Solid tumors possess biological features that are different from those in healthy tissues, which provides opportunities of anticancer treatment by nanomedicines. Due to the presence of the fenestrated tumor vasculatures, nanomedicines can selectively accumulate in tumor tissues by the enhanced permeability and retention (EPR) effect. The acidic pH in tumor interstitium (pH 6.0-7.0) also provides a promising mechanism to trigger the nanomedicines to promote the cellular uptake of cargo drugs. The previously reported stealth liposomes coated with PEG are known to accumulate in tumors owing to their prolonged circulation time. The PEG coating on liposomes can hinder serum protein adsorption and thus prevent rapid elimination by the reticuloendothelial system, thus increasing the liposome circulation time. However, liposomal interaction with cancer cells can also be hindered by the PEG coating. In order to improve the anticancer activity of stealth liposomes, novel synthetic imidazole-based lipids were introduced to the composition of stealth liposomes to develop the pH-sensitive imidazole-based convertible liposomes (ICL). At acidic pH, the imidazole-based lipids would protonate to acquire positive charges, thus clustering with the negatively charged PEGylated lipids. Such lipid-lipid electrostatic interaction would induce phase separation of the bilayer to generate a PEG-free domain that displays excess positive charges. Such newly converted, cationic liposomes at acidic pH in tumor interstitium would have better interaction with negatively charged cancer cells and/or enhanced drug release, therefore overcoming the drawback of traditional stealth liposomes. After synthesizing the imidazole-based lipids DHI, DHMI and DHDMI, we constructed doxorubicin (DOX)-loaded ICL formulations. The physicochemical properties of ICL were characterized, and factors influencing such properties were explored. The pH-triggered acquisition of positive charges of ICL was confirmed by the elevation of ζ- potentials and aggregation with negatively charged model liposomes that mimic bio-membranes at acidic pH 6.0-7.0. Acidic pH-triggered release of ICL was confirmed by drug release assays. It was also found that although the incorporation of cholesterol can remarkably reduce the size and increase the encapsulation efficiency (EE) of ICL, it also hinders the pH-sensitivity of ICL. The morphology of ICL at both pH 7.4 and pH 6.0 was characterized under transmission electron microscopy (TEM), which showed morphological changes in response to acidic pH 6.0, which further supported the proposed pH-sensitivity of ICL. Cytotoxicity assays on 3D MCS of HeLa, A549, MDA-MB-231 and MDA-MB-468 cell lines were conducted to evaluate the anticancer activity of ICL formulations. ICL formulations without cholesterol showed considerably enhanced anticancer activities against MCS compared with the non-sensitive stealth liposomes (NSL). However, incorporation of cholesterol decreased such activities. The IC50 values of cholesterol-free ICL and ICL with cholesterol against MCS strongly suggested that the pH-sensitivity introduced by the imidazole-based lipids would enhance the anticancer activity of stealth liposomes, while the hindrance of the pH-sensitivity by cholesterol would reduce such activities. Taken together, ICL’s pH-sensitivity is correlated with their enhanced anticancer activity than non-sensitive stealth liposomes.

