T cells can fight cancer, but an immunosuppressive tumor microenvironment (TME) disallows them from carrying out their function over time. Upregulation of inhibitory checkpoint molecules such as programmed cell death protein 1 (PD1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) can lead to such an immunosuppressive TME. Despite their widespread use, immune checkpoint blockade (ICB) antibodies targeting checkpoint molecules remain ineffective in most cancer patients. We do not understand why some patients respond to ICB better than others. To understand the heterogeneity of ICB response, we must understand the heterogeneity of the T cell subsets acted upon by such therapies. Here, we ask how T cell subsets change in the presence and absence of ICB. We track T cell clones through their T cell receptor sequences and link phenotypes with T cell receptor specificities. Through multiplexed single cell TCR sequencing, single cell RNA sequencing, and the use of cell- surface CITE-seq antibodies, coupled with surgical biopsy, we longitudinally tracked the fate of individual T cell clones within tumors at baseline and in response to ICB in an immunogenic mouse tumor model. Furthermore, computational clustering of T cells solely based on their gene expression profiles may ignore upstream regulatory mechanisms that control T cell gene expression. Hence, we employed Virtual Inference of Protein-activity by Enriched Regulon (VIPER) analysis to cluster CD8+ and CD4+ T cell phenotypes. VIPER leverages inference of gene regulatory networks to allow full quantitative characterization of protein activity for transcription factors, co-factors, and signaling molecules by assessing the enrichment of their transcriptional targets cell-by-cell among expressed genes. This gave us a window into the transcriptional states and their inferred protein activity. We next developed a computational analysis toolkit to study TCR clonality incorporating sub-sampling of TCR clonotypes, forward and back tracing of shared clones between timepoints, and in turn, inferred shared clonal evolution. We employed the above workflow to MC38 tumor-infiltrating and tumor-draining lymph node-derived CD8+ and CD4+ T cells. We found that T cell phenotypes are highly dynamic within tumors at baseline, in the absence of ICB, particularly within the window that they are responsive to therapy. In the absence of ICB, effector phenotype of CD8+ T cells diminished, while the exhaustion phenotype was enhanced as tumors progressed. Within the CD4+ population, a heterogenous subset of regulatory CD4+ T cells (Tregs) changed phenotype over time, and CD4+ Th1 like effectors, along with stem like progenitor CD4+ showed distinct dynamism. Next, by analyzing responses to therapy within his context, we found that both anti-PD1 and anti-CTLA4 act through distinct mechanisms on CD8+ and CD4+ T cells. Anti-PD1 acted upon intra-tumoral effector CD8+ T cells to slow their progression to terminally differentiated exhausted cells, i.e., increased their persistence within tumors. Anti-CTLA4 therapy increased recruitment of novel effector CD8+ T cell clones to tumors from lymph nodes while diminishing tumor-infiltrating Tregs. ICB also potentiated CD4+ Th1 like phenotype. These results uncovered a behavior pattern of CD8+ and CD4+ T cells within tumors at baseline tumor progression, and then in the presence of ICB. We believe these findings have added to our understanding of the subtleties of T cell phenotypes in tumors, specifically in response to ICB. This will provide a practical framework for designing and validating novel checkpoint blockade therapies in the future.

McMaster University in conjunction with an industrial partner has been designing wireless vibrational condition monitoring sensors for implementation on a vibrating screening machine used in mining applications. A limitation with the current sensor design is their dependency on battery power. In order for the sensors to provide real-time continuous streaming of acceleration data, an alternate power supply was required outside of traditional sources such as batteries or wired power. This thesis outlines the research and development of a power system that harvests the kinetic vibrational energy of a mining screen and converts it into electrical energy for use by a wireless sensor node. During development, multiple prototypes were built and evaluated under laboratory conditions. The core concept of the system is an eccentric pendulum mass excited by the external vibrations of the screening machine used to drive a stepper motor generator. The major design obstacle of the project was how to get the system to self initiate. Both a mechanical and an electrical solution were developed to solve this concern. The final prototype design is fully autonomous, able to react to the start up or shut-down of a screening machine, while also providing a continuous power supply to a wireless vibrational analysis sensor as tested in the lab. With minor optimization, this prototype can be turned into a commercial product for industrial implementation and sale. / Thesis / Master of Applied Science (MASc)

