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Proton therapy, a promising alternative to conventional photon therapy, has gained widespread acceptance in clinical practice. This is attributed to its superior depth-dose curve that has a negligible dose beyond the maximum range of the proton. A proton treatment planning requires a multitude of parameters and are either manually selected or optimized using mathematical formulation. However, a proton treatment plan is also subject to various systematic and random uncertainties that must be taken into account during optimization. Robust optimization is a commonly used method for integrating the setup and range uncertainties in proton therapy. In addition to the uncertainties accounted for during the treatment planning phase, others can arise during the course of treatment and are often hard to predict. Changes in the patient's anatomy represent uncertainties that can significantly affect planned dose delivery. Therefore, adaptive planning is typically performed intermittently or regularly, depending on the changes in anatomy. Paper II included in this thesis proposed a method of adaptive planning that takes into account the impact of the patient's respiratory motion at the treatment site, such as the lungs and abdomen for 4D robust optimization. This method uses dose mimicking to reproduce the results as initially planned.   This additional stage of adaptive planning can introduce new complexities and uncertainties into the treatment process. One such uncertainty arise from daily cone beam computed tomography (CBCT) images which are required for treatment plan adaptation. Several strategies have been proposed in the past to improve the quality of these images, but each strategy has its advantages and disadvantages, depending on the site of treatment. In Paper I, a method was proposed that combined the advantages of other frequently used methods to create an improved method for generating daily images with CT-like image quality. This can contribute towards the goal of online adaptive in the near future with reduced uncertainties. This thesis will provide a brief introduction and an in-depth chapter to elucidate the background, better understand the physics of proton therapy, the process of treatment planning, and the need for adaptive planning. / European Union’s Horizon 2020 Marie Skłodowska-Curie Actions under Grant Agreement No. 955956

This dissertation presents four microbial microcosm-based experimental studies addressing questions related to the causes and consequences of biodiversity. All four studies adopted an approach that integrates ecology and evolutionary biology. Two studies explored the utility of knowledge on species phylogenetic relationships for understanding community assembly (chapter 1) and invasibility (chapter 3). The other two studies investigated the impacts of important ecological factors, including competition (chapter 2) and temporal niches (chapter 4), on adaptive radiation, using the rapidly diversifying bacterium Pseudomonas fluorescens SBW25 as the model organism. The first study, described in Chapter 1, examined how phylogenetic relatedness between competing species affected the strength of priority effects and ecosystem functioning during community assembly. Strong priority effects emerged only when competing bacterial species were phylogenetically most closely related, resulting in multiple community states associated with different assembly histories. In addition, the phylogenetic diversity of bacterial communities effectively predicted bacterial production and decomposition. The second study, described in Chapter 2, explored the role of competition in the adaptive radiation of P. fluorescens. The adaptive radiation was generally suppressed by competition, but its effect was strongly modulated by the phylogenetic relatedness between the diversifying and competing species and their immigration history. The inhibitive effect of competition on adaptive radiation was strongest when phylogenetic relatedness was high and when competitors were introduced earlier. The third study, described in Chapter 3, evaluated the relative importance of phylogenetic relatedness between resident and invading species and phylogenetic diversity of resident communities for invasibility. Laboratory bacterial communities containing a constant number of resident species with varying phylogenetic diversity and relatedness to invaders were challenged by nonresident bacterial species. Whereas invader abundance decreased as phylogenetic relatedness increased as predicted by Darwin's naturalization hypothesis, it was unaffected by phylogenetic diversity. The final study, described in Chapter 4, presented the first experimental demonstration of the maintenance of biodiversity that emerged from adaptive radiation in the presence of temporal niches. Only when provided with temporal niche opportunities were multiple derived phenotypes of P. fluorescens able to coexist as a result of negative frequency-dependent selection. When temporal niche was absent, the specialized phenotypes either did not emerge or were predominated by one superior phenotype.

