Histone acetyltransferases (HATs) are important enzymes in transcriptional control and potential targets for chemotherapeutic intervention in malignant diseases. Among different HAT members, the yeast Esa1 and human Tip60 (the HIV-1 Tat interactive protein, 60KDa) play multiple roles in normal cellular processes including transcription, cell cycle and checkpoint machinery, double strand DNA break repair, apoptosis, and cell cycle progression. Tip60 is also implicated in several human diseases such as prostate cancer, and gastric cancer. These studies suggest that Tip60 is a potential therapeutic target for new cancer treatment. So, we designed experimental work to synthesize and investigate organic inhibitors of Tip60 using different strategies, including substrate analogs, small molecule screening, and modification of the natural product anacardic acid. These studies provide important chemical agents for basic biology research of HAT function, and produce potential lead compounds for future pharmacologic intervention of HAT deregulation in cancer. Currently, of the methods used for the measurement of acetyltransferase activities, many comprise tedious separation procedures and involve enzyme-coupled steps or radioactive materials. These shortcomings have limited their applications in high-throughput screening (HTS) of HAT inhibitors. To circumvent these problems, a homogenous fluorescent HAT assay based on engineered H4 peptide was designed, synthesized, and evaluated. The data showed that these fluorescent reporters can be used to detect the acetyltransferase activities.

In this dissertation, I present an approach for physical construction of large structures. The approach is based on the graph rotation system framework. I propose two kinds of physical structures to represent the shape of design models. I have developed techniques to generate developable panels from any input polygonal mesh, which can be easily assembled to get the shape of the input polygonal mesh. The first structure is called plain woven structures. I have developed the ?projection method? to convert mathematical weaving cycles on any given polygonal mesh to developable strip panels. The width of weaving strips varies so that the surface of the input model can be covered almost completely. When these strip panels are assembled together, resulting shape resembles to a weaving in 3-space. The second structure is called band decomposition structures. I have developed a method to convert any given polygonal mesh into star-like developable elements, which we call vertex panels. Assembling vertex panels results in band decomposition structures. These band decomposition structures correspond to 2D-thickening of graphs embedded on surfaces. These band decompositions are contractible to their original graph. In a 2D-thickening, each vertex thickens to a polygon and each edge thickens to a band. Within the resulting band decomposition, each polygon corresponds to a vertex and each band corresponds to an edge that connects two vertex polygons. Since the approach is based on graph rotation system framework, the two structures do not have restrictions on design models. The input mesh can be of any genus. The faces in the input mesh can be triangle, quadrilateral, and any polygon. The advantages of this kind of large physical structure construction are low-cost material and prefabrication, easy assemble. Our techniques take the digital fabrication in a new direction and create complex and organic 3D forms. Along the theme of architecture this research has great implication for structure design and makes the more difficult task of construction techniques easier to understand for the fabricator. It has implications to the sculpture world as well as architecture.

Computational structural biology Even with rapid advances in structure determination methods, there is a long gap to be bridged between the number of proteins that have been sequenced and the number whose three-dimensional structures have been experimentally elucidated. Experimentally protein structures are determined by X-ray crystallography or by nuclear magnetic resonance spectroscopy (NMR). X-ray crystal structures give a time averaged picture but little information on conformational dynamics. Though NMR gives dynamical information, the technique cannot be applied to systems whose molecular weight is large. Only small proteins fall within the ken of NMR experiments. In most cases the three dimensional structure of the protein alone cannot give a complete picture of its mechanism. It is also essential to know the interactions of proteins with other proteins, with their ligands and substrates in order to have a better understanding of their functioning. Computer modeling and simulations are now indispensable supplements to experimental structural biology. The last word in protein structure prediction method is far from being said but the ever-improving homology and ab-initio modeling methods give rise to optimism that sometime in the near future these methods will become almost as reliable as experimental techniques. Ligand docking onto protein molecules is as challenging a problem as protein structure predicting itself. Computer modeling methods to dock ligands have to search a wide region of conformational space besides taking into consideration issues of charge and shape complementarities.

