ABSTRACT. Most hosts are colonised by a diversity of microbes. Some can be beneficial to the host and provide protection against pathogen infection. Pathogens can readily adapt to challenges from hosts and treatments, but the extent to which conflict from microbes accelerates pathogen evolution is unclear. By experimentally evolving microbial systems, my group has shown that host-protective microbes can have big consequences for the evolution of pathogen virulence and resistance. I will show that some pathogens can adapt to microbial protection at the cost of host exploitation, while others can rapidly evolve generalist defence strategies. This work suggests that host-associated microbes warrant consideration as a driver of infection outcomes and pathogen transmission over time.

ABSTRACT. Evolutionary processes are responsible for the current antibiotic crisis. Surprisingly, they are usually ignored during design of novel therapy, which mainly focuses on finding new drugs. In general, bacteria show an enormous potential to adapt to constant environments, even if extreme such as those defined by many antibiotics. Adaptation may however be more difficult, if conditions change fast. Therefore, rapid fluctuations in the application of drugs may enhance pathogen extinction and minimize resistance evolution. To date, such fast fluctuations are usually not considered for antibiotic therapy. My lab uses evolution experiments in combination with genomics, functional genetics, mathematical modelling, and also analysis of clinical material to explore novel, evolution-informed ideas for antibiotic therapy. I will present some of our most recent results with the model pathogen Pseudomonas aeruginosa that highlight the particular potency of fast sequential treatments and the likely underlying evolutionary and molecular mechanisms.

ABSTRACT. Tuberculosis (TB) continues to be the deadliest human infection caused by bacterial strains of the Mycobacterium tuberculosis complex (MTBC). TB-treatment of a susceptible strain requires, at minimum, a six month regimen comprising of four antibiotics. Once the bacteria develop resistance towards the two most effective drugs isoniazid and rifampicin, the infection is classified as multidrug resistant tuberculosis (MDR-TB) and treatment is changed to more toxic medications for up to two years. In 2016, nearly half a million patients were newly infected with an MDR strain worldwide, killing 240.000. Pharmacokinetic and pharmacodynamic studies have revealed the inability of many anti-TB drugs to reach all sights of infection, e.g. granuloma, at a therapeutic level. Our work is focused on the hypothesis, that exposure to low (ineffective) drug concentrations might particularly select for highly resistant and highly competitive MTBC strain populations. In this study, we designed an in vitro model to investigate the evolutionary effects of moxifloxacin (MFX), a second-line drug which disrupts DNA transcription through binding of the DNA gyrase, and bedaquiline (BDQ), the most recently released anti TB-drug which inhibits ATP synthase. After long-term exposure of the laboratory strain H37Rv to sub-lethal concentrations we analysed mutant enrichment and resistance allele diversity using whole genome sequencing (WGS) and phenotypic assays. When H37Rv is exposed to 1-4 dilution below the minimum inhibitory concentration (MIC) we could almost exclusively recover mutations frequently seen in patient derived isolates resistant to MFX. Preliminary results further suggest that a particular concentration range selects for mutants with higher MICs. There is virtually no data available on mutations that confer resistance to BDQ in MDR-TB patients. Thus, we are confident that our in vitro model also detects clinically relevant BDQ resistance conferring mutations that will contribute to resistance mutation catalogues employed by WGS resistance predictions for personalized medicine approaches.

ABSTRACT. There has been an increased usage of metallic antimicrobial materials to control pathogenic and multi-drug resistant bacteria, yet there is a corresponding need to know if this may lead to genetic adaptations that produce even more dangerous bacterial varieties. Here we utilize experimental evolution to produce strains of Escherichia coli K-12 MG1655 resistant to Gallium Nitrate (Ga3+NO3). Gallium is an analog for iron. By day 10, increased gallium resistance was evident in populations cultured in medium containing a sublethal concentration of gallium. Furthermore, these populations showed increased resistance to ionic silver and iron (III), but not iron (II). There was no increase in traditional antibiotic resistance compared to controls. Genomic analysis identified hard selective sweeps of mutations in several genes in the gallium (III)-resistant lines including; fecA (iron citrate outer membrane transporter), insl1 (IS30 tranposase), one intergenic mutations arsC → / → yhiS; (arsenate reductase/pseudogene); and in one pseudogene yedN ←; (iapH/yopM family). Two additonal significant intergenic polymorphisms were found at frequencies > 0.500 in fepD ← / → entS (iron‑enterobactin transporter subunit/enterobactin exporter, iron‑regulated) and yfgF ← / → yfgG (cyclic‑di‑GMP phosphodiesterase, anaerobic/uncharacterized protein). This study corroborates recent results observed in experiments utilizing pathogenic Pseudomonas strains that also showed that bacteria can rapidly evolve resistance to an atom that mimics an essential micronutrient and illustrates a pleiotropic consequence of this adaptation.

ABSTRACT. Atherosclerotic cardiovascular diseases, chronic inflammatory diseases of multifactorial etiology, are the leading cause of death worldwide. We propose that the evolutionary trajectory of persistent infection at the site of the atheroma may predict disease progression. In this study we identified the source of persistence infection in human atherosclerotic plaque and determined how antibiotic resistance and/or virulence in the pathogen mediate plaque vulnerability. Whole genome sequencing (WGS) was used to identify bacteria from pure cultures obtained from atherosclerotic tissues of living subjects diagnosed with more than 70% occlusion of the carotid artery undergoing carotid endarterectomy (CE). WGS identified the predominant species as S. pasteuri variants (SPVs) in all CE isolates grown in pure culture except in one isolate which was identified as B. licheniformis. All SPVs were found to have multiple antibiotic resistant (AR) and virulent genes which were unique for each sequenced isolate. Unsurprisingly, virulence was negatively co-related with antibiotic resistance in all isolates tested. These variations found in our isolates suggest that while SPVs may remain dormant, they have the potential to become activated under specific physiological conditions. As macrophages play a decisive role at all stages of atherosclerotic lesion progression we treated mouse macrophages (RAW 264.7) with SPVs. All tested SPVs showed their ability to survive phagocytosis and the propensity of highly virulent SPVs to direct macrophages towards an inflammatory (M1) state. In conclusion, we show that (i) persistant infection occurs in atherosclerotic plaques, (ii) diverse AR genes are found within these isolates and (ii) the degree of AR is co-related with virulence. Genetic variation in SPVs may alter host immunity and provide a causal link between infection and atherosclerosis. Thus, mapping the evolutionary trajectories of resistance to virulence and host response may help determine the fate of a vulnerable plaque and ultimately the disease process.

ABSTRACT. To date, studies relating the costs of immune function to growth outcomes have not distinguished between growth deficits as a response to short term energetic deficits, versus changes in growth trajectories as responses to cues of future energetic needs and availability. In part, these alternatives have been difficult to distinguish because the actual energetic costs of growth and other life history allocations, such as reproduction, maintenance, and activity were not available or sufficiently detailed. Here, I address this lack by combining precise data on organ size and tissue specific metabolic rates with detailed population studies providing data on body composition, immune function, activity, and reproduction across the lifespan, to generate detailed estimates of lifetime and age-specific energy allocations for both the Tsimane, a group of Bolivian forager-horticulturalists, and for a cross-section of the United States. Key insights from these estimates include the observation that except in infancy, the costs of physical growth are dwarfed by the costs of maintenance for a larger body, supporting the idea that predictive adaptive responses, rather than constraints, regulate trade-offs with growth. Moreover, given the higher costs of maintenance for Tsimane adults, Tsimane males save 132,000 kcal per year by maintaining an average fat-free-mass of 52kg vs 64kg for the average American. Thus, relative maintenance costs may be a key determinate of adult body size and degree of sexual dimorphism across populations.