L'imagerie est maintenant partie intégrante des traitements de radiothérapie. Avec la technologie CBCT embarquée sur les appareils de traitement, l'imagerie tomographique permet non seulement de repositionner fidèlement le patient tout au long de son traitement mais aussi d'adapter la planification initiale aux modifications quotidiennes de volume. C'est la radiothérapie adaptative, objet des travaux de cette thèse. Nous avons établi les limites techniques de précision de repositionnement des équipements utilisé. Ensuite, à partir des acquisitions CBCT quotidiennes de patients traités pour la prostate, nous avons élaboré une stratégie de traitement basée sur une banque de plans personnalisés. Nous avons mis au point une méthode semi-automatique de sélection du plan de traitement du jour qui a montré une efficacité supérieure à la sélection par des opérateurs expérimentés. Enfin, nous avons quantifié les doses additionnelles à la dose thérapeutique associées à l'utilisation quotidienne de l'imagerie CBCT. En conclusion, on peut dire qu'avec l'imagerie CBCT embarquée, on peut voir ce que l'on veut traiter, irradier ce que l'on a vu et contrôler ce qu'on a traité. / Imaging is now fully integrated in the radiation therapy process. With on-board CBCT systems, tomography imaging allows not only patient positioning but also treatment planning adaptation with patient anatomy modifications, throughout the entire treatment. This is called adaptive radiation therapy, and is the main subject of this PhD thesis. During this work, we measured the repositioning accuracy of the system used. We also developed a treatment strategy using daily CBCT images and a personalized plan database to adapt treatment plan to patient anatomy. We found a way to select the daily treatment plan that shows superiority over operator selection. Then we also quantified the additional dose delivered while using this technique and the impact with regards to the risks added to patients. As a conclusion, with CBCT imaging, radiation therapy has entered an era where one can see what need to be treated, can treat what has been seen and can control what has been treated.

Penstemon is one of North America's largest endemic genera with over 280 described species. These species are distributed throughout most of North America from the Arctic northern latitudes to tropics of Central America. The genus has historically been divided into six subgenera, but has recently been reorganized into two subgenera following some recent phylogenetic studies. I made a comprehensive assessment of the Penstemon genus' geographic distribution utilizing herbaria databases by ecoregion to discuss the general ecologic adaptations of each historic subgenera. I also assessed the Penstemon genus' bee pollinator diversity utilizing online databases of bee specimen collections associated with Penstemon flowers. I investigated the efficacy of utilizing the plastid genomes (plastomes) of 29 species in the Lamiales order, including five newly sequenced Penstemon plastomes, for analyzing phylogenetic relationships and resolving problematic clades. I compared whole-plastome based phylogenies to phylogenies based on individual gene sequences (matK, ndhF, psaA, psbA, rbcL, rpoC2, and rps2) and concatenated sequences. I found that my whole-plastome based phylogeny had higher nodal support than all other phylogenies, which suggests that it provides greater accuracy in describing the hierarchal relationships among taxa as compared to other methods. I found that the genus Penstemon forms a monophyletic clade sister to, but separate from, the Old World taxa of the Plantaginaceae family included in our study. My whole-plastome based phylogeny also supports the rearrangement of the Scrophulariaceae family and improves resolution of major clades and genera of the Lamiales. I evaluated 16 accessions of P. cyaneus with 14 accessions of closely related Penstemon species in common garden in two distinct environments in Aberdeen, ID and Provo, UT during 2018 and 2019. I evaluated the accessions for key commercial seed production traits including survival, plant height, number of stems, and seed production. Both common gardens received supplemental irrigation during 2018, but I withheld irrigation during 2019. Plant survival in our Aberdeen, ID site was not significantly different between years, but survival was a significantly lower in 2019 than in 2018 at our Provo, UT site. The mean survival for P. cyaneus accessions ranged from 56% to 94%, and the mean seed production ranged from 91.2 kg/ha to 397.6 kg/ha. I recommend developing a commercial seed source derived from pooling germplasm of six accessions (PECY3-367, PECY3-371, PECY3-376, PECY3-443, PECY3-457, and PECY3-458). These accessions had mean survival rates of 82-94%, and seed production of 196.2-397.6 kg/ha.