Models of tephra fallout are used to assess volcanic hazards in advance of eruptions and in near-real-time. Current models often approximate the wind field using simplistic assumptions of the atmosphere that cannot account for typical variations in wind velocity that occur in time and three-dimensional space. Here, a widely used mesoscale atmospheric model is used to improve forecasts of the location of the major axis of dispersion for erupting plumes. The Pennsylvania State University-National Center for Atmospheric Research fifth-generation Mesoscale Model (MM5) specializes in atmospheric prediction for regions on the order of ten to hundreds of kilometers on a side. MM5 generates realistic wind fields based on the laws of conservation of mass, energy, and momentum, along with land surface data and atmospheric forecasts and observations.

Technological advances in the recent decades have enabled cancer researchers to probe the disease at multiple resolutions. This wealth of experimental data combined with computational systems biology methods is now leading to predictive models of cancer progression and response to therapy. We begin by presenting our research group’s multis-cale in silico framework for modeling cancer, whose core is a tissue-scale computational model capable of tracking the progression of tumors from a diffusion-limited avascular phase through angiogenesis, and into invasive lesions with realistic, complex morphologies. We adapt this core model to consider the delivery of systemically-administered anticancer agents and their effect on lesions once they reach their intended nuclear target. We calibrate the model parameters using in vitro data from the literature, and demonstrate through simulation that transport limitations affecting drug and oxygen distributions play a significant role in hampering the efficacy of chemotherapy; a result that has since been validated by in vitro experimentation. While this study demonstrates the capability of our adapted core model to predict distributions (e.g., cell density, pressure, oxygen, nutrient, drug) within lesions and consequent tumor morphology, nevertheless, the underlying factors driving tumor-scale behavior occur at finer scales. What is needed in our multi-scale approach is to parallel reality, where molecular signaling models predict cellular behavior, and ultimately drive what is seen at the tumor level. Models of signaling pathways linked to cell models are already beginning to surface in the literature. We next transition our research to the molecular level, where we employ data mining and bioinformatics methods to infer signaling relationships underlying a subset of breast cancer that might benefit from targeted therapy of Androgen Receptor and associated pathways. Defining the architecture of signaling pathways is a critical first step towards development of pathways models underlying tumor models, while also providing valuable insight for drug discovery. Finally, we develop an agent-based, cell-scale model focused on predicting motility in response to chemical signals in the microenvironment, generally accepted to be a necessary feature of cancer invasion and metastasis. This research demonstrates the use of signaling models to predict emergent cell behavior, such as motility. The research studies presented in this dissertation are critical steps towards developing a predictive, in silico computational model for cancer progression and response to therapy. Our Laboratory for Computational & Predictive Oncology, in collaboration with research groups throughout in the United States and Europe are following a computational systems biology paradigm where model development is fueled by biological knowledge, and model predictions are refining experimental focus. The ultimate objective is a virtual cancer simulator capable of accurately simulating cancer progression and response to therapy on a patient-specific basis. / text

Reading is an essential skill for students with physical disabilities which opens up opportunities in many areas of an individual’s life including the acquisition of knowledge, the ability to read for enjoyment, and the chances of gaining employment. Students with physical disabilities often do not read fluently; however, there is a lack of research on instructional methods to address reading fluency with this population. Methodologies used with students who have physical disabilities are often borrowed from other populations (e.g., the use of repeated readings to increase fluency with students with learning disabilities). Additionally, advances in technology suggest the possible use of computers to model reading. This study employed a changing criterion design to examine the use of a treatment package consisting of repeated readings, computer modeling, error correction, and performance feedback on improving reading fluency with students with cerebral palsy. The areas of reading comprehension and accuracy were also examined. An analysis of the data demonstrated that all students were able to increase reading fluency, accuracy, and comprehension from first to final readings within a session (positive nontransfer effects). Analysis of the percentage of nonoverlapping data revealed that three of the four students also showed slight increases in reading fluency on novel passages (positive transfer effects). Although the results of this study indicated that the treatment package was effective with students who have physical disabilities, more research is needed to examine individual components of the treatment package and to evaluate the use of such methods over a lengthier period of time.