The traditional anticancer drugs are distributed in vivo through systemic blood circulation with a very small portion reaching the tumor site. Targeted drug delivery systems are developed in efforts to concentrate the drug molecules in the tissue of interest while reducing the drug distribution to healthy tissues to reduce the side effects. Liposomes are colloidal systems composed of amphiphilic molecules that assemble into vesicle structures in aqueous media. They are common carriers for targeted drug delivery with the advantages of low toxicity, low immunogenicity and the ability of encapsulating both lipophilic and hydrophilic drugs. Prior research indicated the advantages of triggered release in drug delivery systems. As a specific example, a series of trans-2-aminocyclohexanol based lipids (flipids) have been reported to illustrate a promising strategy to render pH-triggered drug delivery systems: pH-triggered conformational switch. Based on the foregoing, we hypothesize that incorporation of lipids with a pH-sensitive conformational switch and a long-saturated lipid tail can improve the anticancer activities of stealth liposomes. In this study, six new flipids with C-16 saturated hydrocarbon tails were designed. Such lipids were synthesized with high yields by introducing a catalyst (Copper (II) tetrafluoroborate) at a key step of the synthetic scheme. pH-sensitive liposomes (fliposomes) composed of flipids were prepared and loaded with the anticancer drug doxorubicin with high encapsulation efficiency. The physicochemical properties of doxorubicin-loaded fliposomes were characterized and their pH-dependent leakage were investigated. The results showed that among all groups fliposomes containing the C-16 trans-2-morpholylcyclohexanol-based flipid (Mor-C16) exhibited the largest increase of release as the pH dropped form pH 7.4 to 6.0, indicating its good potential of serving as a component in pH-triggered drug delivery systems. Three-dimensional multicellular spheroids (3D MCS) are self-assembled microscale tissue analogs in vitro. They better mimic the native and complex tumor microenvironment than the conventional two-dimensional cell culture systems. In this dissertation study, 3D MCS of six different human cancer cells were successfully cultured and their growing conditions were optimized to obtain 3D MCS of tight structure and reproducible size. The constructed 3D MCS carried heterogeneously distributed live and apoptotic cells as well as acidic inside pH based on confocal microscopic imaging studies. The penetration of doxorubicin-loaded Mor-C16 fliposomes into 3D MCS was imaged by confocal microscopy in comparison to doxorubicin-loaded non pH-sensitive liposomes and free doxorubicin. The anticancer activities of doxorubicin-loaded Mor-C16 fliposomes against 3D MCS of three different cell lines was also evaluated by cell viability. Both the fliposome and the non pH-sensitive liposome formulations more efficiently penetrated into two of the three types of 3D MCS compared to free doxorubicin after 4h drug exposure. However, doxorubicin-loaded Mor-C16 fliposome imposed higher cytotoxicity to all three types of 3D MCS compared to doxorubicin-loaded non pH-sensitive liposome over 72 h drug exposure. Taken together, we propose that fliposomes achieved superior activity against 3D MCS by efficient penetration into 3D MCS, followed by enhanced release of the anticancer drug doxorubicin.

No description available.

The application of pulse shape analysis (PSA) and γ-ray tracking techniques has attracted a great deal of interest in the recent years in fields ranging from nuclear structure studies to medical imaging. These new data analysis methods add position sensitivity as well as directional information for the detected γ-rays to the excellent energy resolution of germanium detectors. This thesis focuses on the application of PSA on planar segmented germanium detectors, divided into three separate studies. The pulse shape analysis technique known as the matrix method was chosen due to its ability to treat events with arbitrary number and combinations of interactions within a single detector. It has been applied in two experiments with the 25-fold segmented planar pixel detector -- imaging and polarization measurements -- as well as in a simulation of upcoming detectors for DESPEC at NuSTAR/FAIR. In the first experiment, a point source of 137Cs was imaged. Events where the 662 keV γ-rays scattered once and were then absorbed in a different segment were treated by the PSA algorithm in order to find the locations of these interactions. The Compton scattering formula was then used to determine the direction to the source. The experiment has provided a robust test of the performance of the PSA algorithm on multiple interaction events, in particular those with interactions in adjacent segments, as well as allowed to estimate the realistically attainable position resolution. In the second experiment, the response of the detector to polarized photons of 288 keV was studied. The polarization of photons can be measured through the observation of the angular distribution of Compton-scattered photons, Hence the ability to resolve the interaction locations had once again proven useful. The third study is focused on the performance of the proposed planar germanium detectors for the DESPEC array. As these detectors have not yet been manufactured at the time of this writing, a set of data simulated in GEANT4 was used. The detector response was calculated for two of the possible segmentation patterns -- that with a single pixelated contact and one where both contacts are segmented into mutually orthogonal strips. In both cases, PSA was applied in order to reconstruct the interaction locations from this response. It was found that the double-sided strip detector can achieve an over-all better position resolution with a given number of readout channels. However, this comes at the expense of a small number of complex events where the reconstruction fails. These results have also been compared to the performance of the 25-fold pixelated detector. / QC 20101110

