The overall goal of this work is to predict the mechanical response of an as-built Ti-6Al-4V directed energy deposition component by a dislocation mechanics-based internal state variable model based on the component's geometry and processing parameters. Previous research has been performed to connect additive manufacturing (AM) process parameters including laser power and scanning strategy to different aspects of part quality, such as porosity, mechanical properties, fatigue life, microstructure, residual stresses, and distortion. The lack of predictive capabilities to fully estimate residual stresses and distortion within parts produced via AM have hindered part qualification; however, modeling the AM process can aide in process and geometry optimization compared to traditional trial-and-error methods. The presence of unwanted thermally induced residual stresses and distortion can lead to tolerancing issues, reduced fatigue life, and decreased mechanical performance compared to similar components fabricated with traditional manufacturing methods such as casting and machining. A three-dimensional thermomechanical finite element model calibrated using dual-wave pyrometer thermal image datasets along with temperature- and strain rate-dependent mechanical data is utilized for this work. The purpose of this work is to understand the relationship between a component's temperature history and its resultant distortion and residual stresses.

Multiple myeloma is an aggressive plasma cell cancer that consistently acquires multi-drug resistance and relapses despite initial treatment successes. Patients may go through greater than 10-lines of therapy, highlighting the need for more effective treatment options. Immunotherapies are the latest evolution in targeted cancer treatments, and thus far have displayed impressive results in several hematological cancers, including multiple myeloma. T cells possess robust anti-tumor functions which can be harnessed and refined for the treatment of cancers. Genetic engineering of T cells to express a chimeric antigen receptor (CAR) confers antigen-specific tumor-targeting, and adoptive transfer of patient-derived CAR-engineered T (CAR T) cells has been efficacious in relapsed/refractory multiple myeloma. Despite the high efficacy, CAR T cell therapy for myeloma is associated with serious adverse events, which limits dose levels and patient eligibility. We have developed a novel synthetic antigen receptor platform, called the T cell antigen coupler (TAC) receptor, which has shown comparatively higher efficacy with a reduced pro-inflammatory profile compared with CAR T cells in pre-clinical models. The TAC receptor was purpose-built to co-opt the natural T cell activation machinery and lacks the costimulatory signaling typically incorporated in CAR designs. This thesis investigates strategies to augment TAC T cell function against for multiple myeloma through the evaluation of ancillary pharmacological and protein stimuli that would complement the anti-tumor functions of TAC T cells without modifying the TAC receptor design. In chapter 2, I investigated a strategy combining TAC T cells with the SMAC mimetic LCL161 to provide transient costimulatory effects. While LCL161 boosted TAC T cells survival and proliferation, the drug also enhanced susceptibility of TAC T cells to apoptosis and offered no advantage to the TAC T cells when challenged with myeloma. In chapter 3, I engineered TAC T cells to secrete IL-27 in an attempt to modulate the myeloma microenvironment and support T cell cytolytic function. IL-27 did not enhance the anti-tumor activity of TAC T cells but forced expression of IL-27 led to a reduction in the production of pro-inflammatory cytokines without altering cytotoxicity. In appendix I, I describe the process of optimizing CRISPR/Cas9 editing of primary TAC T cells. This methodology was required for much of the work in chapter 2. Ph.D. Thesis – Arya Afsahi McMaster University – Biochemistry and Biomedical Sciences v In appendix II, I describe an assessment of mRNA-engineering as a method to produce TAC T cells. This approach proved to be therapeutically futile and was not pursued beyond the work described herein. The work presented here highlights methods of combining TAC T cells with a clinically relevant SMAC mimetic, or the cytokine IL-27, and provides insights into the biological mechanisms that are affected by these approaches. / Thesis / Doctor of Philosophy (PhD)

