After becoming interested in the beauty of numbers and the intricate patterns of their behavior, the author concluded that it would be a good idea to make the subject available for students earlier in their educational experience. In this thesis, the author developed four units in combinatorics, namely Fundamental Principles, Permutations, Combinations, and Pascal's Triangle, which are appropriate for third grade level.

Music and emotion are two realms traditionally considered to be unique to human intelligence. This dissertation focuses on furthering artificial intelligence research, specifically in the area of computational creativity, by investigating methods of composing music that elicits desired emotional and physiological responses. It includes the following: an algorithm for generating original musical selections that effectively elicit targeted emotional and physiological responses; a description of some of the musical features that contribute to the conveyance of a given emotion or the elicitation of a given physiological response; and an account of how this algorithm can be used effectively in two different situations, the generation of soundtracks for fairy tales and the generation of melodic accompaniments for lyrics. This dissertation also presents research on more general machine learning topics. These include a method of combining output from base classifiers in an ensemble that improves accuracy over a number of different baseline strategies and a description of some of the problems inherent in the Bayesian model averaging strategy and a novel algorithm for improving it.

The majority of manufacturers provide their customers with volume discounts for placing repeat purchases or placing larger orders. In today's highly competitive market, the topic of how precisely a big number of products should be grouped together naturally emerges.\\In this context, three research questions that were directly relevant to the setting were formulated and their answers were provided. In order to achieve this goal, a number of experiments were carried out. In this particular instance, an algorithm was developed that determines the order combination that is mathematically superior to all others. In this context, an annual order cost saving of 1.33\% could be achieved based on the orders from the year 2021. This could be accomplished without the utilisation of heuristics for a limited number of products at most. In addition, a number of other heuristics have been devised for higher order combination sets. In addition, two other approaches to demand forecasting were investigated, and it was discovered that the time series in this particular instance was insufficient for the application of an RNN-LSTM model.

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.

Glioblastoma (GBM) is the most malignant primary brain tumor without effective therapies. Since bevacizumab was FDA approved for targeting vascular endothelial growth factor receptor 2 (VEGFR2) in adult patients with recurrent GBM, targeted therapy against receptor tyrosine kinases (RTKs) has become a new avenue for GBM therapeutics. In addition to VEGFR, the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) are major RTK targets. However, results from clinical Phase II/III trials indicate that most RTK-targeting therapeutics including tyrosine kinase inhibitors (TKIs) and neutralizing antibodies lack clinical efficacy, either alone or in combination. The major challenge is to uncover the genetic RTK alterations driving GBM initiation and progression, as well as to elucidate the mechanisms toward therapeutic resistance. In this review, we will discuss the genetic alterations in these 5 commonly targeted RTKs, the clinical trial outcomes of the associated RTK-targeting therapeutics, and the potential mechanisms toward the resistance. We anticipate that future design of new clinical trials with combination strategies, based on the genetic alterations within an individual patient's tumor and mechanisms contributing to therapeutic resistance after treatment, will achieve durable remissions and improve outcomes in GBM patients.