This thesis explores the effects of three important factors on a firm's investment and financing decisions, using contingent claim structural model. The first essay investigates how implementation lag impacts investment timing for a levered firm. The main finding is that implementation lag can potentially have a substantial effect on a company’s investment trigger. A crucial determinant of the lag-investment relationship is the fraction of investment cost that has to be incurred upfront. If this fraction is small, investment trigger is a decreasing function of implementation lag and the effect can be economically significant. If this fraction is large, investment trigger can be either increasing or decreasing in lag, but the magnitude of the effect is not large. The second essay investigates how future uncertain growth opportunity impacts a firm's investment timing decision and optimal leverage ratio. The firm has an option to expand profits after the first investment. However, the exercise of the growth option depends not only on the underlying profit flow but also on the uncertain arrival of the growth opportunity. The model illustrates that such uncertainty can significantly impact the initial investment timing for unlevered firm in a non-monotonic way. For levered firm, the future growth uncertainty, along with debt overhang problem, can shape the firm’s financing decision at initial investment. The third essay shows how risk-compensating performance-sensitive debt can be used to mitigate the “overinvestment” agency problem. We show that properly designed performance-sensitive debt can add significant value relative to fixed-coupon debt, and identify the risk-compensation level that maximizes shareholder wealth. The optimal risk-compensation level is found to be smaller than that required to eliminate overinvestment; thus, it is optimal for shareholders to incur some agency cost of overinvestment. / Thesis / Doctor of Philosophy (PhD)

Current treatment for posterior segment ocular diseases requires intravitreal injections administered every 4-6 weeks. The potential for siRNA to be used to treat these diseases is extremely attractive due to the specificity of these molecules and their potential for making long term changes to the expression patterns of the cells. Due to physiological recognition, however siRNA undergoes rapid degradation upon application. The development of cationic nanogels using polymeric “smart” biomaterials with degradable components to transport siRNA is described. pH – sensitive N, N dimethylaminoethyl methacrylate (DMAEMA) was crosslinked with thermo-sensitive diethylene glycol methacrylate (DEGMA), by free radical emulsion-precipitation polymerization. Size, charge and morphology were analyzed to assess potential as a nanovehicle. Through modification of the particle composition, cationic nanogels, determined by zeta potential, with sizes of approximately 160 nm confirmed with dynamic light scattering (DLS), were synthesized. A composition of 55:45 (DEGMA:DMAEMA); a size and charge ideal for cellular uptake. These particles had minimal impact on cell proliferation and exhibited spherical morphology when imaged by TEM at physiological pH. The structure was maintained between pH 3.5-9. Sensitivity to pH was shown by DLS through swelling at physiological pH, which may be useful can be taken advantage of in future studies for loading and release. Degradation with a reducing agent was shown using gel permeation chromatography, DLS and turbidity analysis. The results suggest this formula will undergo degradation in the cell. Reducing environments mimicking intracellular conditions that promoted degradation of the crosslinker showed enhanced release of dexamethasone phosphate as a model drug. Ongoing work is focused on examining gene silencing using these formulations. / Thesis / Master of Applied Science (MASc)

Time-critical networks of various types are widely used in fields such as industrial automation. Many of these time-critical networking solutions are proprietary and closed, which can make them costly to work with. An alternative to these legacy solutions is Time-Sensitive Networking. Time Sensitive Networking, or TSN, is an open standard for time-critical communication over Ethernet hardware and protocols. Compared to proprietary and closed legacy solutions, a TSN can be easier to set up. There is still however a challenge in configuring a TSN since the configuration process is hardware dependent. This thesis sets out to ease the configuration process, making it more user-friendly by providing a tool for the generation of end-host configurations. Currently, no such readily available tool exists for configuration of Linux end-hosts in TSNs. This is done by implementing extensions to the incomplete TSN configuration middleware DETD to a state where it is a suitable solution to this problem. The extensions made to DETD consist of implementing support for configuring listener streams, adding the ability to configure the TAPRIO queueing discipline, and adding support for an additional network interface card in the form of the Intel I210. To verify the functionality of these extensions a simple testbed using two real-time Linux machines is used.

