be the best carrier showing both high association constants and ability to monomerize DOX. AZT is an important antiretroviral drug. The active form is AZT-triphosphate (AZT-TP), formed in metabolic paths of low efficiency. Direct administration of AZT-TP is limited by its poor stability in biological media. So the development of suitable carriers is highly important. In this context we studied the binding of some phosphorilated derivatives to nanoMOFs by spectroscopic methods. The results obtained with iron(III)-trimesate nanoMOFs allowed to prove that the binding of these drugs mainly occurs by strong iono-covalent bonds to iron(III) centers. On the basis of these and other results obtained in partner laboratories, it was possible to propose this highly versatile and “green” carrier system for delivery of phosphorylated nucleoside analogues. The interaction of DOX with nanoMOFs was also studied. Finally the binding of the antimalarial drug, artemisinin (ART) with two cyclodextrin-based carriers,the pb-CyD and a light responsive bis(b-CyD) host, was also studied.

Phasenverhalten, Kristallisation und Morphologie ladungsstabilisierter kolloidaler Mischungen

Die vorliegende Arbeit möchte die Anwendbarkeit ladungsstabilisierter kolloidaler Systeme als Modellsysteme für fundamentale Fragen der Festkörperphysik und Thermodynamik auf binäre Mischungen erweitern. In diesem Kontext untersucht sie das Phasenverhalten und mit ihm im Zusammenhang stehende Eigenschaften von binären Mischungen ladungsstabilisierter, sphärischer kolloidaler Partikel in wässriger Suspension. Da das Verhalten hartkugelähnlicher Systeme durch hohe Fremdionenkonzentrationen bereits gut bekannt ist, konzentriert sich diese Arbeit auf sehr langreichweitig repulsive Systeme unter deionisierten Bedingungen. Neben etablierten Methoden der Mikroskopie und statischer Lichtstreuung zur Phasendiagrammsbestimmung wird auch die Beobachtung der zeitabhängigen Entwicklung des Schermoduls verwendet, um eine langsame Erstarrungskinetik zu studieren. Es werden insbesondere Mischungen aus Komponenten unterschiedlicher Größe und Ladung der Größenverhältnisse 0,9, 0,82, 0,57, 0,39 und 0,37 untersucht. Diese zeigen in dieser Reihenfolge Phasendiagramme mit spindelförmigem fluid/kristallinen Koexistenzbereich wie auch azeotrope und eutektische Phasendiagramme. Die Strukturuntersuchungen aus der statischen Lichtstreuung stehen in praktisch allen Fällen im Einklang mit ungeordneten bcc- Substitutionskristallen, was über Modelle zu Schermodulmessungen bestätigt wird. Für das spindelförmige System wird ein überraschend weiter Koexistenzbereich beobachtet, wie er nicht von der Theorie erwartet wird. Die Lage, aber nicht die Form des Solidus stimmt quantitativ mit Simulationsvorhersagen zu einkomponentigen Systemen überein. Für das eutektische System bei einem Radienverhältnis von 0,57 wird der Einfluss der Schwerkraft auf das Phasenverhalten und die Erstarrungskinetik untersucht. Die der Kristallisation der kleineren Majoritätskomponente vorgelagerte gravitativ unterstützte Entmischung begünstigt hier die Verfestigung. Beobachtet werden Morphologien, die aus anderen Systemen bekannt sind (Facetten, Dendriten), wie auch erstmals eine kollumnare eutektische Morphologie. Aus den Ergebnissen wird der erste umfassende Überblick über das Phasenverhalten deionisierter Mischungen ladungsstabilisierter, sphärischer Partikel erstellt, die eine Diskussion der Daten anderer Autoren und unserer Gruppe über fluid-fluider Phasenseparation und einem System mit oberem azeotropen Punkt mit einschließt. Die meisten metallspezifischen Phasendiagrammtypen können mit ladungsstabilisierten kolloidalen Partikeln reproduziert werden. Die langreichweitig wechselwirkenden Partikel zeigt eine wesentlich verbesserte substitutionelle Mischbarkeit im Vergleich mit Hartkugel- und Metallsystemen. Das Größenverhältnis der sphärischen Partikel nimmt dabei die bestimmende Rolle für den Phasendiagrammtyp ein.