In the middle of the nineteenth century, the train came to Sweden. It has been just over 150 years and a lot has happened. With the train and its station came more then just a means of transportation, it turned Sweden from a developing country into one of the most modern. In the small Swedish cities and on the countryside, the stations became a central node, a meeting point and a place to gather. The train passed through previously isolated areas where the stations became not only just that but also a window towards the rest of the world. This project is a study of the Swedish train station and a humble proposal on how to treat them, what to do with them and when to do it (now).

The thesis project proposes to explore into the design possibilities for the Civic Center for Municipal Corporation of Delhi and extract the richness of the site conditions into architecture through means of computational design. The computational design approach will provide a degree of variance which will be an interesting thing to explore in terms of defining spaces, program and systems.. The design would hinge on to one of the major centers of Delhi and aim to enhance social permeability through means of forms and articulation of spaces. It would cater to all classes of people and help in promoting small local businesses thereby weaving into the social and cultural fabric of India.

It has become possible to say that the metaverse is a great opportunity for investment and trade, as it provides massive financial returns. The metaverse is the next evolution in social connection and the successor to the mobile internet. Non-fungible tokens represent the ownership of unique items in the metaverse and allow the creator to tokenize things like art, real estate, and collectibles. Trading NFT in the metaverse faces challenges, including security, fraud, and scams. Those challenges have negatively affected the stability of this market. “How can NFT trading in metaverse be improved?” is the main question of this thesis to overcome the challenges. The author performed a systematic literature review to survey and explore the possibility of using technologies to reach the ideal use of NFT in the metaverse. The systematic literature review will guide the researcher to gain more information to evaluate it in the research area. Furthermore, Pointing and identifying the gaps and knowledge needed between the research elements. Three main challenges are presented (identity verification, fraud, and ownership) in areas in which technologies that can provide (flexibility, reliability, accuracy, and performance) can apply. Three dominant solutions, smart contracts, oracle nodes, and blockchain are the study and analysis results to realize the research question and identified problem. The elected technologies show an ability to address challenges in different ways and thus maintain the security and effectiveness of trading operations. Also, the result section mentions other solutions not counting on the dominant solutions. Open issues which provide a ground for future research with practical implementations are also discussed.

The urinary bladder is especially subject to infection by virtue of its direct connection to the external urethral opening, and it is natural to anticipate the presence of a well-developed immunological mechanism to respond to this potential threat. The present study describes small, very highly vascular lymph nodes located in the wall of the rabbit bladder, which may be involved in a local response to foreign antigens. The vasculature and structure of these lymph nodes was described using a combination of vascular corrosion casting, ink injection, and light and electron microscopy. The distal abdominal aorta was cannulated, and after clearing the bladder vasculature with buffered saline, one of the following procedures was used: 1) the bladder was perfuse-fixed in preparation for light and electron microscopy; 2) the bladder vasculature was filled with India ink for vessel tracing; or 3) vascular corrosion casts of the vasculature were prepared by infusing resin comprised of a mixture of Mercox, methyl methacrylate monomer, and catalyst. The resulting casts were cleaned with KOH, formic acid, and water in preparation for scanning electron microscopy. Vascular casts and India ink injections revealed the presence of a number of isolated capillary tufts consisting of clusters of one to five 'glomeruli,' closely associated with the major vesicular vessels along the lateral walls of the bladder, and supplied by tertiary branches of these vessels. Light and electron microscopy showed that the capillary tufts represented the blood supply to small, ovoid lymph nodes located near the serosal surface of the bladder wall and usually restricted to the basal half of the bladder. These nodes were encapsulated and exhibited subcapsular sinuses, numerous small blood vessels, a limited number of high endothelial cells, and, occasionally, nerves and a follicular substructure. The nodes contained abundant lymphocytes, stellate stromal cells, macrophages, and eosinophils, but lacked the obvious cortical and medullary organization and germinal centers often seen in larger lymph nodes. Vascular corrosion casts, vascular ink injections, and microscopic examination confirmed the presence of small, highly vascular lymph nodes closely associated with the main vesicular vessels along the lateral walls of the rabbit bladder. A follicular substructure of the nodes appears to correspond with the 'glomerular' capillary arrangement within the nodes as seen with corrosion casts. The rich blood supply may be indicative of the high metabolic demand of lymphatic tissue, and may be altered in response to the level of activity of the node. The close association between the lymphatic tissue and the rich blood supply to the nodes may allow a rapid mobilization of lymphocytes during a local immune response to foreign agents.