The North American genus Speyeria is an especially challenging radiation of butterflies due to ongoing hybridization, incomplete lineage sorting, and similar morphological characters among species. Adaptive radiations often require considerable evidence in order to resolve the evolutionary relationships of closely related individuals. Previous studies of this genus have found paraphyly among species and have been unable to disentangle these taxa due to a lack of data and/or incomplete sampling of the genus. As a result, the interspecific relationships among Speyeria remain unresolved. In an attempt to achieve phylogenetic resolution of the genus, we conducted population genomic and phylogenomic analyses of all North American Speyeria species, as well as several subspecies, based on genome wide markers using the SbfI restriction enzyme and restriction site associated DNA sequencing (RADseq). Together, our analyses recovered 16 species within Speyeria, validating previous taxonomic work. However, consistent with recent molecular analyses, internal relationships have poor support. This lack of resolution indicates Speyeria represent an ongoing adaptive radiation, with incomplete lineage sorting, hybridization, and lack of postzygotic reproductive barriers, supporting this hypothesis.

Ecological opportunity—the availability of open niche space to an evolving lineage—has long been thought to modulate the extent of adaptive diversification. Many microbial evolution experiments have confirmed that ecological opportunity drives diversification of initially homogeneous populations into communities of ecologically distinct sub-lineages (ecotypes). Interactions among ecotypes are crucial for both community function and the maintenance of the ecological diversity produced during adaptive diversification, however the factors influencing the evolution of these interactions remain unexplored. We assessed the influence of ecological opportunity on this process by studying communities of the bacterium Pseudomonas aeruginosa that were evolved in either nutritionally complex (COM) or simple (SIM) environments. We measured the net ecological interactions in these communities by comparing the cellular productivity and competitive fitness of whole communities from each environment to that of their component isolates in both complex and simple media. On average, COM communities had both higher productivity and fitness than their component isolates in complex media, indicating that the components of these communities share net positive interactions. The same was not true of SIM communities, which did not differ in either measure from their component isolates. Follow-up experiments revealed that high fitness in two COM communities was driven by rare variants (frequency < 0.1%) that secrete compounds during growth which inhibit PA14, the strain used as a common competitor for fitness assays. Taken together, our results suggest that environments with high levels of ecological opportunity drive diversification into ecotypes that share net positive ecological interactions. The strong effect of diversity on productivity and fitness we found in newly diversified communities has a number of implications for evolutionary ecology as well as the treatment of P. aeruginosa infections.

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Adaptive radiation – the proliferation of species from a single ancestor and diversification into many ecologically different forms – has long been heralded as an important process in the generation of phenotypic diversity. However, the early stages of adaptive radiation are notoriously elusive to observe and study. In this dissertation, I capitalize on communities of introduced non-native Anolis lizards as analogues of early stage adaptive radiations. In Chapter II, I begin by reviewing the concept of “ecological opportunity” – a classic hypothesis put forward as a potential key to understanding when and how adaptive radiation occurs. In Chapter III, I investigate the mechanisms which allow for coexistence and community assembly among ecologically-similar species. To do this I investigate range dynamics and assembly patterns of introduced anoles on the oceanic island of Bermuda. I discover that interspecific partitioning of the structural environment facilitates species coexistence, however the order of species assembly was an important predictor of final community composition. In Chapter IV, I then investigate how interspecific interactions between coexisting species may drive phenotypic divergence. This is the process of character displacement, which has been widely hypothesized to be an important mechanism driving phenotypic divergence in adaptive radiations. To do this I investigate sympatric and allopatric populations of introduced Cuban brown anoles (Anolis sagrei) and Puerto Rican crested anoles (A. cristatellus) in Miami FL, USA. I identify morphological shifts in sympatry, driven by divergence in habitat use and decreases in abundance. This study provides evidence of how selection on both ecologically and sexually-important traits can both drive phenotypic divergence during character displacement. Finally, in Chapter V, after taking advantage of non-native species as model eco-evolutionary systems in previous chapters, I investigate the potentially harmful effects that their presence may have on vulnerable native biodiversity. To do this I investigate the conservation risk posed by newly-discovered populations of A. sagrei on Bermuda to Critically Endangered endemic Bermuda skinks (Plestiodon longirostris). Through a detailed analysis of habitat use, diet, population size, and morphology of A. sagrei on Bermuda, we conclude it likely poses a high conservation threat to P. longirostris through interspecific competition.