Time domain synthesis of electro-optical birefringent system for optical waveform generation

In this paper is described a novel technique for producing an electro-optical intensity synthesizer which can generate different periodic time domain waveforms through only sine or cosine wave applied-voltages. The synthesizer presented here consists of a series of stages between two polarizers, with each stage consisting of an electro-optic element and a compensator. Every electro-optical element has the same applied-voltage function but different azimuth angles and ratios between the longitudinal and transverse lengths. The main principle is the synthesis of an electro-optic effect and a polarization interference effect in the time domain. This technique is based on an expanded Fourier positive-direction searching algorithm, which can not only simplify the calculation process but also produces many choices of structural parameters for different waveforms generation. A three-stage synthesis of an electro-optical birefringent system for continuous square waveform is undertaken to prove the principle.

Design of a timber Howe truss highway bridge

The span of the bridge was assumed as 100 feet. The type of bridge used is the timber Howe Truss. The height of truss was taken as 20 feet between center lines of top and bottom chords. The width was taken as 18 feet center to center of trusses. The truss was divided up into five panels 20 feet long.

It was designed according to the "General Specifications for Steel Highway Bridges" by Ketchum. For the live load for the floor and its supports, a load of 80 pounds per square foot of total floor surface or a 15 ton traction engine with axles 10 feet centers and 6 feet gage, two thirds of load to be carried by rear axles.

For the truss a load of 75 pounds per square foot of floor surface.

For the wind load the bottom lateral bracing is to be designed to resist a lateral wind load of 300 pounds per foot of span; 150 pounds of this to be treated as a moving load.

The top lateral bracing is to be designed to resist a lateral wind force of 150 pounds per foot of span.

The timber to be used in the bridge is to be Douglas fir.

The unit stresses used for timber are those of the American Railway Engineering Association.

Development of a Cationic Mucic Acid Polymer-Based Nanoparticle siRNA Delivery System

Cancer chemotherapy has advanced from highly toxic drugs to more targeted treatments in the last 70 years. Chapter 1 opens with an introduction to targeted therapy for cancer. The benefits of using a nanoparticle to deliver therapeutics are discussed. We move on to siRNA in particular, and why it would be advantageous as a therapy. Specific to siRNA delivery are some challenges, such as nuclease degradation, quick clearance from circulation, needing to enter cells, and getting to the cytosol. We propose the development of a nanoparticle delivery system to tackle these challenges so that siRNA can be effective.

Chapter 2 of this thesis discusses the synthesis and analysis of a cationic mucic acid polymer (cMAP) which condenses siRNA to form a nanoparticle. Various methods to add polyethylene glycol (PEG) for stabilizing the nanoparticle in physiologic solutions, including using a boronic acid binding to diols on mucic acid, forming a copolymer of cMAP with PEG, and creating a triblock with mPEG on both ends of cMAP. The goal of these various pegylation strategies was to increase the circulation time of the siRNA nanoparticle in the bloodstream to allow more of the nanoparticle to reach tumor tissue by the enhanced permeation and retention effect. We found that the triblock mPEG-cMAP-PEGm polymer condensed siRNA to form very stable 30-40 nm particles that circulated for the longest time – almost 10% of the formulation remained in the bloodstream of mice 1 h after intravenous injection.

Chapter 3 explores the use of an antibody as a targeting agent for nanoparticles. Some antibodies of the IgG1 subtype are able to recruit natural killer cells that effect antibody dependent cellular cytotoxicity (ADCC) to kill the targeted cell to which the antibody is bound. There is evidence that the ADCC effect remains in antibody-drug conjugates, so we wanted to know whether the ADCC effect is preserved when the antibody is bound to a nanoparticle, which is a much larger and complex entity. We utilized antibodies against epidermal growth factor receptor with similar binding and pharmacokinetics, cetuximab and panitumumab, which differ in that cetuximab is an IgG1 and panitumumab is an IgG2 (which does not cause ADCC). Although a natural killer cell culture model showed that gold nanoparticles with a full antibody targeting agent can elicit target cell lysis, we found that this effect was not preserved in vivo. Whether this is due to the antibody not being accessible to immune cells or whether the natural killer cells are inactivated in a tumor xenograft remains unknown. It is possible that using a full antibody still has value if there are immune functions which are altered in a complex in vivo environment that are intact in an in vitro system, so the value of using a full antibody as a targeting agent versus using an antibody fragment or a protein such as transferrin is still open to further exploration.