ABSTRACT. Due to the paucity of longitudinal studies in low income countries, the effect of under-nutrition on blood pressure is less well understood than is the role of over-nutrition. Under the First Thousand Days of Life hypothesis, undernutrition to age two years is more important for adult blood pressure than is undernutrition later in childhood. Under the Predicted Adaptive Response Hypothesis, the greatest risk occurs when the adult nutritional environment is different from the childhood environment. We tested these hypotheses using a prospective cohort study of 1698 individuals in Mali, West Africa. The participants were followed for twenty years (1998 to 2018) and a total of 8500 blood pressure measurements were taken throughout adolescence and young adulthood. We predicted the adult blood pressure for children whose internal BMI z-scores from age 0 to 10 followed one of 5 trajectories: constant at z=-1, 0, or +1, transitioning from z=0 to z=-1, and transitioning from z=-1 to z=0. We found that in the first ten years of life there was no critical window in which undernutrition was more strongly associated with later blood pressure; instead its effects were cumulative. Moreover, at each level of adult BMI, the highest blood pressure was found in persons who had a childhood z-score trajectory of -1 to -1 and the lowest blood pressure was observed in persons who had a childhood z-score trajectory of +1 to +1. The catch-up (-1 to 0) and catch-down (0 to -1) trajectories were intermediate and similar to each other. In sum, it was good to be big in childhood and small in adulthood. These results are significant because they disentangle the effects of childhood and adult nutrition on blood pressure. Further they go against two prominent hypotheses in the evolution and public health field.

ABSTRACT. Obstructed labour is a leading cause of maternal and neonatal morbidity and mortality. Most cases result from discordance of dimensions between the foetal head and the mother’s pelvis. Traditionally, this has been attributed to the Obstetrical Dilemma (OD). The associated hypothesis posits that a narrow pelvis is selected for efficiency during bipedal locomotion, while the birth of large-headed newborns contrastingly favours a broader pelvic configuration in females. The consequent evolutionary trade-off can potentially explain the unique challenges during childbirth, sexual dimorphism in human pelvic shape, and the unusual degree of nervous system immaturity in our neonates. Recently, several aspects of the original OD hypothesis have been challenged, raising doubts about its validity and reigniting academic debate. Specifically, it has been proposed that a mother’s energy availability, rather than spatial constraints of her pelvis, might limit gestation length. Experimental data also reportedly indicate that the wider pelvis of women compared to men does not entail increased energetic costs for bipedal locomotion. Moreover, thermoregulatory pressures or abdomino-pelvic stability needs, instead of locomotor costs, may conflict with obstetrical advantages of a broader pelvis. Finally, cephalo-pelvic disproportion might have been exacerbated relatively recently following the emergence of agriculture, with maternal stature and pelvic dimensions decreasing as a result of less secure food availability. Here, we review available evidence with the aim of identifying and emphasizing aspects of the obstetrical dilemma that remain pertinent for both evolutionary studies and clinical contexts. Although the alternative hypotheses currently envisaged are not mutually exclusive, we show that each fails to explain all aspects of the obstetrical dilemma. Specifically, the evolution of our complex birth process, neurologically immature neonates, and marked sexual dimorphism in human pelvic shape remain problematic. We conclude that there is still no valid alternative to the obstetrical dilemma hypothesis.

ABSTRACT. Cephalo-pelvic disproportion results mainly from a misfit between the maternal pelvis and fetal head size. It remains the dominant cause for obstructed labour, and an important indication for Caesarean section. Traditionally, the obstetrical dilemma hypothesis explained this as a trade-off between the antagonistic selection for large-brained neonates and biomechanically efficient, or narrower pelvis equipped for bipedal locomotion. Recently the obstetrical dilemma hypothesis has been challenged by a series of alternative explanations, including “the ecological model”, which posits that cephalo-pelvic disproportions only exacerbated relatively recently, when maternal stature and pelvic dimensions decreased due to unsteady food availability.

To further evaluate the ecological model, we analyse a large data set of birth records between 1896 and 1945 from the archives of the maternal hospital Basel, Switzerland, to better understand the multifaceted and interrelated aspects of maternal and offspring body size. Analysed data included head circumference, length and weight of the neonate, type of head presentation and position, birth complications, parity, as well as maternal stature and external pelvic dimensions. This dataset permits the assessment of both fetal and maternal development; specifically, growth and stature relationships including changes in pelvic dimensions across different generations during times of fluctuating socioeconomic stress These factors generate complex interactions that potentially intensify the obstetrical dilemma.

Moreover, we explore the relationship between external and internal pelvic dimensions in a worldwide skeletal sample to better understand the causes of obstructed labour, namely cephalo-pelvic disproportion. We demonstrate that several external pelvic dimensions are useful predictors of birth canal size, while stature itself is only weakly related to pelvic measures. This is at odds with previous studies highlighting the importance of maternal stature for cephalo-pelvic disproportion. Our findings suggest that the ecological model is no valid alternative to the obstetrical dilemma hypothesis.

ABSTRACT. Interest in evolutionary medicine is fueled by the observation that many evolutionary principles have direct applications to clinical practice. Although the scope of evolutionary medicine is broad, this discipline may be particularly well suited to emergency medicine and critical care, in which clinical decisions frequently have life and death consequences. I will provide examples – starting with a review of fever and its treatment - of how evolutionary biology can be applied to emergent conditions. Opportunities to improve emergency and critical care with evolutionary medicine fall into two broad categories: I. understanding adaptation in human physiology and pathophysiology. II. recognizing evolutionary tradeoffs in disease phenotypes and in the response to medical treatments. This talk will review several of the most promising applications of evolutionary medicine in these categories and will offer a road map for leveraging evolutionary medicine in emergency and critical care.

ABSTRACT. The influence of the mother’s behavior on the development of the fetus has been of interest for many years. The Barker hypothesis is based on the connections between the maternal food intake and birth weight as well as many NCDs later in the life of the baby. As one of the most successful interventions in terms of energy intake in pregnancy the screening for gestational diabetes has influenced pregnancies since more than ten years now. With the control of glucose in the maternal blood the baby’s exposure to glucose can be well monitored and the sometimes dramatic consequences of macrosomia, hyperinsulinism and hypoglycemia in the fetus can be avoided. Therefore, the behavior of the mother during pregnancy, and now growing evidence that the pre-pregnancy phase is as important, should be of concern and mothers should be instructed carefully about the options. New research investigates the changes of the microbiome during pregnancy. As studies show not only the classical sites like mouth, intestine and vaginal microbiome change in the course of pregnancy, there is also a placental microbiome that might influence pregnancy outcomes.

ABSTRACT. Introduction: Common strategies for reducing body weight rely on limiting energy intake and restricting food choices. However, these strategies have often been proven ineffective in achieving long-term and sustainable weight reduction. More recently, mindful eating as an alternative weight management strategy has gained increasing attention, yet systematic reviews on intuitive or mindful eating published so far present contradictory results. Methods: We performed a systematic review and meta-analysis on randomized controlled trials on weight loss programs based on mindful or intuitive eating. We analysed results using meta-regressions. Results: We included a total of ten studies and found a significant weight loss effect of mindful eating strategies compared to non-intervention controls (-0.348 kg, 95% CI: -0.591 to -0.105, p=0.005). However, there was no difference compared to conventional diet programs (p=0.99). Reduction of BMI (-0.137 kg/m2, 95% CI: -0.365 to 0.091, p=0.240) or waist circumference (-0.358 cm, 95% CI: -0.916 to 0.200, p=0.209) were not statistically significant. Discussion: Mindful eating could be a practical approach to weight control. Limitations of this study include the unbalanced sex, origin, and place of residence of the participants and the short duration of interventions. Future research should aim at investigating long-term effects and include a more heterogeneous study population, and how to translate these results into public health practice.

ABSTRACT. Medical and public health interventions can have a large beneficial impact at low cost for entire populations even if the relative effects itself are small. However, this equally applies to harms of public health intervention, which may have substantial negative impact even if the relative increase in risk is small. Thus on a population level these benefits and harms counterbalance one another and it is of great importance to have quantitative estimates of that benefit harm balance of medical and public health interventions and policies. Evolutionary Medicine may inform such benefit-harm assessment by informing (at least) two key steps. Firstly, the question and decision making context needs to be carefully designed and must include “all” determinants and consequences of a medical or public health intervention on population health. It is well possible that current benefit harm assessments fail to consider more long-term benefits and harms across the lifetime of a population. Although rarely done so far, Evolutionary Medicine could inform the decision making context by identifying determinants, from the genotype to the phenotype, along the life history of a specific population at issue. Secondly, modelling different scenarios of how a medical or public health intervention impacts on population health, again from the genotype to the phenotype depends on certain assumptions. Evolutionary Medicine may help to design such analyses. This talk will discuss how insights from Evolutionary Medicine may inform benefit harm assessments of medical and public health interventions and the impact this may have on the development of policies and recommendations.