The European Commission Bioeconomy Strategy aims to stimulate an ecologically sustainable economy to mitigate climate change, declining biodiversity, and as an economic and social strategy meant to provide jobs and stimulate growth. The aim of this research project is to understand how the European Commission Bioeconomy Strategy is being interpreted and implemented in two different rural European regions, Inner Scandinavia, and the Alpine region, and based on those findings discuss how a sustainable bioeconomy strategy can be understood primarily in relation to the ecological sustainability goals of decarbonizing the economy and protecting biodiversity. This project has through literature studies and a case study with interviews, field observations and a spatial analysis of the territory using Corine Land Cover data highlighted the importance of links between governance and policy as enablers of ecologically, socially, and economically sustainable bioeconomy strategies. The results indicate three models comprised of distinct landscape types associated with specific bioeconomy strategies that are discussed in relation to the key concepts, bioeconomy, and sustainability. The analysis demonstrates that certain bioeconomy strategies may provide economic and social sustainability and not necessarily ecological effects. In fact, certain bioeconomy strategies, despite being framed as sustainable, may even be detrimental for ecological sustainability

Azopolymers represent a wide class of polymeric systems in which the azobenzene chromophores are either incorporated into the main chain or covalently attached to it as a part of side chain. Light with an appropriate wavelength induces cyclic trans-cis isomerization, which results in preferred orientation of the trans-isomers perpendicular to the light polarization. Most azopolymer materials directionally deform in the presence of various light polarizations. In this thesis, a study is presented for photoinduced deformations in glassy side-chain azopolymers under different irradiation patterns. In particular, the photodeformations are investigated under homogeneous irradiation with linearly and circularly polarized light, and under inhomogeneous irradiation with intensity and polarization interference patterns. It is proposed to explain these mechanical deformations using the orientation approach, which takes into account the reorientation of the chromophores. Due to the rigid attachment of the chromophores with the main chain, the backbone segments in side-chain azopolymers should reorient into the polarization plane, which is accompanied by appearance of light induced stress. To describe the time evolution of light induced stresses, the side-chain azopolymers are modeled as an ensemble of rigid segments in presence of the effective orientation potential. Implementing the stress in a viscoplastic material model of the finite element software ANSYS, it is shown that a square azopolymer post elongates along the polarization for the linearly polarized light and contracts along the propagation direction for the circularly polarized light. Also, the deformations in the elongated oriented colloids under intensity interference patterns are modeled and it is found that the formation of beads and wave-like structures are in accordance with the experiment. The orientation approach also reproduces the peculiar structures at the edges of thin azopolymer film under polarization interference patterns. Hence, the orientation approach correctly predicts local variations of the light induced stress in each illumination pattern for both initially isotropic and highly oriented materials. With this, it is proved that the orientation approach implements a self-sufficient and convincing mechanism to describe photoinduced deformation in azopolymer materials, which does not rely on the photo-fluidization concept. The viscoplastic material modeling, developed in this thesis, can be used to describe the inscription of intricate surface structures under complex interference patterns.

The advancement of technology has led to an increase in the demand for ultra-low end-to-end network latency in real-time applications with a target of below 10ms. The IEEE 802.1 Time-Sensitive Networking (TSN) is a set of standards that supports the required low-latency wired communication with ultra-low jitter for real-time applications. TSN is designed for fixed networks thus it misses the flexibility of wireless networks.To overcome this limitation and to increase its applicability in different applications, an integration of TSN with other wireless technologies is needed. The fifth generation of cellular networks (5G) supports real-time applications with its Ultra-Reliable Low Latency Communication (URLLC) service. 5G URLLC is designed to meet the stringent timing requirements of these applications, such as providing reliable communication with latencies as low as 1ms. Seamless integration of TSN and 5G is needed to fully utilize the potential of these technologies in contemporary and future industrial applications. However, to achieve the end-to-end Quality of Service (QoS) requirements of a TSN-5G network, a significant effort is required due to the large dissimilarity between these technologies. This thesis presents a comprehensive and well-structured snapshot of the existing research on TSN-5G integration that identifies gaps in the current research and highlights the opportunities for further research in the area of TSN-5G integration. In particular, the thesis identifies that the state of the art lacks an end-to-end mapping of QoS requirements and traffic forwarding mechanisms for a converged TSN-5G network. This lack of knowledge and tool support hampers the utilisation of ground-breaking technologies like TSN and 5G. Hence, the thesis develops novel techniques to support the end-to-end QoS mapping and traffic forwarding of a converged TSN-5G network for predictable communication.Furthermore, the thesis presents a translation technique between TSN and 5G with a proof-of-concept implementation in a well-known TSN network simulator. Moreover, a novel QoS mapping algorithm is proposed to support the systematic mapping of QoS characteristics and integration of traffic flows in a converged TSN-5G network. / PROVIDENT