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.

Stability analysis of RF amplifiers based on MIMO pole-zero identification

Spurious oscillations are one of the principal issues faced by microwave and RF circuit designers. The rigorous detection of instabilities or the characterization of measured spurious oscillations is still an ongoing challenge. This project aims to create a new stability analysis CAD program that tackles this chal- lenge. Multiple Input Multiple Output (MIMO) pole-zero identification analysis is introduced on the program as a way to create new methods to automate the stability analysis process and to help designers comprehend the obtained results and prevent incorrect interpretations. The MIMO nature of the analysis contributes to eliminate possible controllability and observability losses and helps differentiate mathematical and physical quasi-cancellations, products of overmodeling. The created program reads Single Input Single Output (SISO) or MIMO frequency response data, and determines the corresponding continuous transfer functions with Vector Fitting. Once the transfer function is calculated, the corresponding pole/zero diagram is mapped enabling the designers to analyze the stability of an amplifier. Three data processing methods are introduced, two of which consist of pole/zero elimina- tions and the latter one on determining the critical nodes of an amplifier. The first pole/zero elimination method is based on eliminating non resonant poles, whilst the second method eliminates the poles with small residue by assuming that their effect on the dynamics of a system is small or non-existent. The critical node detection is also based on the residues; the node at which the effect of a pole on the dynamics is highest is defined as the critical node. In order to evaluate and check the efficiency of the created program, it is compared via examples with another existing commercial stability analysis tool (STAN tool). In this report, the newly created tool is proved to be as rigorous as STAN for detecting instabilities. Additionally, it is determined that the MIMO analysis is a very profitable addition to stability analysis, since it helps to eliminate possible problems of loss of controllability, observability and overmodeling.

Structural capital, innovation capability, and company performance in technology-based colombian firms

[EN] In today s economy, innovation is considered to be one of the main driving forces behind business competitiveness, if not the most relevant one. Traditionally, the study of innovation has been addressed from different perspectives. Recently, literature on knowledge management and intellectual capital has provided new insights. Considering this, the aim of this paper is to analyze the impact of different organizational conditions i.e. structural capital on innovation capability and innovation performance, from an intellectual capital (IC) perspective. As regards innovation capability, two dimensions are considered: new idea generation and innovation project management. The population subject to study is made up of technology-based Colombian firms. In order to gather information about the relevant variables involved in the research, a questionnaire was designed and addressed to the CEOs of the companies making up the target population. The sample analyzed is made up of 69 companies and is large enough to carry out a statistical study based on structural equation modelling (partial least squares approach) using PLS-Graph software (Chin and Frye, 2003). The results obtained show that structural capital explains to a great extent both the effectiveness of the new idea generation process and of innovation project management. However, the influence of each specific organizational component making up structural capital (organizational design, organizational culture, hiring and professional development policies, innovation strategy, technological capital, and external structure) varies. Moreover, successful innovation project management is the only innovation capability dimension that exerts a significant impact on company performance.

Algorithm of far-field centre estimation based on phase-only matched filter

Estimation of the far-field centre is carried out in beam auto-alignment. In this paper, the features of the far-field of a square beam are presented. Based on these features, a phase-only matched filter is designed, and the algorithm of centre estimation is developed. Using the simulated images with different kinds of noise and the 40 test images that are taken in sequence, the accuracy of this algorithm is estimated. Results show that the error is no more than one pixel for simulated noise images with a 99% probability, and the stability is restricted within one pixel for test images. Using the improved algorithm, the consumed time is reduced to 0.049 s.

A Real-Time Sliding Mode Control for a Wind Energy System Based on a Doubly Fed Induction Generator

In this paper, a real time sliding mode control scheme for a variable speed wind turbine that incorporates a doubly feed induction generator is described. In this design, the so-called vector control theory is applied, in order to simplify the system electrical equations. The proposed control scheme involves a low computational cost and therefore can be implemented in real-time applications using a low cost Digital Signal Processor (DSP). The stability analysis of the proposed sliding mode controller under disturbances and parameter uncertainties is provided using the Lyapunov stability theory. A new experimental platform has been designed and constructed in order to analyze the real-time performance of the proposed controller in a real system. Finally, the experimental validation carried out in the experimental platform shows; on the one hand that the proposed controller provides high-performance dynamic characteristics, and on the other hand that this scheme is robust with respect to the uncertainties that usually appear in the real systems.

Image-Based Delineation and Classification of Built Heritage Masonry

Fundacion Zain is developing new built heritage assessment protocols. The goal is to objectivize and standardize the analysis and decision process that leads to determining the degree of protection of built heritage in the Basque Country. The ultimate step in this objectivization and standardization effort will be the development of an information and communication technology (ICT) tool for the assessment of built heritage. This paper presents the ground work carried out to make this tool possible: the automatic, image-based delineation of stone masonry. This is a necessary first step in the development of the tool, as the built heritage that will be assessed consists of stone masonry construction, and many of the features analyzed can be characterized according to the geometry and arrangement of the stones. Much of the assessment is carried out through visual inspection. Thus, this process will be automated by applying image processing on digital images of the elements under inspection. The principal contribution of this paper is the automatic delineation the framework proposed. The other contribution is the performance evaluation of this delineation as the input to a classifier for a geometrically characterized feature of a built heritage object. The element chosen to perform this evaluation is the stone arrangement of masonry walls. The validity of the proposed framework is assessed on real images of masonry walls.