In chapter 4, nanoparticle targeting and endosomal escape are further discussed with respect to the cMAP nanoparticle system. A diboronic acid entity, which gives an order of magnitude greater binding (than boronic acid) to cMAP due to the vicinal diols in mucic acid, was synthesized, attached to 5kD or 10kD PEG, and conjugated to either transferrin or cetuximab. A histidine was incorporated into the triblock polymer between cMAP and the PEG blocks to allow for siRNA endosomal escape. Nanoparticle size remained 30-40 nm with a slightly negative ca. -3 mV zeta potential with the triblock polymer containing histidine and when targeting agents were added. Greater mRNA knockdown was seen with the endosomal escape mechanism than without. The nanoparticle formulations were able to knock down the targeted mRNA in vitro. Mixed effects suggesting function were seen in vivo.

Chapter 5 summarizes the project and provides an outlook on siRNA delivery as well as targeted combination therapies for the future of personalized medicine in cancer treatment.

Pan-biogeografia dos ungulados viventes (Mammalia: Cetartiodactyla e Perissodactyla) da região Neotropical, da Zona de Transição Sul-americana e região Andina: aspectos históricos e conservacionistas

Os ungulados viventes (Cetartiodactyla e Perissodactyla), nas regiões estudadas, são representados por 11 gêneros e 24 espécies. O presente estudo propõe reconhecer os padrões de distribuição destas espécies, a partir da aplicação do método pan-biogeográfico de análise de traços. Este método auxilia no entendimento a priori dos padrões congruentes de distribuição e numa compreensão de padrões e processos de diferenciação geográfica no tempo e no espaço, reconstruindo a biogeografia de táxons. Em relação a aspectos conservacionistas, o método foi aplicado na identificação de áreas prioritárias para conservação. A aplicação do método consiste basicamente na marcação das localidades de ocorrência dos diferentes táxons em mapas, sendo estas localidades conectadas por intermédio de linhas seguindo um critério de mínima distância, resultando nos chamados traços individuais que foram plotados nos mapas de biomas da América Central e do Sul do programa ArcView GIS 3.2. A superposição destes traços individuais define um traço generalizado, sugerindo uma história comum, ou seja, a preexistência de uma biota ancestral subsequentemente fragmentada por eventos vicariantes. A interseção de dois ou mais traços generalizados corresponde a um nó biogeográfico, que representa áreas compostas e complexas, nas quais se agrupam distintas histórias biogeográficas. Para a análise pan-biogeográfica foi utilizado o software ArcView GIS 3.2 e a extensão Trazos 2004. A partir da superposição dos 24 traços individuais, foram reconhecidos cinco traços generalizados (TGs): TG1, Mesoamericano/Chocó, composto por Mazama pandora, M. temama e Tapirus bairdii; TG2, Andes do Norte (Mazama rufina, Pudu mephistophiles e Tapirus pinchaque); TG 3, Andes Centrais (Hippocamelus antisensis, Lama guanicoe, Mazama chunyi e Vicugna vicugna) ; TG4, Patagônia chilena (Hippocamelus bisulcus e Pudu puda).; TG5, Chaco/Centro oeste do Brasil (Blastocerus dichotomus, Catagonus wagneri e Ozotocerus bezoarticus); e um nó biogeográfico em Antioquia no noroeste da Colômbia. As espécies Mazama americana, M.bricenii, M.goazoubira, M.nana, Tapirus terrestris, Tayassu pecari e T. tajacu não participaram de nenhum dos traços generalizados. Os padrões de distribuição formados a partir dos traços generalizados indicam que os ungulados viventes sofreram uma fragmentação e diferenciação no Pleistoceno, relacionadas a eventos históricos ocorridos na região Neotropical, na Zona de Transição Sul-americana e na região Andina, explicados pelos movimentos ocorridos nas Zonas de Falhas Tectônicas da América Central e do Sul, por vulcanismo e pelas mudanças climáticas. A formação do platô Altiplano-Puna revelou ser uma barreira geográfica, tanto em tempos pretéritos como em tempos atuais, para a maioria da biota sul-americana, com exceção dos camelídeos, que habitam estas áreas da Argentina, do oeste da Bolívia e sudoeste do Peru. O nó biogeográfico confirmou a presença de componentes bióticos de diferentes origens, constituindo uma área com grande diversidade biológica e endêmica, sugerindo assim uma unidade de conservação no noroeste da América do Sul.