Kinematics and statics of cable-driven parallel robots by interval-analysis-based methods

In the past two decades the work of a growing portion of researchers in robotics focused on a particular group of machines, belonging to the family of parallel manipulators: the cable robots. Although these robots share several theoretical elements with the better known parallel robots, they still present completely (or partly) unsolved issues. In particular, the study of their kinematic, already a difficult subject for conventional parallel manipulators, is further complicated by the non-linear nature of cables, which can exert only efforts of pure traction. The work presented in this thesis therefore focuses on the study of the kinematics of these robots and on the development of numerical techniques able to address some of the problems related to it. Most of the work is focused on the development of an interval-analysis based procedure for the solution of the direct geometric problem of a generic cable manipulator. This technique, as well as allowing for a rapid solution of the problem, also guarantees the results obtained against rounding and elimination errors and can take into account any uncertainties in the model of the problem. The developed code has been tested with the help of a small manipulator whose realization is described in this dissertation together with the auxiliary work done during its design and simulation phases.

Measurement of LSP-induced residual stresses and fatigue life on thin-walled aluminium alloys specimens

This thesis work encloses activities carried out in the Laser Center of the Polytechnic University of Madrid and the laboratories of the University of Bologna in Forlì. This thesis focuses on the superficial mechanical treatment for metallic materials called Laser Shock Peening (LSP). This process is a surface enhancement treatment which induces a significant layer of beneficial compressive residual stresses underneath the surface of metal components in order to improve the detrimental effects of the crack growth behavior rate in it. The innovation aspect of this work is the LSP application to specimens with extremely low thickness. In particular, after a bibliographic study and comparison with the main treatments used for the same purposes, this work analyzes the physics of the operation of a laser, its interaction with the surface of the material and the generation of the surface residual stresses which are fundamentals to obtain the LSP benefits. In particular this thesis work regards the application of this treatment to some Al2024-T351 specimens with low thickness. Among the improvements that can be obtained performing this operation, the most important in the aeronautic field is the fatigue life improvement of the treated components. As demonstrated in this work, a well-done LSP treatment can slow down the progress of the defects in the material that could lead to sudden failure of the structure. A part of this thesis is the simulation of this phenomenon using the program AFGROW, with which have been analyzed different geometric configurations of the treatment, verifying which was better for large panels of typical aeronautical interest. The core of the LSP process are the residual stresses that are induced on the material by the interaction with the laser light, these can be simulated with the finite elements but it is essential to verify and measure them experimentally. In the thesis are introduced the main methods for the detection of those stresses, they can be mechanical or by diffraction. In particular, will be described the principles and the detailed realization method of the Hole Drilling measure and an introduction of the X-ray Diffraction; then will be presented the results I obtained with both techniques. In addition to these two measurement techniques will also be introduced Neutron Diffraction method. The last part refers to the experimental tests of the fatigue life of the specimens, with a detailed description of the apparatus and the procedure used from the initial specimen preparation to the fatigue test with the press. Then the obtained results are exposed and discussed.