Several Fungal species have the potential to cause a broad spectrum of diseases in humans, ranging from mild superficial to disseminated invasive infections that involve the bloodstream and vital organs. Invasive fungal infections are severe, life-threatening diseases that result in the deaths of 1.5 million patients each year. The most common fungal species responsible for the majority of invasive fungal infections include Candida, Cryptococcus, and Aspergillus. The current treatment options for invasive fungal infections are restricted to three classes of antifungals: Azoles, polyenes, and echinocandins. The emergence of new fungal species, especially C. auris, marked by high resistance profiles and increased mortality rates (30-60%), has further exacerbated the limitations in its therapeutic options. This emphasizes the urgent need for effective alternatives to combat these deadly pathogens. C. auris isolates exhibited high resistance capability especially against azole (fluconazole) and polyene (amphotericin B) antifungals. Here, we utilized the combinatorial strategy to screen ~3400 FDA-approved drugs and clinical compounds to identify hits that can enhance/restore the antifungal activity of azoles and amphotericin B against resistant C. auris. The HIV protease inhibitors (lopinavir and ritonavir) were identified as potent enhancers to the antifungal activity of azole drugs (fluconazole, voriconazole and itraconazole). We confirmed that lopinavir and ritonavir have the capability to interfere with fungal efflux pump machinery. The in vivo efficacy of the combination of azole antifungals and HIV protease inhibitors was also evaluated to discover the best combination of itraconazole, lopinavir and ritonavir. Three drugs (lansoprazole, rolapitant and idebenone) were identified to effectively enhance the antifungal effects of amphotericin B and overcome its resistance in C. auris. Furthermore, the synergistic interactions of these combinations were applied on other medically important Candida, Cryptococcus, and Aspergillus species. In a comprehensive mechanistic study, we discovered that lansoprazole interferes with an essential target in the fungal mitochondrial cytochrome system, cytochrome bc1. This interference induces oxidative stress in fungal cells and subsequently enhances the antifungal activity of amphotericin B. For rolapitant, a transcriptomic analysis along with ATP luminescence assays confirmed that rolapitant at sub-inhibitory concentrations significantly interferes with ATP production in C. auris. For idebenone, checkerboard assays confirmed the synergistic interactions between amphotericin B and idebenone against a diversity of medically important fungal species. This combination exhibited a rapid fungicidal activity within 4 hours. Additionally, the cytotoxicity of this combination was assessed in a cell line model of kidney cells. Based on the potent in vitro and in vivo synergistic relationships observed for the identified combinations, it can be concluded that our approach offers a new hope to restore the antifungal activity of the existing antifungal drugs, even against resistant fungal infections. Additionally, it provides valuable insights into identifying novel targets to overcome resistance in multidrug-resistant fungal pathogens. / Doctor of Philosophy / Fungi comprise a diverse group of organisms that interact with humans in many good and bad aspects. Candida auris, a recently identified fungus, poses a significant threat to patients with weak immune systems. Infections with C. auris can be associated with mortality rates of up to 60%. Notably, this fungus is characterized by its powerful spreading capability and displays extraordinary resistance to antifungal agents, rendering many existing antifungal drugs ineffective. As a result, there is an unmet need to find efficient treatments for such deadly fungal infections. In this study, several drugs were identified with the potential to restore the activity of traditional antifungal drugs. The study identified four promising drugs (lopinavir, lansoprazole, rolapitant, and idebenone) with the potential to enhance the activity of the antifungal drugs against C. auris. lopinavir showed great potential to enhance the activity of azole antifungals, including fluconazole, voriconazole, and itraconazole. Furthermore, three other drugs (lansoprazole, rolapitant, and idebenone) were identified for their potential to enhance the activity of amphotericin B, which is considered a last-line antifungal therapy. We clarified the mechanisms by which these drugs could restore the activity of antifungal agents. Finally, we confirmed the effectiveness of these combinations in animal models, providing valuable insights into their potential for clinical applications. In summary, our research has opened promising avenues to overcome resistance and develop new treatments for hard-to-treat fungal infections.

A study is presented of the instability mechanisms of a damped axisymmetric circular disk of uniform thickness rotating about its axis with constant angular velocity and subjected to various transverse space-fixed loading systems. The natural frequencies of spinning floppy disks are obtained for various nodal diameters and nodal circles with a numerical and an approximate method. Exploiting the fact that in most physical applications the thickness of the disk is small compared with its outer radius, we use their ratio to define a small parameter. Because the nonlinearities appearing in the governing partial-differential equations are cubic, we use the Galerkin procedure to reduce the problem into a finite number of coupled weakly nonlinear second-order equations. The coefficients of the nonlinear terms in the reduced equations are calculated for a wide range of the lowest modes and for different rotational speeds. We have studied the primary resonance of a pair of orthogonal modes under a space-fixed constant loading, the principal parametric resonance of a pair of orthogonal modes when the disk is subject to a massive loading system, and the combination parametric resonance of two pairs of orthogonal modes when the excitation is a linear spring. Considering the case of a spring moving periodically along the radius of the disk, we show how its frequency can be coupled to the rotational speed of the disk and lead to a principal parametric resonance. In each of these cases, we have used the method of multiple scales to determine the equations governing the modulation of the amplitudes and phases of the interacting modes. The equilibrium solutions of the modulation equations are determined and their stability is studied. / Master of Science

Electromagnetic induction (EM) methods have been utilised in a recent surge of archaeological applications across continental Europe, Ireland and Scandinavia. Development of multi-exploration depth instruments and improvements to instrument stability have improved its reputation as an effective method for mapping archaeological remains. Despite these advances, EM methods are comparatively lacking in rigour when for British sites. Through a structured scheme of experimental analysis and fieldwork, this thesis develops an understanding of the responses of EM instruments over a range of British archaeology, including earthworks, field systems, burials, modern remains, and a Cistercian abbey; the results of which demonstrate its effective over a diversity of environments. The impact of instrument-based issues on the collected measurements was quantified through a scheme of experiments targeting instrument drift, calibration and elevation. Dedicated instrument operation and processing workflows were developed based on the collective field and experimental results, which recommend best practice guidelines for improving the quality and accuracy of collected data. The link between instrument measurements and buried archaeology was further developed through a structured analysis of the EM datasets with complementary earth resistance and magnetic results. The integration of the EM, earth resistance and magnetic datasets was utilised to develop an enhanced archaeological characterisation of subsurface features. While the earth resistance and magnetic methods generally responded to different aspects of the buried archaeology, the EM surveys were able to detect a range of responses evident in the results of the former methods. Therefore, the role of EM methods within this characterisation are shown to “bridge the gap” between the earth resistance and magnetic methods, while providing a comprehensive characterisation of the remains in their own right. / The supplementary material files from Appendix 2 are not available online.