ABSTRACT. Whereas much of biomedical science relies on the laboratory experiment as its gold-standard methodology to disprove hypotheses, investigations of historical fact in the evolutionary sciences require a time-controlled multidisciplinary approach akin to forensic science that is equally rigorous in disproving its hypotheses. When detractors, scientific and otherwise, disparage paleobiological hypotheses as “untestable” they may use the term “just-so story” pejoratively to dismiss them as fanciful fiction, drawing a comparison with the popular Just-So Stories published by Anglo-Indian author Rudyard Kipling in the early twentieth century. The experimental method tests hypothetical predictions in a uniformitarian empirical framework that is ahistorical and mechanism-focused, while the forensic method tests retrodictions in a uniformitarian empirical framework that is historical and narrative in focus. Both methods are fully compatible with each another, and non-falsified hypotheses must conform with empirical results obtained through either method. A thoroughly tested onto-phylogenetic (“evo-devo”) narrative is an essential component of Evolutionary Medicine, driving research, educational, and clinical advances. Clinical experience amply demonstrates that therapies which ignore evolutionary history and rest solely on ahistorical and mechanistic assumptions lead to less-than-optimal patient outcomes. To operationalize the retrodictive approach an anthropogenic (“human-origins”) matrix is constructed using an array of 9 paradigmatic tools, including rigorous temporal calibration, applied across 7 categories of narrative elements, including environmental context and adaptations, in order to assess hypotheses. Drawing an analogy to Kipling’s unfalsifiable “How the Rhinoceros Got His Skin” (1902) the anthropogenic matrix is used to construct a falsifiable narrative of evolutionary and developmental anatomy of the human integument, with clinical implications.

ABSTRACT. There is a global epidemic of chronic kidney disease (CKD), and current therapies do not halt progression. Three key factors contribute to progression of CKD: 1) > 10-fold variation in nephron number (NN) at birth; 2) nephron hypertrophy resulting from low NN; 3) 50% decrease in NN with normal aging. These responses are products of evolution, constrained by energy availability. The rapid evolution of humans was a product of brain growth: adults devote 20% of resting metabolism to the brain. The kidney consumes more oxygen (per gram) than the brain and tubular sodium reabsorption is driven mainly by oxidative phosphorylation (OXPHOS) by mitochondria (MT). The aim of the present analysis of published reports was to apply principles of evolutionary bioenergetics to elucidate risk factors for CKD. Plasticity of nephrogenesis results from determination of progenitor cell fate in response to the maternal nutritional environment by switching between glycolytic and OXPHOS metabolism. If maternal nutrition is restricted, sensors of hypoxia (HIF) and energy availability (AMPK) respond by diverting fetal energy from nephrogenesis to brain development, resulting in lower NN. This tradeoff permits survival through reproductive years, but increases the risk of CKD in adulthood by activation of cell death pathways by MT-generated reactive oxygen species (ROS) increasing risk for progressive CKD. Idoxyl sulfate, a uremic toxin that accumulates in patients with CKD, stimulates renal hypertrophy and production of ROS. Tubular hypertrophy resulting from reduced NN is stimulated by upregulation of mTOR, a nutrient sensor that promotes hypermetabolism. Enlarging tubular cells reach a critical volume for oxygen diffusion below which MT respiration is impaired (“critical pO2”), increasing ROS accumulation. By stimulating AMPK and suppressing mTOR, calorie restriction can slow progression of CKD and normal aging. Kidney structure and function are the product of evolutionary adaptation constrained by bioenergetics with tradeoffs leading to CKD.

ABSTRACT. A couple of different species including men, monkeys, fruit bats and few others lost the ability for endogenous vitamin C synthesis due to a mutation of the gene encoding the encyme L-gulono-lactone-oxidase (GLO) The most accepted hypothesis for this selection was the availability of food sources rich in vitamin C. However, this would not explain a selective pressure on different species at different time points during evolution. In contrast to the synthesizing species all non-synthesizing express a specific glucose transporter (GLUT1) on their red blood cells (RBC). GLUT1 transports Glucose but preferentially Vitamin C if a membrane bound protein, stomatin, couples to GLUt1. To evaluate whether GLUt1 creates a real benefit we measured Vitamin C uptake in human RBC and in pigs with functional GLO. Indeed, Vitamin C was only transported into human RBC but not in pig RBC. The ability of RBCs to accumulate an intracellular electron pool decreases the daily required amount of vitamin c during seasonal changes of the availability from food and seemed to be the key for the survival of individuals without vitamin C biosynthesis. Further this recycling was energetic more efficient than the de novo synthesis of ascorbate from glucose which explains the survival of this GLO-lacking but GLUT1 positive phenotype. Diabetic patients have lower blood Vitamin C-levels. We propose that in diabetic patients an altered Glut-1 and Stomatin interaction in RBC result in decreased DHA uptake and subsequently lower vitamin C concentrations. Indeed we could show that despite equal vitamin C plasma levels, intra-RBC vitamin C concentrations in the diabetic group were significantly decreased. Decreased intra-erythrocyte vitamin C level could lead to decreased vitamin C recycling and increased renal elimination of the vitamin (diketo-gulono-acid). In this case, the required daily intake (RDI) of vitamin C for diabetic patients should be reconsidered

ABSTRACT. Antibiotics are rapidly losing efficacy due to the evolution and spreading of resistant bacteria. Approaches that reduce selection for resistance are therefore desperately needed. One such approach is the development of treatments targeting bacterial virulence factors. The reasoning is that anti-virulence drugs aim at reducing pathogen virulence instead of viability, and should therefore exert weaker selection for resistance than conventional antibiotics. Another possibility is to manage infections using combinations of multiple compounds, exploiting specific interactions between drugs that can select against resistant mutants. We have previously shown that combination therapy between antibiotics and anti-virulence compounds is effective against the opportunistic pathogen Pseudomonas aeruginosa. Here we tested whether the addition of an antivirulence compound (gallium, a siderophore-quencher, or furanone C-30, a quorum-sensing-inhibitor) to antibiotic treatments (ciprofloxacin, colistin, meropenem or tobramycin) can revert selection for antibiotic resistance. We evolved antibiotic-resistant bacteria and competed them against susceptible clones under antibiotic treatment alone or under combination treatments. We found that, for five out of eight drug combinations, the antibiotic-resistant clones maintained a relative fitness advantage in presence of the antivirulence compounds. Conversely, in three out of eight drug combinations we observed that the addition of the anti-virulence could indeed reverse selection for antibiotic resistance. Mechanistic analysis revealed that the reversion of selection is unlinked to whether drug combinations were antagonistic or synergistic, but suggest that the certain mechanisms of antibiotic resistance make bacteria more susceptible to the anti-virulence drugs. Such cross-sensitivity was especially apparent for tobramycin resistant mutants treated with both gallium and furanone, making these drug combinations a promising new way to limit or even reverse the spread of antibiotic resistance.

ABSTRACT. The spread of antibiotic resistance causes a rapid loss of treatment efficacy. Drug combination therapies have been proposed as one option to maintain efficacy, because simultaneous resistance against multiple drugs is less likely to evolve. Alternatively, antivirulence compounds that target virulence factors rather than cell viability are also considered to be relatively evolutionary robust as they do not directly kill bacteria. Here, we combine these two approaches using the bacterium Pseudomonas aeruginosa as a model pathogen. We combined four clinically relevant antibiotics, ciprofloxacin, colistin, meropenem, and tobramycin, with either gallium, quenching iron-scavenging siderophores, or furanone C-30, a quorum sensing inhibitor. For all drug combinations, we (a) assessed treatment efficacy, (b) quantified drug interaction patterns (ranging from synergy to antagonism), and (c) tested whether combination therapy was still effective against antibiotic-resistant clones. We exposed P. aeruginosa PAO1 to a 9x9 concentration matrix for each drug pair and found that combination therapy was effective in inhibiting both growth and virulence factor production. The nature of drug interaction was concentration dependent, resulting in a mosaic of antagonistic and synergistic interactions across the concentration matrix. Interestingly, the degrees of synergy for growth and for virulence factor inhibition were often positively correlated. Moreover, we found that many drug combinations were still effective against bacteria that were resistant against the specific antibiotic used. Our work provides a first systematic analysis of combination therapy involving an antibiotic to kill pathogens, and an antivirulence to disarm them, and reveals that such combinations could be an effective tool to manage P. aeruginosa infections, even in presence of antibiotic resistant clones.