No description available.

Wireless sensor networks have become a rapidly growing research field in recent years. They are envisioned to have a wide range of applications in military, environmental and many other fields. We examine the performance of wireless sensor network applications to aeronautical telemetry. To date, test ranges have relied on a single telemetry ground station for the reception of packets from all air borne transmitters. We researched an alternate means of achieving this same goal with fewer resources. It is a well known fact that communication power and bandwidth are the most expensive commodities in wireless communications. The telemetry world is ever in need of ways and means to reduce power requirements of its networks while maximizing the use of available bandwidth. In our alternate method, packets will be reliably transported to a centrally located monitoring station in a series of hops. We will effectively reduce the power requirements of the network by minimizing the distance coverage of the sensor nodes. We will also explore different network topologies with a view to maximizing the use of available bandwidth. The alternate method will present a less expensive way to implement telemetry networks. Currently, telemetry networks make use of a single, huge and expensive base station receiving packets from all airplanes in test. Affordable sensor nodes placed strategically on the range and configured properly will achieve the same goal in a cost effective, power saving and bandwidth considerate manner.

Mesh adaptation techniques are used to modify complex finite element meshes to reduce analysis time and improve accuracy. Modification of all-hexahedral meshes has proven difficult to the unique connectivity constraints they exhibit. This thesis presents an automated tool for local, conformal refinement of all-hexahedral meshes based on the insertion of multi-directional twist planes into the spatial twist continuum. The contributions of this thesis are (1) the ability to conformally refine all entities of an all-hexahedral element mesh, (2) the simplification of template insertion to multi-directional refinement. The refinement algorithm is divided into single hex sheet operations, where individual refinement steps are performed completely within a single hex sheet, and parallel sheet operation, where each refinement step occurs within two parallel hex sheets. Combining these two procedures facilitates the refinement of any mesh feature. Refinement is accomplished by replacing original mesh elements with one or more of six base templates selected by the number of nodes, flagged for refinement on the element. The refinement procedures are covered in detail with representative graphics and examples that illustrate the application of the techniques and the results of the refinement.

A Decision Support model for planning Intercity Railways is presented in this research. The main aim of the model is to generate inputs for the logit model existing in the Virginia Tech Transportation Systems Analysis Model (TSAM). The inputs required by the TSAM logit model are travel time, travel cost and schedule delay. Travel times and travel costs for different rail technologies are calculated using a rail network and actual or proposed rail schedules. The concept of relational databases is used in the development of the network topology. Further, an event graph approach is used for analysis of the generated network. Shortest travel times and their corresponding travel costs between origin-destination pairs are found using Floyd's algorithm. Complete itineraries including transfers (if involved) are intrinsically held in the precedence matrix generated after running the algorithm. A standard mapping technique is used to obtain the actual routes. The algorithms developed, have been implemented in MATLAB. Schedules from the North American Passenger rail system AMTRAK are used to generate the sample network for this study. The model developed allows the user to evaluate what-if scenarios for various route frequencies and rail technologies such as Accelerail, High Speed Rail and Maglev. The user also has the option of modifying route information. Comparison of travel time values for the mentioned technology types in different corridors revealed that frequency of service has a greater impact on the total travel time in shorter distance corridors, whereas technology/line-haul speed has a greater influence on the total travel time in the longer distance corridors. This tool could be useful to make preliminary assessments of future rail systems. The network topology generated by the algorithm can further be used for network flow assignment, especially time-dependent assignment if used with dynamic graph algorithms. / Master of Science