1. We assessed the hypothesized negative correlation between the influence of multiple predators and body condition and fecundity of the European hare, from 13 areas in the Netherlands. 2. Year-round abundance of predators was estimated by hunters. We quantified predator influence as the sum of their field metabolic rates, as this sum reflects the daily food requirements of multiple individuals. We determined the ratio between body mass and hindfoot length of hares as an index of body condition and the weight of their adrenal gland as a measure of chronic exposure to stress, and we counted the number of placental scars to estimate fecundity of hares. 3. As hypothesized, we found that the sum of field metabolic rate of predators was negatively correlated with body condition and the number of placental scars, whereas it was positively related to the weight of the adrenal glands. In contrast to the sum of the field metabolic rate, the total number of predators did not or weakly affect the investigated risk responses. 4. The sum of the field metabolic rate can be a useful proxy for the influence of multiple predators and takes into account predator abundance, type, body weight, and food requirements of multiple predators. 5. With our findings, our paper contributes to a better understanding of the risk effects of multiple predators on prey fitness. Additionally, we identify a potential contributor to the decline of European hare populations.
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New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose–response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals.
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Introduction: Strenuous physical stress induces a range of physiological responses, the extent depending, among others, on the nature and severity of the exercise, a person’s training level and overall physical resilience. This principle can also be used in an experimental set-up by measuring time-dependent changes in biomarkers for physiological processes. In a previous report, we described the effects of workload delivered on a bicycle ergometer on intestinal functionality. As a follow-up, we here describe an analysis of the kinetics of various other biomarkers. Aim: To analyse the time-dependent changes of 34 markers for different metabolic and immunological processes, comparing four different exercise protocols and a rest protocol. Methods: After determining individual maximum workloads, 15 healthy male participants (20–35 years) started with a rest protocol and subsequently performed (in a cross-over design with 1-week wash-out) four exercise protocols of 1-h duration at different intensities: 70% Wmax in a hydrated and a mildly dehydrated state, 50% Wmax and intermittent 85/55% Wmax in blocks of 2 min. Perceived exertion was monitored using the Borg’ Rating of Perceived Exertion scale. Blood samples were collected both before and during exercise, and at various timepoints up to 24 h afterward. Data was analyzed using a multilevel mixed linear model with multiple test correction. Results: Kinetic changes of various biomarkers were exercise-intensity-dependent. Biomarkers included parameters indicative of metabolic activity (e.g., creatinine, bicarbonate), immunological and hematological functionality (e.g., leukocytes, hemoglobin) and intestinal physiology (citrulline, intestinal fatty acid-binding protein, and zonulin). In general, responses to high intensity exercise of 70% Wmax and intermittent exercise i.e., 55/85% Wmax were more pronounced compared to exercise at 50% Wmax. Conclusion: High (70 and 55/85% Wmax) and moderate (50% Wmax) intensity exercise in a bicycle ergometer test produce different time-dependent changes in a broad range of parameters indicative of metabolic activity, immunological and hematological functionality and intestinal physiology. These parameters may be considered biomarkers of homeostatic resilience. Mild dehydration intensifies these time-related changes. Moderate intensity exercise of 50% Wmax shows sufficient physiological and immunological responses and can be employed to test the health condition of less fit individuals.
While the creation of an energy deficit (ED) is required for weight loss, it is well documented that actual weight loss is generally lower than what expected based on the initially imposed ED, a result of adaptive mechanisms that are oppose to initial ED to result in energy balance at a lower set-point. In addition to leading to plateauing weight loss, these adaptive responses have also been implicated in weight regain and weight cycling (add consequences). Adaptions occur both on the intake side, leading to a hyperphagic state in which food intake is favored (elevated levels of hunger, appetite, cravings etc.), as well as on the expenditure side, as adaptive thermogenesis reduces energy expenditure through compensatory reductions in resting metabolic rate (RMR), non-exercise activity expenditure (NEAT) and the thermic effect of food (TEF). Two strategies that have been utilized to improve weight loss outcomes include increasing dietary protein content and increasing energy flux during weight loss. Preliminary data from our group and others demonstrate that both approaches - especially when combined - have the capacity to reduce the hyperphagic response and attenuate reductions in energy expenditure, thereby minimizing the adaptive mechanisms implicated in plateauing weight loss, weight regain and weight cycling. Past research has largely focused on one specific component of energy balance (e.g. hunger or RMR) rather than assessing the impact of these strategies on all components of energy balance. Given that all components of energy balance are strongly connected with each other and therefore can potentially negate beneficial impacts on one specific component, the primary objective of this application is to use a comprehensive approach that integrates all components of energy balance to quantify the changes in response to a high protein and high energy flux, alone and in combination, during weight loss (Fig 1). Our central hypothesis is that a combination of high protein intake and high energy flux will be most effective at minimizing both metabolic and behavioral adaptations in several components of energy balance such that the hyperphagic state and adaptive thermogenesis are attenuated to lead to superior weight loss results and long-term weight maintenance.