ABSTRACT. Background: The syndrome of sleep disturbance has been reported in overendurance athletes [1,2]. Despite a number of proximate explanations, the functional or adaptive perspectives of this disorder are currently unexplored [3]. The identification of a natural animal model would advance the development of a non-proximate understanding of this disorder. This study was, therefore, designed to identify such a natural animal model.

Methods: To identify a natural animal model for overreaching exercise, formal methods of systematic review were used. Literature from Zoological Records, Biosis, and Pubmed between the years of 1999 and 2007 were reviewed [4,5,6,7,8,9,10,11,12]. These results were synthesized and sourced, excluding duplicates and articles that did not relate to overreaching exercise in animals or sleep disorders. Further selection criteria included identifying animals that fit specific criteria (i.e. animals that exercised excessively and suffered from insomnia and/or other sleep disorders).

Results: From an initial 6323 articles identified, 10 sources that fit our inclusion criteria were selected and analyzed to identify potential natural animal models for this phenomenon [4,5,6,7,8,9,10,11,12]. Since birds were noted to be consistently identified to exercise over prolonged periods of time during long distance flying, search terms were then refined to “birds with insomnia,” AND “birds with sleep disorders,” “migratory sleeplessness,” AND “restlessness after migration.” These studies were reviewed to identify relevant physiology and the existence of data to support the use of these species as natural models. One species in particular, the migrating white crowned sparrow, represented a possible natural model that we identified through systematic review [4]. Early EEG work suggested differential sleep patterns during periods of migration vs. non-migration with migration as a surrogate for exercise in overendurance athletes [4, 13,14].

Conclusion: The identification of a natural animal model provides the basis for developing a nonproximate adaptive hypothesis for sleep disturbance in overendurance human athletes.

ABSTRACT. Pellagra caused the “3Ds” of Dementia and Diarrhoea plus a characteristic Dermatitis (Casal’s necklace). Pellagra was an intriguing ecological model of premature ageing and of societal and transgenerational breakdown. In 18thC European epidemics it was recognised as an atavistic degeneration of evolutionary importance but this, like the broad neuropsychiatric phenotype, has been forgotten. Pellagra is caused by Nicotinamide (Vitamin B3) deficiency on a low meat and high maize diet - a reverse on the meat-rich omnivorous diet on which we evolved our cognitive strengths. Gut dysbioses were common as was TB – the latter association is curious as TB excretes nicotinamide that is an anti-TB antibiotic as are analogues, such as Isoniazid. Under some dietary circumstances this may be a nutritional symbiotic-dysbiotic relationship “farming” TB within immunologically fenced granulomas. We link the unexplained reduction of TB in the UK 1850-1950 with increased meat (and nicotinamide) intake and consequently with disease and demographic transitions toward longevity and immune intolerance with more auto-immune disease and lower fertility. This transition can reverse at times of dietary stress in wars. Correlations will be shown between increased meat intake and longevity with lowered TB and fertility rates mirrored across the contemporary world. Suppression of the need to utilise the “in house” tryptophan degradation pathway to yield nicotinamide known to affect immune tolerance (including to the foetus) could provide a biochemical mechanism - including for the “Hygiene hypothesis” as “Old Friends” such as TB disappear. (Rook G. 2019: The Immune System in the Oxford Textbook of Evolutionary Medicine by Brune M & Schiefenhovel W).

ABSTRACT. Background: A strike with a sporting implement in effect is a cod from the stance or in the stride with initial rotation at the hips followed by the shoulders and upper arms. A cod in the first half of a running stride after heel strike with the position of internal rotation, adduction and flexion of the hip, with knee flexion allowing increased external rotation and abduction at the knee has been suggested as a position of risk. Programs to prevent injuries, in particular rupture of the anterior cruciate ligament, have met mixed results with interest in proximal muscles playing a role in stabilizing joints. Training in the sagittal plane has not improved change of direction performance.   Aims: Analysis of the role of GM in the kinetics and kinematics of the lower limb in cod   Methods: Literature review   Results: GM moment arms are changed in all three planes by the greater trochanter in humans by providing a pulley effect with flexion of the hip providing torque in cod.   Discussion and Conclusions: In the first half of the stride in deceleration after lateral foot placement from the line of the stride,cod may be initiated by horizontal abduction of the distal insertion portion of GM with the knee in neutral or varus position. In propulsion,the secound half of the stride,the proximal insertion portion of GM externally rotates the hip further,increasing the torque rotating the pelvis with the leg moving into the “position of risk”. This position now termed “the position of increased performance “ angles the ground reaction force by the lower leg further away from the centre of mass enabling generation of more angular momentum while limbs are closer to the vertical axis through the centre of mass.

Specificity training is suggested with the incentive of improved performance.

ABSTRACT. Background Anatomy related to bipedalism

Aims Comparative and functional anatomy of pelvic rotation in man and chimpanzee.

Methods Literature review

Results The majority of moment arms of the muscles across the human hip increase their tendency towards internal rotation as flexion of the hip progresses from zero to ninety degrees.

As expected, internal rotation torque increases considerably as the hip flexes, but external rotation torque also increases unexpectedly up to five percent.

Gluteus maximus (GM)moment arms previously assessed are altered in all three planes by the greater trochanter in man providing a pulley effect with flexion of the hip as the greater trochanter slides medially to GM pushing it laterally.

Superficial GM and its tendinous insertion to the ileotibial band, shifts progressively anteriorly over the greater trochanter with increasing flexion.

This effect is enhanced by the angle of inclination of the femur..

Discussion and Conclusions: The deep posterior quarter of GM likely evolved from Ischiofemoralis in chimpanzees by moving its distal insertion proximally, improving external rotation of the hip.

The stronger biarticular connection of GM with greater moment arms stabilizes the more flexible knee in transfer of increased torque in the coronal and transverse planes from hip to tibia and in a closed chain horizontally abducts the hip to rotate the pelvis with increased flexion.

Insertion of posterior GM, via the posterior iliotibial band, stabilizes and holds external rotation of the tibia with flexion of the knee up to 90 degrees in a closed chain as it’s moment arm of insertion as it runs around and inferior to the femoral condyle becomes more ideally placed in the transverse plane.

Comparative anatomy from the big toe to the thumb involving transverse rotation evolved along with bipedalism.

Major implications are in research,sport performance and injury prevention.

ABSTRACT. Introduction: Autism Spectrum Disorder (ASD) is a large set of neurodevelopmental disorders of complex aetiology. A mix of genetic and environmental factors are likely to cause ASD. Genetic risk for autism comes from common genetic variation. Genomic imprinting refers to genes that have different expression patterns according to the parent of origin - being silenced when imprinted. Paternally active genes increase resource extraction from the mother and reduce resource burden on the father.

Children with ASD show consistent overgrowth during their first 1-2 years of life. Recently, it has been shown that children with higher birth weight and length have an increased risk of developing ASD. This overgrowth and apparent larger birth weight and length are consistent with the notion that a paternally biased genome might underlie the risk for ASD.

Methods: The study compared height, weight, head circumference and thoracic circumference for age-matched (ages 4-8 years old) male children with ASD (n=30) with neurotypical children (n=33).

Results: No clinically significant differences were found among the two groups.

Discussion/Conclusions: After weaning, relative paternal contribution to a child's somatic development would increase, thus one would expect paternally active genes to start changing the child's behaviour, so as to make the child less demanding of resources (overall, and thus also on the father), with a counterweight represented by maternally active genes. A relative overabundance of paternally active genes would explain the data presented here, that shows children with ASD being no different from controls. Given the fact presented by other studies, that children with ASD seem to get a head start in growth, the lack of differences found in this 4-8 years old group indicates that children with ASD might actually fall behind in somatic growth, or at least stagnate by middle childhood.