This project was basically exploratory in the electrical properties of carbon nanotube (CNT) based materials. The direct current (DC) conductivity of CNT/polymer composites was computed by using equivalent circuit method and a three dimensional (3-D) numerical continuum model with the consideration of tunneling conduction. The effects of the potential barrier of polymer and the tortousity of CNTs on the conductivity were analyzed. It was found that both of percolation threshold and DC conductivity can be strongly affected by the potential barrier and the tortousity. The influence of contact resistance on DC conductivity was also computed, and the results revealed that contact resistance and tunneling resistance had significant influences on the conductivity, but did not affect the percolation threshold. The microstructure-dependent alternating current (AC) properties of CNT/polymer composites were investigated using the 3-D numerical continuum model. It was found that AC conductivity and critical frequency of CNT/polymer composites can be enhanced by increasing the curl ratio of CNTs. In the mid-range CNT mass fraction, with increasing curl ratio of CNTs, AC conductivity, interestingly, became frequency-dependent in low frequency range, which cannot be explained by reference to the percolation theory. A proper interpretation was given based on the linear circuit theory. It was also found that the critical frequency can also be affected by the size of CNT cluster. Series numerical formulas were derived by using a numerical capacitively and resistively junction model. In particular, this work introduced an equivalent resistor-capacitor (RC) circuit with simple definitions of the values of contact resistance and average mutual capacitance for CNT/polymer nanocomposites. Theoretical results were in good agreement with experimental data, and successfully predicted the effect of morphology on the AC properties of CNT/polymer composites. DC and AC conductivities of multi-walled carbon nanotube (MWCNT)/graphene oxide (GO) hybrid films were measured for selected MWCNT mass fractions of 10%, 33.3%, 50%, 66.7%, and 83.3% using four-probe method. The experimental results were fitted using scaling law, and relatively high percolation threshold was found. This high percolation threshold was understood in terms of the potential energy and intrinsic ripples and warping in the freestanding graphene sheets. The capacitance of these hybrid films were measured using the voltmeter-ammeter-wattmeter test circuit with different voltages and heat treatments. The MWCNT/GO film showed relatively high specific capacitance (0.192F/cm3 for the mass fraction of 83.3%) and power factor compared to conventional dielectric capacitors. Both of measured capacitance and power factor can be enhanced by increasing testing voltages. The capacitance of MWCNT/GO films rapidly decreased after heat treatments above 160 ℃. This decrease was caused by redox reaction in the GO sheets. The capacitive behaviour of MWCNT/GO hybrid films was also interpreted by using the equivalent circuit model. Single-walled carbon nanotube (SWCNT) and SWCNT/Poly(vinyl alcohol) (PVA) films were used to form a piezoresistive strain sensor. Both of static and dynamic strain sensing behaviours of SWCNT and SWCNT/PVA films were measured. It was found that the sensitivities of these films decreased with increasing their thicknesses. The SWCNT film with a thickness of 1900 nm and SWCNT/PVA film exhibited viscoelastic sensing behaviour, because van der Waals attraction force allowed axial slippages of the smooth surface of nanotubes. A numerical model was derived based on the dynamic strain sensing behaviour. This model could be useful for designing CNT strain sensors. Finally, thermoelectric power (TEP) of deformed SWCNT films with various thicknesses was measured. It was observed that positive TEP of SWCNT films increased with increasing stain above the critical point. The experimental results were fitted by using a numerical model in terms of a variation of Nordheim-Gorter relation and fluctuation induced tunneling (FIT) model. From the numerical model, it was found that the increase of TEP above the critical strain resulted from the positive term of the contribution from the barrier region, and the effect of barrier regions decreases with increasing the thickness of the film.

Nanopores (1 – 10 nm diameter) constructed in solid-state membranes, have shown promise as next-generation biopolymer analysis devices offering both high resolution and high throughput. One promising application of nanopores is in the analysis of nucleic acids, such as DNA. This involves translocation experiments in which DNA is placed in an ionic solution and is forced through a nanopore with the aid of an applied electric field. The modulation of ionic current through the pore during DNA translocation can then be correlated to various properties of the biopolymer such as the length. To optimally design and operate nanopore devices, it would be advantageous to develop an accurate computer simulation methodology to predict the physics of the translocation process. Hence, I have developed a physically accurate, computationally efficient simulation methodology to predict and analyze the physics of biopolymer translocation through solid-state (silicon nitride) nanopores. The overall theme of this thesis is to use this simulation methodology to thoroughly investigate important issues in the physics underlying translocation experiments and thereby determine the effects of key structural and operation parameters, such as nanopore dimensions, applied voltage, hydrodynamic interactions, solvent viscosity, and the polymer chain length. The results from these simulation studies can assist in not only proper nanopore design, but also help determine the proper experimental environments and parameters for nanopore operation.