Stimulating investment in pearl farming in Solomon Islands: Final report

The overall objective of the project is the reduction of poverty in rural areas of Solomon Islands through creation of livelihoods based on sustainable aquaculture. This fits within the over-arching goals of the WorldFish Center in the Pacific to reduce poverty and hunger in rural communities, and with the Ministry of Fisheries and Marine Resources (MFMR) to stimulate rural development and to develop aquaculture. It has been recognised that the nature of the pearl farming industry means that a high chance of success requires a long term investment from an established pearl farming organisation. This project has been specifically designed to compile the elements of a pre-feasibility study to provide offshore pearl companies with sufficient information to investigate the potential for long-term investment in pearl farming in Solomon Islands. This report also includes the following 6 appendices: Appendix I) Past research and development on black-lip pearl oysters in Solomon Islands; Appendix II) Suitability of habitats in the Solomon Islands and other regions of the Pacific for growth of black-lip and silver-lip pearl oysters; Appendix III) Water temperature and cyclone frequency in the Solomon Islands and other key regions of the Pacific: implications for pearl farming; Appendix IV) Abundance, size structure and quality of silver-lip pearl oysters in Solomon Islands; Appendix V) Solomon Islands: the investment climate for pearl farming; Appendix VI) Pearl farming policy and management guidelines.

Stock evaluation and development of a breeding program for common carp (Cyprinus carpio) in Karnataka, India: progress of a research project

Common carp (Cyprinus carpio) is the single most important species for aquaculture in the state of Karnataka, India, where it is generally grown in polyculture with Indian major carps. Precocious maturation and unwanted reproduction in the species have been identified as constraints to increase production in aquaculture and culture-based fisheries in Karnataka state. Stocks of C. carpio obtained from Hungary (Amur and P3), Indonesia (Rajdanu) and Vietnam (SV) are being assessed alongside two local stocks (L-BRP and L-FRS) in a series of culture performance trials with the objective of setting up a base population for selective breeding. The paper presents progress of research being undertaken at the Fisheries Research Station, University of Agricultural Sciences, Bangalore, India.

Catching and rearing postlarval cleaner shrimp for the aquarium trade: results from a WorldFish Center project in Solomon Islands

Between 1999 and 2003, the WorldFish Center in Solomon Islands conducted research into the feasibility of a new fishery based on the capture and culture of postlarval coral reef fish for the live fish trade. The work was carried out in two phases: a research phase from late 1999 to the end of 2002; and a “finetuning” phase in 2003. Most of the species were of value to the marine aquarium trade, with very few live reef food fish recorded. The most valuable ornamentals were the banded cleaner shrimp, Stenopus species. Cleaner shrimp were harvested using crest nets, the method being modified with the addition of a solid, water-retaining cod-end designed to increase survival at capture. Grow-out techniques were improved by rearing the shrimp separately in jars to prevent aggression. The jars were painted black to protect the shrimp from sunlight. An economic model using experimental catch data and farm gate prices indicates that the fishery based on shrimp, supplemented with small numbers of lobster and fish is economically viable. The next step will be setting up a demonstration farm in a village in the Western Province of Solomon Islands.

Impact evaluation of community-based coastal resource management projects in the Philippines

The benefits of decentralizing the management of coastal resources to local governments and resource users have long been recognized, but the best systems for coastal resources management depend on many factors. A number of community-based management and co-management projects were started in the Philippines in the early 1980s. This report describes a comparative assessment of these projects to determine where improvements can be made in the design of future community-based coastal resource management projects. Early and continuing involvement by project beneficiaries is one of the factors that contributes to the success of the project development, implementation, and evaluation.

Community-based coastal resource management in Orion (Bataan, Philippines) : building community property rights in a fishing community

The Community-based Coastal Resource Management Project in Orion, Bataan, Philippines was started in 1991. The village level fishers organizations have formed a municipal-wide association called the Samahan at Ugnayan ng Pangisdaan sa Orion (SUGPO). It represents 70% of the small-scale fishers in Orion and has taken on the task of rehabilitating the degraded fishing grounds. The experience in Orion indicates that coastal resource management can be successful if the fishers have ownership of the program and the costs and benefits of the program are distributed equally in a manner acceptable to them.

The Environment Agency/DEFRA Evidence and Measures Project: Practical Solutions - Moston Brook

This is the final presentation from the Moston Brook Evidence and Measures project which ran from September 2012 to March 2013. Moston Brook water body is part of the River Irwell Pilot Catchment and the objective of the project was to devise reliable measures (actions) which were based on existing evidence and that could be implemented in years 2 and 3 by the Environment Agency and its partner to help meet Water Framework Directive (WDF) requirements and community aspirations. The presentation summarises the main suspected causes of WDF failure, the evidence for this, the main causes for failure in the sub-catchments resulting from the evidence found, and identifies measures to carry out, which will address the WDF failures and improve the quality of the water. This presentation can be used to inform others on how to improve the water quality of Moston Brook, and also to support other similar initiatives.