Buildings require a lot of energy during all their lifetime, from the construction site to the use and demolition. The building sector contributes to a large part of the total emissions of greenhouse gases and consume a large amount of water and energy resources, so the material components used in the building sector have gained an important role in the discourse of sustainability. The tendency is to use natural renewable materials that generates lower environmental impact than conventional ones and are able to fulfil the required structural and architectural needs. Wood is a traditional material with a long and proud history and has been reintroduced in the construction site thanks to its sustainable characteristics. Wood used for building applications, i.e. timber, is capable to capture CO2 from the atmosphere and incorporate so-called carbon storage. Moreover, low process energy requirements and high recyclability increase the potential of timber to become a major building material. On the other hand, the considerable growing demand for highly transparent envelopes has recently resulted in massive introduction of glass as a façade component. The main objective of this thesis was therefore to elaborate on the question if it is possible to merge the positive aspects of these two materials. The thesis starts with a discussion on hybrid, composite and combined materials. The key concept is to merge two or more materials with different characteristics, which result in a finished product with better overall properties than the starting constituents. However, such building material systems are not well categorized and a new term is therefore introduced to describe the combination between wood and glass: engineered wood glass combination (EWGC). The product is then described presenting the characteristics and properties of wood and glass and the structural benefits of the whole panel. The EWGC product possesses some advantageous properties like transparency, stiffness and strength for glass and the ductile nature of timber when used under compression. Moreover, this wood-glass element enables load transfer of horizontal forces through the glass pane so that the additional metal bracing elements for stiffening the building can be omitted. Then the study goes deeper in the architectural possibilities and different potential types of assembly are described. However, only few profiles have been tested and this has resulted in the market production of only one type of panel that is currently used in the construction site. Moreover, the shape of the EWGC is suitable to integrate systems that can control the ventilation rate and solar gains, allowing the development of advanced integrated façades that ensure the comfort condition inside the building. EWGC is also seen to be highly potential as an ecological alternative to conventional structural sealant aluminium-glass façade. For this reason, the life cycle assessment (LCA) of different materials is discussed in order to evaluate their environmental impacts. LCA results are strongly dependent on the calculation boundaries and the choice of database, but it stands out that aluminium, as a construction material for glazing elements, requires up to 4 times higher primary energy demand and produces up to 16 times more CO2 emission than timber based combined panels. Despite some weak points, e.g. the lack of standardized regulations and people’s preconceptions about wood, the overall conclusion is that EWGC has the potential to be used for future building envelopes of multi-storey timber buildings.

An architectural proposal for the upcoming UNFCCC COP 25 climate talks, promoting sustainability and the global export of engineered timber from Sweden.

BACKGROUND: Aberrant MET receptor tyrosine kinase (RTK) activation leads to invasive tumor growth in different types of cancer. Overexpression of MET and its ligand hepatocyte growth factor (HGF) occurs more frequently in glioblastoma (GBM) than in low-grade gliomas. Although we have shown previously that HGF-autocrine activation predicts sensitivity to MET tyrosine kinase inhibitors (TKIs) in GBM, whether it initiates tumorigenesis remains elusive. METHODS: Using a well-established Sleeping Beauty (SB) transposon strategy, we injected human and cDNA together with a short hairpin siRNA against (SB-hHgf.Met.ShP53) into the lateral ventricle of neonatal mice to induce spontaneous glioma initiation and characterized the tumors with H&E and immunohistochemistry analysis. Glioma sphere cells also were isolated for measuring the sensitivity to specific MET TKIs. RESULTS: Mixed injection of SB-hHgf.Met.ShP53 plasmids induced de novo glioma formation with invasive tumor growth accompanied by HGF and MET overexpression. While glioma stem cells (GSCs) are considered as the tumor-initiating cells in GBM, both SB-hHgf.Met.ShP53 tumor sections and glioma spheres harvested from these tumors expressed GSC markers nestin, GFAP, and Sox 2. Moreover, specific MET TKIs significantly inhibited tumor spheres' proliferation and MET/MAPK/AKT signaling. CONCLUSIONS: Overexpression of the HGF/MET axis along with p53 attenuation may transform neural stem cells into GSCs, resulting in GBM formation in mice. These tumors are primarily driven by the MET RTK pathway activation and are sensitive to MET TKIs. The SB-hHgf.Met.ShP53 spontaneous mouse glioma model provides a useful tool for studying GBM tumor biology and MET-targeting therapeutics.