This diploma thesis is aimed to the possibilities of using low-temperature plasma in various fields of science, research and production with the main focus is given to applications in medicine and environmental applications. In the practical part is presented design a computer model for simulation of the plasma behavior in the above areas. This model is a hybrid type and as a working gas is used oxygen.

Submitted by LUCAS MENEZES FELIZARDO null (lucas_menfel@aluno.feis.unesp.br) on 2016-10-20T17:08:51Z No. of bitstreams: 1 Lucas Felizardo 4.pdf: 4057715 bytes, checksum: d731799585df721c5ec0ec455b5d3418 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-10-26T18:42:24Z (GMT) No. of bitstreams: 1 felizardo_lm_me_ilha.pdf: 4057715 bytes, checksum: d731799585df721c5ec0ec455b5d3418 (MD5) / Made available in DSpace on 2016-10-26T18:42:24Z (GMT). No. of bitstreams: 1 felizardo_lm_me_ilha.pdf: 4057715 bytes, checksum: d731799585df721c5ec0ec455b5d3418 (MD5) Previous issue date: 2016-02-01 / Com o aumento da população mundial e com sua concentração cada vez maior no meio urbano uma gama de problemas vem se apresentando relacionado a esse aumento populacional de maneira direta ou indireta, esse êxodo das pessoas para os grandes centros urbanos vem alterando o espaço geográfico desse ambiente bem rapidamente, principalmente na região do sudeste brasileiro onde os processos de industrialização são mais evidentes. Com essa migração a ocupação e o uso do solo vêm sendo ocupada nem sempre da forma que os planos diretores das cidades recomendam proporcionando na maioria dos casos impactos negativos nos recursos naturais. As alterações antrópicas realizadas nessas áreas, como desmatamento e a urbanização, estão promovendo um desequilíbrio ao meio ambiente afetando áreas drenadas pelas bacias hidrográficas, a complexidade do ambiente urbano e de sua infraestrutura de drenagem tem uma influência inerente no escoamento superficial, este escoamento gera inundações urbanas, que impõe desafios à modelagem, a simulação destes cenarios exigem dados detalhados de elevação. Os problemas acarretados pela ocupação desordenada da bacia vêm sendo abordados em inúmeros estudos de casos que demonstram que o uso e ocupação do solo de forma inadequada e desordenada, muitas vezes, com obras mal dimensionadas, acarretam grandes prejuízos socioeconômicos. O planejamento integrado de uma bacia urbana é o único meio de viabilizar seus usos, sem que isso acarrete em um maior desequilíbrio do meio físico, e nesse cenário que com os dados de obtidos da bacia do Córrego do Mineirinho foi feito a modelagem de cenários de eventos de precipitação e seus possíveis efeitos no meio físico com compilações e um único software. O córrego do mineirinho e outras bacias da região já vem sendo estudadas por inúmeros pesquisadores seus resultados obtidos com múltiplas ferramentas computacionais se mostram compatíveis com os que obtivemos com o uso de apenas um software para realizar todas as fases do processo desde o pré-processamento de imagens de satélite a produção de modelos em 3D de inundação de eventos de precipitação em inúmeros cenários. / With the increasing world population and its increasing concentration in urban areas a range of issues has been presented related to this population increase directly or indirectly, this exodus of people to large urban centers is changing the geographic space that environment very quickly, especially in the Brazilian southeast region where industrialization processes are most evident. With this migration the occupation and land use have been busy not always the way the master plans of cities recommend providing in most cases negative impacts on natural resources. Anthropogenic changes made in these areas, as deforestation and urbanization, are promoting an imbalance to the environment affecting the watershed drained areas, the complexity of the urban environment and its drainage infrastructure has an inherent influence on runoff, this flow generates floods urban, which poses challenges to modeling. The simulation of these scenarios require detailed elevation data. The problems posed by irregular occupation of the basin have been addressed in numerous studies that demonstrate that the use and occupation of inappropriate and disorderly manner, often with poorly scaled works, present major socioeconomic losses. Integrated planning of an urban basin is the only means of enabling their uses, without incurring a greater imbalance in the physical environment, and in this scenario with data obtained from Mineirinho Stream basin was made scenario modeling precipitation events and their potential effects on the physical environment with a unique compilations and software. The stream Mineirinho and other basins in the region has already been studied by numerous researchers their results with multiple computational tools to show compatible with those obtained using only one software to perform all phases of the process from the pre-processing satellite images to produce 3D models of flood precipitation events in many scenarios.