ABSTRACT. BACKGROUND: The work of nurses and correctional officers alike has long been pointed at as among the most stressful in the world. OBJECTIVE: The aim of the study was to evaluate the prevalence and level of occupational burnout among 214 hospital nurses and 201 correctional officers from Bulgaria. One of the focuses was to examine whether gender roles or occupational roles were more related to burnout. METHODS: The study used a descriptive cross-sectional inter-occupational comparative survey design. The sample was composed of employees working in two different occupations – nurses and correctional officers. A self-administered MBI-Bulgarian version questionnaire was used. The information was gathered at the work place of respondents between November 2014 and March 2015. The participation was voluntary, individually and anonymously without any financial compensation. The only qualification in the sample selection was that the employee had direct contact with patients and inmates respectively. Results were analyzed using descriptive statistics of the data (mean, standard deviation, number and percentage), and presented in the form of tables, using the SPSS 17.0. Other statistical analysis methods that were used include non-parametric analysis. A p-value of < 0.05 was considered as statistically significant level. RESULTS: The level of emotional exhaustion and personal accomplishment of nurses were significantly higher than that of correctional officers. Mean depersonalization score of correctional officers was significantly higher than that of nurses. Correctional officers demonstrated a higher prevalence of burnout syndrome compared with nurses. To examine whether gender is associated with burnout, Mann-Whitney U test was utilized to assess gender differences of correctional officers. Our results suggest that being male or female is not a critical determinant of burnout. CONCLUSION: Correctional officers were found to have a higher prevalence of burnout syndrome compared with nurses.

ABSTRACT. Adolescent depression is a major emerging public health issue (Hertz et al, 2016) with an increasing prevalence in the US (Mojtabai, 2016). Bullying during adolescence is associated with depression and suicidal idealization (Brunstein, 2007). Appearance-based bullying is most common in this age group (Jacobson, 2017). The “Oddity Effect”, a tendency for group living animals to preferentially not assort with phenotypically different individuals (Landeau, 1986), may represent a natural animal model for appearance-based bullying in humans. However, there currently are no identified model species. The goals of this study are to identify animal taxa in which the “Oddity Effect” has been reported as a first step in evaluating species with potential suitability as a model organism for appearance-based bullying. We used formal methods systematic review to identify the taxonomic range of species in which the “Oddity Effect” has been demonstrated. Twenty species including both invertebrate (plankton) and vertebral taxa (fish, birds, and mammals) were definitively determined to exhibit this collective behavior. Some emergent collective behaviors in non-human animals have been established to also occur in groups of humans (Neda et al, 2002; Milgram et al, 1969). The “Oddity Effect” is phenomenologically similar to several aspects of human appearance-based bullying. The species identified through this study may represent naturally-occurring models appearance-based bullying in humans. This study invites further investigation of the “Oddity Effect” in the identified species to provide insight in the investigation of evolutionary origins of appearance-based bullying and potentially larger xenophobic tendencies in humans.

ABSTRACT. The large freshwater snail Pomacea canaliculata is a constant and intractable pest to Thailand’s native fauna and agriculture plants. Thus, considerable research needs to be done on the molecular cellular events that take place during feeding and reproduction. We explored the neural control centre of P. canaliculata, targeting the cerebral/visceral ganglia to isolate genes responsible for driving chemoreception and reproductive behaviour. Through de novo transcriptome sequencing, we produced 60,377,982 raw reads corresponding to 4.9 Gb clean read data. From this, 179,974 contigs were assembled with Trinity and used to construct 82,029 unigenes. Distinct genes were then annotated with Blastx yielding 31,472 unigenes above the cut-off e-value set at 10-5 , with ESTscan database query analyses yielding up to 7,287 known unigene hits. Further analysis using Liquid Chromatography Mass Spectroscopy (LCMS), and our own pipeline for identification of G-protein coulpled receptors and peptides, it led to the identification of 30 gene transcripts directly involved primarily in reproduction for P. canaliculata. To target genes involved in chemoreception, we isolated the upper and lower tentacles of the snail and performed another transciptome analysis. Using CLC genomics suite (v.7.1), we performed a general assembly analysis of both tissues, with the analysis revealing ≈ 3.8 Gb and 4.15 Gb clean data respectively. From this 34 putative Gprotein coupled receptors were identified using THMM 2.0, with preliminary bioassays suggesting that anyone of these receptors could be stimulated by rice leave extract ( n = 74 ; p value = 0.003214). We expect that some of these receptors when activated, are the initial player in a signal transduction cascade which ultimately produces a nerve impulse that is transmitted to the brain stimulating chemoattracting behavior.

ABSTRACT. Objectives. Low degree of fluctuating asymmetry (FA) is proposed as a signal of developmental stability and good genetic quality, thus individuals with low FA should be in better biological condition and have better health. Facial FA levels are reflecting mostly the conditions of the first trimester of pregnancy, when the cardiovascular system and digestive tracts are developing. Therefore, we analyse a potential relationship between levels of facial FA and risk factors of cardiometabolic disease (i.e., hypertension and cholesterol levels). Method. The participants were 263 women aged 45-92 (mean=60.9; SD=10.94) and 81 men aged 47-87 (mean=64.9; SD=10.83) from rural population at the Mogielica Human Ecology Study Site in Southern Poland. Fasting blood sample was collected for cholesterol (total, LDL and HDL-cholesterol) levels analyses. Degree of facial FA was calculated from facial images, according to standard procedures. Age, body mass, smoking, diabetes, alcohol consumption and taking drugs lowering cholesterol were included as potential covariates in the analyses. Results. Among women lower level of facial FA was associated with lower risk of hypertension [OR=0.87; 95% CI: 0.76-0.99], lower concentration of total cholesterol (R2=0.12; p=0.04) and LDL-cholesterol (R2=0.05; p=0.02). Facial FA was not related to levels of HDL-cholesterol (p=0.19). No statistically significant results were observed for men. Conclusions. Our results suggest that among older women (but not men) higher degree of facial FA might be a visual biomarker of poorer health. This study adds to the growing body of evidence that favourable early developmental conditions are important for better later-life health and might be preferable from the evolutionary point of view.

ABSTRACT. Meinier is a county near the city of Geneva, Switzerland. Following an initial study aiming to identify its residents' health needs, the local authority formally engaged our Institute to try to resolve the problems disclosed, which were of socio-economic and psycho-social nature. Our objective was to demonstrate that a collaborative approach to implementing effective intersectorial health promotion works at county level and that there is a need for a new role for public health, working at county level. Numerous meetings of the inhabitants gradually developed into a community-wide dialogue, leading them to clearly define their requirements. Old people felt isolated and wished to remain in the village, rather than enter a nursing home elsewhere. Young families could not get established because of a lack of available housing and nonexistent day care facilities for children. Social links between people had diminished. Further difficulties arose from poor mobility. Given these findings the inhabitants drew together to develop a more equitable society, in a partnership between the authorities and our Institute. A participative intersectorial approach allowed a global program to be put together, which particularly united housing, urbanism, ecology and mobility. The project, driven completely by community participation, is now in its fourteenth year, its 40 million dollar budget adopted by community vote. One prominent aspect is the new village center, with its sheltered housing for the elderly, affordable accommodation for young families, child day care, a games library, shops and a restaurant as well as an intergenerational park and living space. The learning and experience gained in terms of community participation and of behavioral and social health determinants has been very important for all concerned.

A collaborative approach to implementing effective intersectorial health promotion works at county level and there is a need for a new health professional profile (the county practitionner).

ABSTRACT. Background: Approximately 47% of previously treated TB cases become multi-drug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) in Armenia. The major known risk factor is the TB treatment ‘lost to follow-up’ (LFU) associated with the insufficient TB knowledge. The aim of this study was to assess whether the level of education received by TB patients and their families during inpatient treatment might influence the MDR/RR-TB development in Armenia.