20 svenska barn diagnostiseras årligen med barntumören neuroblastom (NB). Läkemedelsresistens och intratumoral heterogenitet försvårar behandlingen och 50-60% av hög-risk NB-patienter drabbas av återfall. Subpopulationer av resistenta celler har identifierats i hög-risk NB-cellinjer, vilket belyser behovet av nya behandlingsalternativ. Dessa celler har visats vara känsliga mot antimetaboliter, som är S-fas specifika läkemedel. Syftet med detta projekt är att utvärdera antimetaboliter som singelbehan-dling eller i kombination med kemoterapi som en ny behandlingsmetod i resistenta NB-celler. Cellvia-bilitiet, cellåterväxt efter långtidsbehandling och cellcykelarrest samt cellcykelns förlopp analyserades på en panel bestående av de fem TP53-muterade ultra-högrisk NB-cellinjerna Kelly, SK-N-DZ, SK-N-AS, BE(2)-C och SK-N-FI. Läkemedlena som utvärderades var kemoterapierna doxorubicin (doxo) och cisplatin samt antimetaboliterna cytarabine (Ara-C), gemcitabine, 5-fluorouracil (5-FU) och hy-droxyurea (HU). Resultaten indikerar att Kelly och SK-N-FI var de cellinjer som var mest känsliga mot kombinationer av doxo tillsammans med antimetaboliter. Detta styrktes ytterligare av analysen av cellcykelarrest som visade att dessa cellinjer föredrar att arrestera i S-fas. Cellinjerna SK-N-DZ, SK-N-AS och BE(2)-C var mindre känsliga mot kombinationsbehandlingarna och visade preferens för att arrestera i andra faser av cellcykeln. Eftersom cellinjerna visade variationer i cellcykelarrest så föreslår vi en utvärdering av trippelkombinationer med läkemedel som är G2/M-fas specifika för att ytterligare eliminera resistenta subpopulationer. / Every year, 20 Swedish children are diagnosed with the pediatric tumor neuroblastoma (NB). Therapy resistance and intratumor heterogeneities complicate treatment of NB and ultimately, 50-60% of high- risk NB patients relapse. Subpopulations of resistant cells have been identified in high-risk NB cell lines, which elucidates the need for novel treatment options. These cells have been suggested to be sensitive to the S-phase specific drugs antimetabolites. The objective of this project is to evaluate antimetabolites as monotherapy and in combination with chemotherapy as a novel treatment option in high-risk NB. Analyses of cell viability, cell regrowth following long-term treatment, and cell cycle progression and mitotic arrest were performed in a panel of five TP53 mutated ultra-high risk NB cell lines, Kelly, SK- N-DZ, SK-N-AS, BE(2)-C, and SK-N-FI. The evaluated drugs were the chemotherapies doxorubicin (doxo) and cisplatin, and the antimetabolites cytarabine (Ara-C), gemcitabine, 5-fluorouracil (5-FU), and hydroxyurea (HU). Obtained results indicated that out of the tested cell lines, Kelly and SK-N-FI are the most sensitive to combinations of doxo with antimetabolites. This was further corroborated via analysis of cell cycle progression and mitotic arrest which demonstrated that Kelly and SK-N-FI have a preference for S-phase arrest. Cell lines SK-N-DZ, SK-N-AS, and BE(2)-C were less sensitive to combination treatments and showed preference for arrest in other phases of the cell cycle. Since resistant cell lines show variations in mitotic arrest, we suggest evaluating triple combinations with targeted treatments for G2/M-phase, in order to further eliminate resistant subpopulations.

Yes / Earthquake response spectrum is the most popular tool in the seismic analysis and design of structures. In the case of combined primary-secondary (P-S) systems, the response of the supporting P substructure is generally evaluated without considering the S substructure, which in turn is only required to bear displacements and/or forces imposed by the P substructure (¿cascade¿ approach). In doing so, however, dynamic interaction between the P and S components is neglected, and the seismic-induced response of the S substructure may be heavily underestimated or overestimated. In this paper, a novel CQC (Complete Quadratic Combination) rule is proposed for the seismic response of linear light S substructures attached to linear P substructures. The proposed technique overcomes the drawbacks of the cascade approach by including the effects of dynamic interaction and different damping in the substructures directly in the cross-correlation coefficients. The computational effort is reduced by using the eigenproperties of the decoupled substructures and only one earthquake response spectrum for a reference value of the damping ratio.