Melanoma skin cancer is the abnormal growth of the melanocytes – the pigmented cells located in the epidermis. The current gold standard diagnostic technique for determining whether a lesion is cancerous involves subjectively examining suspicious lesions and performing an invasive biopsy to confirm melanoma. This method may neglect some lesions or cause scarring from biopsies that turn out to be benign. Thus, impedance-based detection using a multi-electrode device was investigated as a noninvasive technique to diagnose melanoma skin cancer. The multi-electrode device was designed with 8 equally spaced Ag/AgCl electrodes surrounding one central electrode at a 5 mm radius. The electrodes were held in place by a vice-like mechanism using three circular Delrin sections. The electrodes were interfaced to an 8:1 multiplexer and National Instruments Educational Laboratory Virtual Instrumentation Suite (ELVIS) for measurement control and impedance analysis. The ELVIS system, multiplexer, and electrode device were validated for accuracy with various values of resistors and capacitors. Raw and cooked chicken thigh meat and skin were tested to evaluate the capabilities of the electrode device to discern different tissue types and tissue moisture contents by impedance measurements. EpidermTM and Melanoma tissue-engineered skin analogues, provided by MatTek Corporation, were tested to mimic the in situ disease state. The electrode device was found to produce reliable measurements for known electrical components with resistances between 10 ohms and 100 k-ohms and capacitances between 10 nF and 10 uF. The measurements from the chicken tissues and tissue-engineered skin constructs – excluding cooked chicken skin data – fell within the reliable range of the electrode device and were thus considered reliable as well. All analyses concluded that a statistical difference between the impedances of raw meat and raw skin, cooked meat and raw meat, and EpidermTM and Melanoma existed. Therefore, the hypothesis that a multi-electrode device could differentiate between melanoma and healthy skin tissues based on impedance measurements was satisfied.

Yes / This paper investigated the bond characteristics between eight types of nanofillers modified reactive powder concrete (RPC) and plain steel bars, aiming to explore the modifying mechanisms and establish a bond-slip relationship model for nanofillers modified RPC and steel bar interface. The experimental results indicated that the incorporation of nanofillers can increase the bond strength and reduce the slip between RPC and plain steel bars. It was shown that a 2.15 MPa/20.5% of absolute/relative increase in cracking bond strength, a 1.25 MPa/10.3% of absolute/relative increase in ultimate bond strength, a 2.35 MPa/22.4% of absolute/relative increase in residual bond strength, a 0.592 mm/56.5% of absolute/relative reduction in ultimate bond slip, and a 1.779 mm/52.1% of absolute/relative reduction in residual bond slip were the best achieved due to the addition of various nanofillers. The enhancement of nanofillers on RPC-steel bar interface has been mainly attributed to RPC microstructure improvement, optimization of intrinsic compositions, and elimination of defects in the interface, especially the underside near steel bar, due to the nano-core effect of nanofillers enriched in the interface. In addition, the bond-slip relationship of nanofillers modified RPC-steel bar interface can be accurately described by the proposed model considering an initial branch. / The authors would like to thank the funding offered by the National Science Foundation of China (51978127 and 51908103), and the Fundamental Research Funds for the Central Universities (DUT21RC(3)039).

Modular housing is an important segment of the factory-built housing industry, in the Mid-Atlantic. In 1998, a study was conducted to assess the structural needs and requirements of this industry. This study addressed three questions. (1) What is the current and future state of the industry? (2) What structural material trends are present between 1992 - 2000? (3) What opportunities exist for product substitution and development of new structural materials? This study found that the modular housing industry in the Mid-Atlantic region is growing. The greatest barrier to market expansion is transportation costs. Expansion is expected in the South and Midwest regions of the US. Most competition comes from site-built and manufactured homebuilders. To stay competitive, respondents plan to increase customization options and home size. The need for cost effective, quality structural materials is a growing concern. Softwood dimensional lumber has been decreasing since 1992 and is expected continue to decrease through 2000. Decreases are due to design changes and quality concerns. The use of engineered lumber has increased in order to compensate for decreases in dimensional lumber necessary to meet the structural needs of the industry. Using factor analysis and perceptual mapping techniques, dimensional lumber was not perceived to be as suited for structural building applications as engineered lumber. However, respondents felt that engineered lumber tended to be more expensive. Perceptual mapping also identified gaps between the ideal needs of building applications and the ability of current materials to meet those needs. Opportunities for new product development exist where gaps occurred. / Master of Science

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