Methods: In 2016 utilizing the International Accreditation and WHO TB Care Standards we evaluated the level of Patient and Family Education (PFE) standard compliance, applying a mixed method study design. Data exploring practices and the level of policies applied were collected through 15 in-depth interviews and a standardized checklist and analyzed using scoring system converted to percentages. We also looked at 5-year (2012-2016) treatment outcomes for the pulmonary drug-susceptible TB patients to disclose any trend between LFU, and ‘treatment failure’ (TF) as indicators of MDR/RR-TB development.

Results: Several processes were not standardized and consistent leading to meet the PFE standard minimally (26%). The trend analysis showed a strong relation between the treatment outcomes throughout the years. Decrease in LFU rates in 2012-2013 (12.6% - 8.9%) and continuous increase in 2013-2015 (8.9% - 12.6%) resulted in similar tendency for TF one year later: (1.5% - 1.1%) in 2013-2014 and (1.1% - 1.6%) in 2014-2016 conforming that those drug-susceptible TB patients who discontinued treatment, most probably had relapses in the following year and failed the drug-susceptible TB treatment because became drug-resistant.

Conclusion: Lack of education/counseling of drug-susceptible TB patients during their treatment might lead to higher rates of LFU and facilitate the MDR/RR-TB development in Armenia.

ABSTRACT. Abstract Objective Oxidative stress due to iron overload is implicated in clinical manifestation of beta-thalassemia/hemoglobin E (beta-thal/HbE). In the present study, we investigated the cellular adaptation against oxidative stress in -Thal/HbE patients. Methods Twenty pediatric beta-thal/HbE patients and 20 healthy controls were recruited in the study. Oxidant status was determined by measurement of plasma lipid peroxidation, blood glutathione (GSH) and iron study. Expression of glutamate-cysteine ligase catalytic (GCLC) and a modifier (GCLM) subunit, heme oxygenase-1 (HO-1) and biliverdin reductase (BVR) were determined by Western blot analysis and reverse-transcription polymerase chain reaction. The electrophoretic mobility shift assay was performed to determine the role of Nrf2, a transcription factor involved in the cellular protection against oxidative stress. Results Blood samples from patients exhibited iron overload, elevation of lipid peroxidation and marked reduction of GSH. GCLC and GCLM was up-regulated about 3-4 fold when compared with controls. GCLC protein levels were correlated with serum iron. In thassemia. protein and gene expression of HO-1 were not difference from control whereas protein expression of BVR was increased. There was the enhanced binding activity of the oligonucleotide probe for Nrf2-driven antioxidant response element with nuclear protein from blood mononuclear cells of thalassemia subjects. Discussion The cellular response is operating in beta-Thal/HbE patients to defense with oxidant stress due to the iron overload. Such adaptive response is mediated by activation of Nrf-2 transcription factor, thereby up-regulates antioxidant enzyme GCLC and BVR to alleviate the stress.

ABSTRACT. Background: From the previous study in animals, Thumbergia laurifolia has been reported to possess anti-inflammatory effect. Its action might be similar to non-steroidal anti-inflammatory drugs, which commonly cause gastrointestinal side effects. Objective: To study the anti-ulcerogenic activity of T. laurifolia extract in animals. Materials and Methods: Male Sprague Dawley rats were used. Anti-ulcerogenic activity of T. laurifolia extract was tested by using four in vivo models including those the gastric ulcer was induced by HCl/EtOH, restraint water immersion stress, indomethacin as well as pylorus ligation model. Results: T. laurifolia extract at the doses of 100, 200 and 400 mg/kg caused the decrease of gastric ulcer formation induced by HCl/EtOH and restraint water immersion stress. Moreover, the extract at the doses of 200 and 400 mg/kg decreased the gastric ulcer formation induced by indomethacin. Regarding to the mechanism of anti-ulcerogenic action, the extract at the dose of 400 mg/kg decreased the gastric secretion as evidenced by the reduction of total acidity n the pylorus ligation model. Conclusion: The findings of this study indicates that the T. laurifolia extract possesses anti-ulcerogenic activity in animals.

ABSTRACT. Media health literacy have proven to be associated with health information seeking and with health literacy may be predicted by patient’s Shared Decision Making. This study adopts a cross-sectional design to investigate whether the information ability has the mediating/moderating effects between health literacy and shared medical decision making. All participants completed the health literacy, ehealth literacy, and shared medical decision making questionnaires, respectively. The shared medical decision making index was used as an outcome measure. The mediation models and mediating hypotheses were tested by applying hierarchical multiple regression analyses. The results of this study show that female health literacy scores higher than male, ehealth literacy and shared medical decision making; medical students’ Health education manual score was significantly higher than that of non-medical students. The finding suggests that the college students’ e-health literacy has fully mediating effects between health literacy and shared medical decision making. Overall, it is important for health providers to consider the notion that more ehealth literacy may sometimes, but not always, be better. Discussion highlights the need to examine nonlinear as well as linear relationships.

ABSTRACT. Background and Aim Childhood obesity remains the most important risk factor of developing type 2 diabetes, dyslipidemia and hypertension in children. In the U.S.A, the Center of Disease Control and Prevention (CDC) estimates that greater than one third of the children and adolescents were overweight or obese. In recent years, cases of pediatric type 2 diabetes in children have been diagnosed more frequently and at younger ages than previously seen. Pediatric obesity and type 2 diabetes are more likely to continue into adulthood. The objective of this study is to report the association of obesity in children 18 years old or younger with type 2 diabetes, dyslipidemia and hypertension.

Method The study population consisted of all patients seen in a pediatric endocrinology clinic. An analysis of ICD10 diagnosis codes was performed for a two year period from 2015 to 2016, to evaluate the association of diagnoses of obesity and abnormal weight gain with type 2 diabetes and other co-morbidities. Results: Of 250 overweight, obese or morbidly obese patients identified, thirty six patents (14%) had dyslipidemia, 26 (1%) had type 2 diabetes and 20 (less than 1 %) had hypertension.

Conclusion: The global pediatric obesity epidemic has allowed adult-type diseases to occur in children. Obese children may have the weight of adults and this has created the evolution of diseases which have been historically limited to adult population (ie: Type 2 diabetes) in children. All obese pediatric patients should be evaluated for comorbidities that include type 2 diabetes, dyslipidemia and hypertension. This screening should continue throughout life if obesity persists. The natural progression of comorbidity usually starts with dyslipidemia but often includes type 2 diabetes in adulthood. Early identification and therapy of these diseases in children can prevent their progression and complications.

ABSTRACT. Essential oils have been used for extensive applications of variety of wellness throughout documented history. With massive advancement in science, essential oils today have undergone numerous refining methods to give an improved effect. Determination of the antibacterial activities alone and in combination of lavender and chamomile essential oils is what the researched study explained. Three laboratory strains of cultured bacterial (Pseudomonas aeruginosa, ATCC 27858; Staphylococcus aureus, ATCC 6538 and Escherichia coli ATCC), were used in this analysis. The stock cultures were maintained at −20oC and the sub-cultured onto Tryptone Soya agar (TSA) was incubated at 37oC for 24 hours. The fractional inhibitory concentration index (FIC) was used in determining the oils interaction. The FIC was calculated by dividing the minimum inhibitory concentration (MIC) value of the combined essential oils with the MIC value of each essential oil placed in the combination. The ΣFIC was calculated by adding these two values. Lavender oil showed the greatest antimicrobial effect, with the lowest MIC values of 2mg/mL for both Pseudomonas aeruginosa and Escherichia coli and 4mg/mL for Staphylococcus aureus pathogens compared to chamomile oil when used individually. The combination of chamomile and lavender essential oils in various ratios indicated synergistic effect for all the nine ratios analysed. The minimum inhibitory concentration analysis indicated that these oils have favorable antimicrobial interactions when in combination, that are 100% and 70.4% synergistic and additive effects for the oils selected and this will offer potential for the common use of combining oils in achieving a greater therapeutic result.