Design Simulation for Solar Energy Research and Education

Solar research is primarily conducted in regions with consistent sunlight, severely limiting research opportunities in many areas. Unfortunately, the unreliable weather in Lewisburg, PA, can prove difficult for such testing to be conducted. As such, a solar simulator was developed for educational purposes for the Mechanical Engineering department at Bucknell University. The objective of this work was to first develop a geometric model to evaluate a one sun solar simulator. This was intended to provide a simplified model that could be used without the necessity of expensive software. This model was originally intended to be validated experimentally, but instead was done using a proven ray tracing program, TracePro. Analyses with the geometrical model and TracePro demonstrated the influence the geometrical properties had results, specifically the reflector (aperture) diameter and the rim angle. Subsequently, the two were approaches were consistent with one another for aperture diameters 0.5 m and larger, and for rim angles larger than 45°. The constructed prototype, that is currently untested, was designed from information provided by the geometric model, includes a metal halide lamp with a 9.5 mm arc diameter and parabolic reflector with an aperture diameter of 0.631 meters. The maximum angular divergence from the geometrical model was predicted to be 30 mRadians. The average angular divergence in TraceProof the system was 19.5 mRadians, compared to the sun’s divergence of 9.2 mRadians. Flux mapping in TracePro showed an intensity of 1000 W/m2 over the target plane located 40 meters from the lamp. The error between spectrum of the metal halide lamp and the solar spectrum was 10.9%, which was found by comparing their respective Plank radiation distributions. The project did not satisfy the original goal of matching the angular divergence of sunlight, although the system could still to be used for optical testing. The geometric model indicated performance in this area could be improved by increasing the diameter of the reflector, as well as decreasing the source diameter. Although ray tracing software provides more information to analyze the simulator system, the geometrical model is adequate to provide enough information to design a system.

Dynamic modeling, simulation and control design of a parafoil-payload system for ship launched aerial delivery system (SLADS)

The objective of this research was to develop a high-fidelity dynamic model of a parafoilpayload system with respect to its application for the Ship Launched Aerial Delivery System (SLADS). SLADS is a concept in which cargo can be transfered from ship to shore using a parafoil-payload system. It is accomplished in two phases: An initial towing phase when the glider follows the towing vessel in a passive lift mode and an autonomous gliding phase when the system is guided to the desired point. While many previous researchers have analyzed the parafoil-payload system when it is released from another airborne vehicle, limited work has been done in the area of towing up the system from ground or sea. One of the main contributions of this research was the development of a nonlinear dynamic model of a towed parafoil-payload system. After performing an extensive literature review of the existing methods of modeling a parafoil-payload system, a five degree-of-freedom model was developed. The inertial and geometric properties of the system were investigated to predict accurate results in the simulation environment. Since extensive research has been done in determining the aerodynamic characteristics of a paraglider, an existing aerodynamic model was chosen to incorporate the effects of air flow around the flexible paraglider wing. During the towing phase, it is essential that the parafoil-payload system follow the line of the towing vessel path to prevent an unstable flight condition called ‘lockout’. A detailed study of the causes of lockout, its mathematical representation and the flight conditions and the parameters related to lockout, constitute another contribution of this work. A linearized model of the parafoil-payload system was developed and used to analyze the stability of the system about equilibrium conditions. The relationship between the control surface inputs and the stability was investigated. In addition to stability of flight, one more important objective of SLADS is to tow up the parafoil-payload system as fast as possible. The tension in the tow cable is directly proportional to the rate of ascent of the parafoil-payload system. Lockout instability is more favorable when tow tensions are large. Thus there is a tradeoff between susceptibility to lockout and rapid deployment. Control strategies were also developed for optimal tow up and to maintain stability in the event of disturbances.

Three dimensional finite element simulation of polymer melting and flow in a single-screw extruder : optimization of screw channel geometry

