A Study of the Coevolution of Digital Organisms with an Evolutionary Cellular Automaton

This paper presents an Evolutionary Cellular Automaton (ECA) that simulates the evolutionary dynamics of biological interactions by manipulating strategies of dispersion and associations between digital organisms. The parameterization of the different types of interaction and distribution strategies using configuration files generates easily interpretable results. In that respect, ECA is an effective instrument for measuring the effects of relative adaptive advantages and a good resource for studying natural selection. Although ECA works effectively in obtaining the expected results from most well-known biological interactions, some unexpected effects were observed. For example, organisms uniformly distributed in fragmented habitats do not favor eusociality, and mutualism evolved from parasitism simply by varying phenotypic flexibility. Finally, we have verified that natural selection represents a cost for the emergence of sex by destabilizing the stable evolutionary strategy of the 1:1 sex ratio after generating randomly different distributions in each generation.

The architecture of phenotypic flexibility within a complex trait: an empirical case study using avian thermogenic performance

ABSTRACTReversible modifications to trait values can allow individuals to match their phenotypes to changing environmental conditions, a phenomenon known as phenotypic flexibility. A system’s capacity for flexibility may be determined by its underlying architecture, and these relationships can have important implications for both organismal adaptation and the evolvability of acclimatization responses. Theory provides two possible alternatives to explain the ways in which lower-level traits respond to environmental challenges and contribute to phenotypic flexibility in complex, whole-organism traits: symmorphosis predicts correspondence between structure and demand across all levels of a physiological system, while the alternative predicts that influence is concentrated in select elements of a physiological network. Here we provide a rich dataset — composed of 20 sub-organismal, physiological traits paired with whole-organism metabolic rates for 106 adult Dark-eyed Juncos (Junco hyemalis) — to explore the mechanistic basis of phenotypic flexibility in complex traits. When exposed to synthetic temperature cues, these individuals have previously been shown to increase their thermogenic capacity (Msum) and enhance their ability to maintain their body temperature in the cold. We show that the relationships among a number of the traits that contribute to Msum varied as the environmental context changed. Moreover, variation in Msum in response to temperature acclimation was correlated with only a handful of subordinate phenotypes. As a result, avian thermogenic flexibility does not appear to be a symmorphotic response. If this is generally true of complex traits, it suggests that simple and reversible modifications can significantly impact whole-organism performance, and thus that the evolution of phenotypic flexibility in a single component part could impart flexibility for the entire system.

Humidity, huddling & the hibernation energetics of big brown bats (Eptesicus fuscus)

During winter, many mammals hibernate and lower their body temperature and metabolic rate (MR) in prolonged periods of torpor. Hibernators will use energetically expensive arousals (i.e., restore body temperature and MR) presumably to re-establish water balance. Some hibernating mammals however will huddle in groups, possibly to decrease energetic costs and total evaporative water loss (EWL), although the benefit is not fully understood. Research on the relationship between behaviour, physiology, water loss, and energy expenditure of bats during hibernation is especially important because of a fungal disease called white-nose syndrome (WNS). To date, 12 North American bat species are affected by WNS, however big brown bats (Eptesicus fuscus) appear resistant, although the underlying mechanism is poorly understood. The overall objective of my thesis was to understand the influence of humidity and huddling on the behavioural and physiological responses of hibernating big brown bats. To test my hypotheses, I used a captive colony of hibernating big brown bats (n = 20). Specifically, for Chapter 2, I first tested the hypothesis that big brown bats adjust huddling and drinking behaviour depending on humidity, to maintain a consistent pattern of periodic arousals, and therefore energy balance during hibernation. I found that bats hibernating in a dry environment did not differ in arousal/torpor bout frequency, or torpor bout duration throughout hibernation but drank at twice the rate as bats in a humid environment. Bats in the dry treatment also had shorter arousals, and huddled in a denser huddle, potentially to reduce rates of total EWL. During late hibernation, for Chapter 3, I used open-flow respirometry to test two additional hypotheses, first that phenotypic flexibility in total EWL helps explain the tolerance of hibernating big brown bats for a wide range of humidity relative to other bat species. I found that dry-acclimated bats had lower rates of total EWL, compared to bats acclimated to humid conditions. I then tested the second hypothesis that big brown bats can use huddling to mitigate the challenge of dry conditions. I found that, for humid-acclimated bats, rates of total EWL were reduced with huddling bats but there was no effect of huddling on EWL for bats acclimated to dry conditions. These results suggest that the ability of big brown bats to reduce rates of total EWL through acclimation may reduce the need to huddle with conspecifics to avoid water loss and thus dehydration. Overall, my thesis suggests that big brown bats use both behavioural and physiological mechanisms to reduce water loss which could allow them to exploit habitats for hibernation that are unavailable to other bat species and could also help explain their apparent resistance to WNS.

Temperature heterogeneity correlates with intraspecific variation in physiological flexibility in a small endotherm

Phenotypic flexibility allows individuals to reversibly modify trait values and theory predicts an individual’s relative degree of flexibility positively correlates with the environmental heterogeneity it experiences. We test this prediction by integrating surveys of population genetic and physiological variation with thermal acclimation experiments and indices of environmental heterogeneity in the Dark-eyed Junco (Junco hyemalis) and its congeners. We combine field measures of thermogenic capacity for 335 individuals, 22,006 single nucleotide polymorphisms genotyped in 181 individuals, and laboratory acclimations replicated on five populations. We show that Junco populations: (1) differ in their thermogenic responses to temperature variation in the field; (2) harbor allelic variation that also correlates with temperature heterogeneity; and (3) exhibit intra-specific variation in thermogenic flexibility in the laboratory that correlates with the heterogeneity of their native thermal environment. These results provide comprehensive support that phenotypic flexibility corresponds with environmental heterogeneity and highlight its importance for coping with environmental change.

Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance

The tumor microenvironment (TME) is a complex and ever-changing “rogue organ” composed of its own blood supply, lymphatic and nervous systems, stroma, immune cells and extracellular matrix (ECM). These complex components, utilizing both benign and malignant cells, nurture the harsh, immunosuppressive and nutrient-deficient environment necessary for tumor cell growth, proliferation and phenotypic flexibility and variation. An important aspect of the TME is cellular crosstalk and cell-to-ECM communication. This interaction induces the release of soluble factors responsible for immune evasion and ECM remodeling, which further contribute to therapy resistance. Other aspects are the presence of exosomes contributed by both malignant and benign cells, circulating deregulated microRNAs and TME-specific metabolic patterns which further potentiate the progression and/or resistance to therapy. In addition to biochemical signaling, specific TME characteristics such as the hypoxic environment, metabolic derangements, and abnormal mechanical forces have been implicated in the development of treatment resistance. In this review, we will provide an overview of tumor microenvironmental composition, structure, and features that influence immune suppression and contribute to treatment resistance.

A Novel Personalized Systems Nutrition Program Improves Dietary Patterns, Lifestyle Behaviors and Health-Related Outcomes: Results from the Habit Study

Personalized nutrition may be more effective in changing lifestyle behaviors compared to population-based guidelines. This single-arm exploratory study evaluated the impact of a 10-week personalized systems nutrition (PSN) program on lifestyle behavior and health outcomes. Healthy men and women (n = 82) completed the trial. Individuals were grouped into seven diet types, for which phenotypic, genotypic and behavioral data were used to generate personalized recommendations. Behavior change guidance was also provided. The intervention reduced the intake of calories (−256.2 kcal; p < 0.0001), carbohydrates (−22.1 g; p < 0.0039), sugar (−13.0 g; p < 0.0001), total fat (−17.3 g; p < 0.0001), saturated fat (−5.9 g; p = 0.0003) and PUFA (−2.5 g; p = 0.0065). Additionally, BMI (−0.6 kg/m2; p < 0.0001), body fat (−1.2%; p = 0.0192) and hip circumference (−5.8 cm; p < 0.0001) were decreased after the intervention. In the subgroup with the lowest phenotypic flexibility, a measure of the body’s ability to adapt to environmental stressors, LDL (−0.44 mmol/L; p = 0.002) and total cholesterol (−0.49 mmol/L; p < 0.0001) were reduced after the intervention. This study shows that a PSN program in a workforce improves lifestyle habits and reduces body weight, BMI and other health-related outcomes. Health improvement was most pronounced in the compromised phenotypic flexibility subgroup, which indicates that a PSN program may be effective in targeting behavior change in health-compromised target groups.

A combined lifestyle intervention induces a sensitization of the blood transcriptomic response to a nutrient challenge

The global population is growing older. As age is a primary risk factor of (multi)morbidity, there is a need for novel indicators to predict, track, treat and prevent the development of disease. Lifestyle interventions have shown promising results in improving the health of participants and reducing the risk for disease, but in the elderly population, such interventions often show less reliable or subtle effects on health outcomes. This is further complicated by a poor understanding of the homeodynamics and the molecular effects of lifestyle interventions, by which their effects of a lifestyle intervention remain obscured. In the Growing Old Together (GOTO) study, we examined the responses of 164 healthy, elderly men and women to a 13-week combined physical and dietary lifestyle intervention. In addition to collecting blood samples at a fasted state, we sampled blood also 30 minutes following a standardized meal. This allows us to investigate an intervention response not only in the traditional fasted state, but also in the blood metabolic and cellular responses to a nutrient challenge. We investigated the transcriptomic and metabolomic responses to this nutrient challenge, how these responses relate to each other, and how this response is affected by the lifestyle intervention. We find that the intervention has very little effect on the fasted blood transcriptome, but that the nutrient challenge induces a large translational inhibition, and an innate immune activation, which together comprise a cellular stress response that is stimulated by the intervention. A sex-specific analysis reveals that although the same set of genes respond in the same direction in both males and females, the magnitude of these effects differ, and are modulated differently by the intervention. On the other hand, the metabolomic response to the nutrient challenge is largely unaffected by the intervention, and the correlation between the metabolomic nutrient response and transcriptomic modules indicates that the change in transcriptomic response to the nutrient challenge is independent from a change in cellular metabolomic environment. This work constitutes a glance at the acute transcriptomic stress response to nutrient intake in blood, and how a lifestyle intervention affects this response in healthy elderly, and may lead to the development of novel biomarkers to capture the phenotypic flexibility of health.

The Influence of Cellulose-Type Formulants on Anti-Candida Activity of the Tyrocidines

Candida species are highly adaptable to environmental changes with their phenotypic flexibility allowing for the evasion of most host defence mechanisms. Moreover, increasing resistance of human pathogenic Candida strains has been reported against all four classes of available antifungal drugs, which highlights the need for combinational therapies. Tyrocidines are cyclic antimicrobial peptides that have shown synergistic activity with antifungal drugs such as caspofungin and amphotericin B. However, these cyclodecapeptides have haemolytic activity and cytotoxicity, but they have been used for decades in the clinic for topical applications. The tyrocidines tend to form higher-order structures in aqueous solutions and excessive aggregation can result in variable or diminished activity. Previous studies have shown that the tyrocidines prefer ordered association to celluloses. Therefore, a formulation with soluble cellulose was used to control the oligomer stability and size, thereby increasing the activity against Candida spp. Of the formulants tested, it was found that commercial hydroxy-propyl-methyl cellulose, E10M, yielded the best results with increased stability, increased anti-Candida activity, and improved selectivity. This formulation holds promise in topical applications against Candida spp. infections.