ABSTRACT. Human pathogens need their host for survival and perpetuation. Some of these pathogens do not have any non-human reservoir and therefore killing humans is not considered in their long-term evolutionary interest. However, there are diseases like Human African Trypanosomiasis, Visceral Leishmaniasis, HIV, Ebola, and Tuberculosis which kill almost 100% to 50% of the untreated humans [1]. Pathogens that kill most of their host or cause severe sickness in the majority of the cases incur major cost in terms of transmission due to either host death or its immobility. This is one of the reasons why the spread of Ebola has been so limited [2]. But the diseases like Sleeping sickness, Visceral Leishmaniasis, HIV and TB have managed to not only kill their most of the hosts but have also thrived within the population. This could be understood by the “Killer move” hypothesis. These pathogens move into the body of their new human hosts much before they kill the primary infected ones. The cost that they incur from the death of the host gets significantly lowered due to the delayed virulence. This evolutionary balance has helped these deadly diseases to sustain themselves within the human population. This strategy is no lesser than a “killer move” and we should be worried of an emerging pathogen, which is inherently virulent and could be evolutionarily favoured for such a strategy. These types of pathogens have always been a major threat to humans.

References:

1. https://en.wikipedia.org/wiki/List_of_human_disease_case_fatality_rates 2. https://www.who.int/csr/disease/ebola/one-year-report/factors/en/

ABSTRACT. It is widely appreciated that humans evolved to be physically active, and that physical activity is good for your health. But why and to what extent is exercise (that is, voluntary unnecessary physical activity for the sake of health and fitness) medicine? In this talk, I will make the case that a medicalized perspective on exercise (Exercise is Medicine®) excludes important evolutionary insights that have practical value for resolving widespread confusion and controversies over the relationship between exercise dose and type and chronic non-infectious diseases. Using heart disease and osteoarthritis as test cases, I will tackle four issues. First to what extent is physical inactivity a mismatch? Second, how and why does physical activity slow aging? Third, to what extent does exercise lead to trade-offs that potentially compromise health? I will conclude by exploring how an evolutionary perspective on exercise can help bridge the gap between evolutionary medicine as a field of academic inquiry and a practical tool to help prevent and treat disease.

ABSTRACT. Understanding the forces that shape variation in host-associated bacterial communities within- and between host species is key to understanding the evolution and maintenance of metaorganisms, and importantly, recent studies indicate that coevolving microbial taxa are more likely to be associated with human disease. In this study, we used a combined approach to investigate evolutionary divergence in the gut microbiome between the Eastern Mus musculus musculus and the Western Mus musculus domesticus mouse subspecies. This includes (i) a survey of gut microbial variation across the geographic range of the two subspecies, (ii) QTL mapping of gut microbial traits in a cross involving hybrids of the two subspecies, and (iii) cultivation and bacterial genome sequencing of microbial traits identified in both (i) and (ii). Accordingly, indicator species analysis reveals taxa belonging to Bacteroides and Lactobacillus as potentially important microbial traits that differ between species. By performing QTL mapping in 320 second-generation hybrid intercrossed mice, we identified a total of 28 unique host loci involving 41 bacterial taxa, including the previously identified Bacteroides and Lactobacillus indicator taxa. Analysis of host candidate genes points towards circadian rhythms as an important trait, whose host genetic- and/or microbial basis may have diverged since the common ancestor of the two species. Given the emerging relationships between disturbances in circadian rhythms, the gut microbiome and metabolic disorders, an understanding of ongoing evolution of these traits in the mouse model system may provide important insight and potential targets for treating human metabolic disorders.

ABSTRACT. Aging is a complex process, with many associated time-dependent phenotypes. The gut microbiota has long been postulated as an important factor in shaping healthy aging. It is now known that the microbiota composition changes during aging, with taxa that are rare in adults becoming dominant in the elderly and shifting towards more beneficial microbes further occurring in centenarians. The observation that inflammation, associated with aging, can modulate and be modulated by the microbiota further supports the microbes as a key piece for the aging multifactorial process. The combination of the time-dependent inflammatory and ecological processes should lead to an altered pattern of evolutionary change of a gut commensal lineage. Aiming at testing this hypothesis we performed a genomic analysis of a labelled bacterial strain comparing the pattern and rate of evolution in cohorts of old and young adult mice, with controlled genetic and lifestyle factors. Overall, this study examines mechanisms of bacterial adaptation in aging mammals and will contribute to understanding the role of evolution to the diversity of the microbiota and its genetic structure in the context of aging.

ABSTRACT. Microbes living with hosts can protect them against pathogen infection. Although microbes can have great evolutionary potential, the conditions under which they might evolve to protect their host remain elusive. It is hypothesized that a high risk of infection favours the evolution of protective traits by microbes, but infection is often temporally heterogeneous in nature (e.g., seasonality). We thus tested the effect of temporal heterogeneity in infection on the evolution of microbe-mediated protection. We experimentally coevolved protective microbes, Enterococcus faecalis, with populations of Caenorhabditis elegans nematode hosts, in treatments varying the infection frequency with virulent Staphylococcus aureus. Temporal heterogeneity involved pathogen exposure every host generation, alternating host generations, every fifth host generation or never, and we additionally investigated the effect of initial pathogen presence. Our results show that microbe-mediated protection evolved in those host-E.faecalis associations under constant or alternating generations of pathogen infection. Initial exposure to the pathogen did not influence the evolutionary outcome. Overall, our results indicate, that pathogen presence is required in sufficiently small intervals to drive the evolution of microbe-mediated protection. The results from this study illuminate the relationship between temporal variation in pathogen infection and selection for host-protection by an organism’s resident microbiota.

ABSTRACT. Human microbiomes influence health and well-being in myriad ways, both beneficial and detrimental. The oral microbiome is associated with both local and systemic inflammatory diseases and poor oral health may indicate poor systemic health. Ancient dental calculus provides a unique opportunity to study an authentic human microbiome prior to introduction of industrialization-associated changes, such as high-sugar diets and antibiotic use, that are considered contributors to modern systemic inflammatory diseases. Data from such studies may reveal methods of adaptation by the microbiome that are discordant with host physiology and promote industrialization-associated metabolic disorders, and, further, may suggest microbiome-targeted therapies. Defining a historical normal oral microbiome is critical to identifying microbiome changes, and here we characterize historic dental calculus from a cohort of 48 Victorian-period British individuals and compare it to modern dental calculus and modern dental plaque. Dental calculus does not typically accumulate as much today as historically, and clinical oral microbiome research studies focus primarily on living dental plaque biofilm. However, plaque and calculus reflect different conditions of the oral biofilm, and differences in microbial characteristics between the sample types have not yet been systematically explored. Comparisons between microbial, protein, and metabolomic profiles revealed distinct taxonomic and metabolic functional profiles between plaque, modern calculus, and historic calculus, but not between calculus collected from healthy teeth and periodontal disease-affected teeth. Bacterial species co-exclusion was related to biofilm environment. Proteomic profiling revealed that healthy-tooth samples contain low levels of bacterial virulence proteins and a robust innate immune response. Overall, we find that there are there are systematic microbial differences between plaque and calculus related to biofilm physiology, and recognizing these differences is important for accurate data interpretation in studies comparing dental plaque and calculus.

ABSTRACT. Adaptive therapy (AT) aims to control tumour burden by maintaining therapy-sensitive cells to exploit their competition with resistant cells. This relies on the assumption that resistant cells have impaired cellular fitness. Using a model of resistance to a pharmacological cyclin-dependent kinase inhibitor (CDKi), we have shown that this assumption is valid when competition between cells is spatially structured. We generated CDKi-resistant cancer cells and found that they have reduced proliferative fitness and stably rewired cell cycle control pathways. Low-dose CDKi outperformed high-dose CDKi in controlling tumour burden and resistance in tumour spheroids, but not in monolayer culture. We have further used mathematical modelling to examine how tumour spatial structure can amplify the fitness penalty paid by resistant cells. This presentation will especially focus on the evolutionary theory that underlies AT, and on defining conditions under which the strategy promises to be most effective in the clinic.

ABSTRACT. In this talk I ask the question "can we optimize a life-style change or treatment against cancers, so as to both have minimal impacts on health and meet therapeutic objectives"? I present a general mathematical model that probe this problem and yield some surprising and promising findings.