Single-screw extrusion is one of the widely used processing methods in plastics industry, which was the third largest manufacturing industry in the United States in 2007 [5]. In order to optimize the single-screw extrusion process, tremendous efforts have been devoted for development of accurate models in the last fifty years, especially for polymer melting in screw extruders. This has led to a good qualitative understanding of the melting process; however, quantitative predictions of melting from various models often have a large error in comparison to the experimental data. Thus, even nowadays, process parameters and the geometry of the extruder channel for the single-screw extrusion are determined by trial and error. Since new polymers are developed frequently, finding the optimum parameters to extrude these polymers by trial and error is costly and time consuming. In order to reduce the time and experimental work required for optimizing the process parameters and the geometry of the extruder channel for a given polymer, the main goal of this research was to perform a coordinated experimental and numerical investigation of melting in screw extrusion. In this work, a full three-dimensional finite element simulation of the two-phase flow in the melting and metering zones of a single-screw extruder was performed by solving the conservation equations for mass, momentum, and energy. The only attempt for such a three-dimensional simulation of melting in screw extruder was more than twenty years back. However, that work had only a limited success because of the capability of computers and mathematical algorithms available at that time. The dramatic improvement of computational power and mathematical knowledge now make it possible to run full 3-D simulations of two-phase flow in single-screw extruders on a desktop PC. In order to verify the numerical predictions from the full 3-D simulations of two-phase flow in single-screw extruders, a detailed experimental study was performed. This experimental study included Maddock screw-freezing experiments, Screw Simulator experiments and material characterization experiments. Maddock screw-freezing experiments were performed in order to visualize the melting profile along the single-screw extruder channel with different screw geometry configurations. These melting profiles were compared with the simulation results. Screw Simulator experiments were performed to collect the shear stress and melting flux data for various polymers. Cone and plate viscometer experiments were performed to obtain the shear viscosity data which is needed in the simulations. An optimization code was developed to optimize two screw geometry parameters, namely, screw lead (pitch) and depth in the metering section of a single-screw extruder, such that the output rate of the extruder was maximized without exceeding the maximum temperature value specified at the exit of the extruder. This optimization code used a mesh partitioning technique in order to obtain the flow domain. The simulations in this flow domain was performed using the code developed to simulate the two-phase flow in single-screw extruders.

Magnesium - Tellurium by Powder Methods

Today considerable work is being done in the compressed metal powder field which is gradually ob­taining prominence as a valuable branch of metallurgy. The mass of data, however, has led to many different ideas on the results of sintering.

Long-Range Pollution Transport: Trans-Atlantic Mechanisms and Lagrangian Modeling Methods

Over the past several decades, it has become apparent that anthropogenic activities have resulted in the large-scale enhancement of the levels of many trace gases throughout the troposphere. More recently, attention has been given to the transport pathway taken by these emissions as they are dispersed throughout the atmosphere. The transport pathway determines the physical characteristics of emissions plumes and therefore plays an important role in the chemical transformations that can occur downwind of source regions. For example, the production of ozone (O3) is strongly dependent upon the transport its precursors undergo. O3 can initially be formed within air masses while still over polluted source regions. These polluted air masses can experience continued O3 production or O3 destruction downwind, depending on the air mass's chemical and transport characteristics. At present, however, there are a number of uncertainties in the relationships between transport and O3 production in the North Atlantic lower free troposphere. The first phase of the study presented here used measurements made at the Pico Mountain observatory and model simulations to determine transport pathways for US emissions to the observatory. The Pico Mountain observatory was established in the summer of 2001 in order to address the need to understand the relationships between transport and O3 production. Measurements from the observatory were analyzed in conjunction with model simulations from the Lagrangian particle dispersion model (LPDM), FLEX-PART, in order to determine the transport pathway for events observed at the Pico Mountain observatory during July 2003. A total of 16 events were observed, 4 of which were analyzed in detail. The transport time for these 16 events varied from 4.5 to 7 days, while the transport altitudes over the ocean ranged from 2-8 km, but were typically less than 3 km. In three of the case studies, eastward advection and transport in a weak warm conveyor belt (WCB) airflow was responsible for the export of North American emissions into the FT, while transport in the FT was governed by easterly winds driven by the Azores/Bermuda High (ABH) and transient northerly lows. In the fourth case study, North American emissions were lofted to 6-8 km in a WCB before being entrained in the same cyclone's dry airstream and transported down to the observatory. The results of this study show that the lower marine FT may provide an important transport environment where O3 production may continue, in contrast to transport in the marine boundary layer, where O3 destruction is believed to dominate. The second phase of the study presented here focused on improving the analysis methods that are available with LPDMs. While LPDMs are popular and useful for the analysis of atmospheric trace gas measurements, identifying the transport pathway of emissions from their source to a receptor (the Pico Mountain observatory in our case) using the standard gridded model output, particularly during complex meteorological scenarios can be difficult can be difficult or impossible. The transport study in phase 1 was limited to only 1 month out of more than 3 years of available data and included only 4 case studies out of the 16 events specifically due to this confounding factor. The second phase of this study addressed this difficulty by presenting a method to clearly and easily identify the pathway taken by only those emissions that arrive at a receptor at a particular time, by combining the standard gridded output from forward (i.e., concentrations) and backward (i.e., residence time) LPDM simulations, greatly simplifying similar analyses. The ability of the method to successfully determine the source-to-receptor pathway, restoring this Lagrangian information that is lost when the data are gridded, is proven by comparing the pathway determined from this method with the particle trajectories from both the forward and backward models. A sample analysis is also presented, demonstrating that this method is more accurate and easier to use than existing methods using standard LPDM products. Finally, we discuss potential future work that would be possible by combining the backward LPDM simulation with gridded data from other sources (e.g., chemical transport models) to obtain a Lagrangian sampling of the air that will eventually arrive at a receptor.