ABSTRACT. The degradation of human health due to environmental exposures is likely greater than for any other cause of disease. Environmental exposures include environmental contaminants, dietary additives, pharmaceuticals and others. Unfortunately, many exposure-caused diseases are difficult to discover and predict, often being revealed only after decades of retrospective research. This problem highlights the great need for more sensitive methods to detect health degradation. We have developed such a methodology, called Organismal Performance Assay (OPA), which utilizes the extreme competition present in mouse societies to reveal health and performance differences between treatment and control mice competing in seminatural enclosure populations. We will overview published and unpublished data evaluating the efficacy of OPAs to reveal health degradation, where other modern assessment approaches have failed; examples include 1) health consequences of three recalled or blacklisted pharmaceuticals, 2) the genomic swapping of paralogous Hox genes, 3) the first demonstration of health degradation due to human relevant doses of dietary refined sugars, and 4) inbreeding depression. Since the major readout of OPAs is reproductive success (Darwinian fitness), the interpretation is clear, and allows direct comparison of insults; prompting questions such as: would you rather be on the American diet or have had your parents be first cousins? OPAs suggest it is a toss-up, as both result in a 35% loss of fitness. The toxicology community has embraced new sets of tools made possible by modern molecular approaches. We submit that in vitro and ex vivo approaches have proven insufficient, failing to detect adversity due either to having ambiguous measures of health or failure to stress-test the relevant systems. With ambiguous testing methods, and a policy of innocent until proven guilty, the bulk of the toxicity testing burden falls on the public. OPAs show promise of being an important contributor for fulfilling this public health demand.

ABSTRACT. There is tremendous value in professionals in fields such as evolutionary medicine and public health sharing their expertise with a broad, general audience. However, systems of evaluation and reward for academics typically place a strong emphasis on publishing in peer-reviewed venues, while most publications for a general audience are not peer-reviewed. Several models have been developed for the publication of peer-reviewed papers that review scientific topics for a broad audience, however there have been few such efforts in evolutionary biology and related disciplines. I present analyses of a variety of article metrics, demonstrating that when this approach has been tried, these papers have been very well read and received. For example, every single “Topic Page” that has been published in PLOS Computational Biology and PLOS Genetics has received a greater number of views than the average research paper published in that journal during the same month. Even more telling, each of these review articles for a general audience has received a greater number of citations in peer-reviewed journals than the average research paper in the same journal. Reviews for general audiences in other publications, including the journal Genetics and the online publication Nature Knowledge similarly show high rates of being cited in peer-reviewed journals. This suggests opportunities for researchers to reach both professional and general audiences with broad-audience review papers. It further suggests that scientific journals can both disseminate disciplinary knowledge to a broad audience, and boost impact factors and other journal metrics by incorporating appropriate types of reviews intended for general audiences.

ABSTRACT. While most of the data on early life plasticity originate from longitudinal, epidemiological or anthropological studies of living people, bioarchaeology (the study of past populations in their archaeological context) can provide extensive insight into the developmental origins of health and disease from a deep time perspective. Through the study of human remains, we can collect information about patterns across the life course analogous to longitudinal analyses, considered the gold standard for studies of contemporary populations. Here, we provide an overview of the contributions bioarchaeology can make to evolutionary medicine using the DOHaD framework. We demonstrate insights that can be gained by leveraging evidence in three research directions that have made significant contributions to the field. These are: i) consideration of transition states (demographic, epidemiological, nutritional), ii) evidence of social inequalities, and iii) bioarchaeological studies of children and childhood. Through these three approaches and using case studies, we will explore the insights provided by bioarchaeology concerning the nature of individual frailty and stress responses as well as the influence of critical windows in growth and development on later life health experiences. We explore the nature of population responses to changing environmental conditions and provide a deep time perspective into how these responses have shaped health experiences in the past. In a world with increasing socioeconomic disparity, we also demonstrate how the bioarchaeological record, by drawing upon past contexts, can inform our understanding of the social determinants of health. While critically evaluating both the strengths and limitations of bioarchaeological data, we thus demonstrate the significant contributions that can be made to evolutionary medicine through the direct examination of osteological remains from archaeological populations, as well as the relevance of these contributions to current population adaptation and response.

ABSTRACT. Paleopathology is the study of ancient diseases. By using skeletal and mummified remains as well as indirect evidence such as images or other historical data pathologies are studied. Often - but not always - these studies are focusing on historic times spans only not on larger evolutionary timespans. Nevertheless, the established discipline of paleopathology can contribute to the field of evolutionary medicine; exemplary, since the evolution and secular trends of disease and its contributing factors can be very fast. The aim of this keynote lecture is to highlight not only the general impact and pitfalls of paleopathology as a discipline but with s specific focus on the evolution of disease. A major issue is the apparent lack of evidence is some paleopathological cases as well as the fact that often e.g., methodologies are not specifically tested for such ancient samples. Based on our long-term experience, challenges such as how to define undisputed criteria for providing sound paleopathological data will be presented. Disease load and its very specific impact on an individual both, purely physiologically but also functionally, are often difficult to assess retrospectively only. Therefore, some of our most recent studies used comparative well-documented case series to address this. Finally, in this presentation the need for an “Paleo-One Health initiative” will be outlined. With such evidence-based criteria and with the incorporation of holistic ecological data, paleopathology - as a discipline - shall be most beneficial for the advancement of the research field of evolutionary medicine.

ABSTRACT. Humans are the only living hominoid that habitually stands upright and walks on two legs. The adoption of erect posture as habitual imposed substantial changes on spinal morphology and biomechanics. One of the major morphological changes is the increased curvatures found in the human spine. There is an ongoing debate about whether humans ''pay'' for becoming bipedal by suffering from a high prevalence of back pain and spinal pathology. In order to answer this question, we explored the relationship between sagittal spinal posture and spinal pathologies, back pain, and health-related quality of life. We found that spinal posture closely correlates with spinal pathology. Individuals with a well-aligned spine – within the neutral zone defined as moderate spinal curvatures and the line of gravity close to the acetabulum – have a better quality of life, less back pain, and less spinal pathology. Individuals out of the neutral zone, with accentuated or with decreased pelvic incidence and spinal curvatures, are at a higher risk for developing spinal pathology, back pain, and reduced quality of life. All of this indicates that adopting an erect posture and bipedalism has an impact on human's spinal health because variation in curvatures outside the neutral zone is associated with more spinal pathology, back pain, and lower quality of life, than those within this zone.

ABSTRACT. The transfer of pathogens between animals and humans has occurred for millennia and remains a public health issue today. Although the focus has traditionally centred on pathogens transmitted from animals to humans (zoonoses), the reality is that the direction of transmission is just as often the other way (reverse zoonoses). This on-going cross-species transfer of pathogens is best understood through investigations of the environmental factors driving microbial evolution, in particular those affecting the transmission of a pathogen to a new host. The dramatic changes in domestic environments that occurred as human populations and their relationships with animals transitioned between hunting/foraging, herding/farming and urban/industrial had major impacts on pathogen evolution through the opportunities for transmission they provided, and on humans and animals by the resulting effects on pathogen virulence. These changes included crowding, often in unsanitary conditions, and the mixing of species whose interactions were much more limited than in their natural environments. Human induced environmental changes were often dramatic and both facilitated the evolution of new pathogens, i.e.: the morbilliviruses (canine distemper/measles/rinderpest), and expanded the transmission opportunities and host ranges of pathogens such as Mycobacterium spp and Burkholderia mallei. Although the challenges posed by the fragmentary nature of the archaeological record can make it difficult to definitively diagnose diseases in the past, an evolutionary perspective that considers how various domestic environments would impact pathogen transmission and virulence can provide important insights as to why specific diseases occurred when and where they did, and their potential for causing future outbreaks.

ABSTRACT. Mitochondria usually pass from mother to offspring, whereas males rarely transmit mitochondria. Selection is, therefore, blind to male-specific mitochondrial phenotypes. A mutation with a strongly deleterious effect in males but only a weak effect in females is nearly neutral, because only the female-specific consequences can be selected. This sex-biased `selective sieve' inevitably causes deleterious mitochondrial mutational effects to accumulate more strongly in males than in females. But the actual force could in fact be weak and of little consequence. So, does this asymmetric selective sieve truly impose a burden on male health? Several studies suggest that the answer might be yes. However, not enough data have been collected to provide a definitive answer. Modern genetic techniques suggest several new studies that could tell us more clearly whether this sex-biased selective filter shapes observed patterns of disease.