Multiscale methods for shape constraints in deconvolution: Confidence statements for qualitative features

We derive multiscale statistics for deconvolution in order to detect qualitative features of the unknown density. An important example covered within this framework is to test for local monotonicity on all scales simultaneously. We investigate the moderately ill-posed setting, where the Fourier transform of the error density in the deconvolution model is of polynomial decay. For multiscale testing, we consider a calibration, motivated by the modulus of continuity of Brownian motion. We investigate the performance of our results from both the theoretical and simulation based point of view. A major consequence of our work is that the detection of qualitative features of a density in a deconvolution problem is a doable task, although the minimax rates for pointwise estimation are very slow.

Thermal release rate studies of nuclear reaction products from polycrystalline metal matrices

The thermal release rate of nuclear reaction products was investigated in offline annealing experiments. This work was motivated by the search for a high melting catcher material for recoiling products from heavy ion induced nuclear fusion reactions. Polycrystalline refractory metal foils of Ni, Y, Zr, Nb, Mo, Hf, W, and Re were investigated as catcher metals. Diffusion data for various tracer/host combinations were deduced from the measured release rates. This work focuses on the diffusion and the release rate of volatile p-elements from row 5 and 6 of the periodic table as lighter homologues of the superheavy elements with Z ≥ 113 to be studied in future experiments. A massive radiation damage enhancement of the diffusion velocity was observed. Diffusion trends have been established along the groups and rows of the periodic table based on the dependence of diffusion velocity on atomic sizes.

THEORETICAL STUDIES ON THE METHODS OF RECONSTRUCTING PHYLOGENETIC TREES FROM DNA SEQUENCE DATA (MOLECULAR EVOLUTION, HOMINOID EVOLUTION, COMPUTER SIMULATION)

(1) A mathematical theory for computing the probabilities of various nucleotide configurations is developed, and the probability of obtaining the correct phylogenetic tree (model tree) from sequence data is evaluated for six phylogenetic tree-making methods (UPGMA, distance Wagner method, transformed distance method, Fitch-Margoliash's method, maximum parsimony method, and compatibility method). The number of nucleotides (m*) necessary to obtain the correct tree with a probability of 95% is estimated with special reference to the human, chimpanzee, and gorilla divergence. m* is at least 4,200, but the availability of outgroup species greatly reduces m* for all methods except UPGMA. m* increases if transitions occur more frequently than transversions as in the case of mitochondrial DNA. (2) A new tree-making method called the neighbor-joining method is proposed. This method is applicable either for distance data or character state data. Computer simulation has shown that the neighbor-joining method is generally better than UPGMA, Farris' method, Li's method, and modified Farris method on recovering the true topology when distance data are used. A related method, the simultaneous partitioning method, is also discussed. (3) The maximum likelihood (ML) method for phylogeny reconstruction under the assumption of both constant and varying evolutionary rates is studied, and a new algorithm for obtaining the ML tree is presented. This method gives a tree similar to that obtained by UPGMA when constant evolutionary rate is assumed, whereas it gives a tree similar to that obtained by the maximum parsimony tree and the neighbor-joining method when varying evolutionary rate is assumed. ^