Growth differentiation factor 15 (GDF15) is a stress-induced cytokine secreted into the circulation by a number of tissues under different pathological conditions such as cardiovascular disease, cancer or mitochondrial dysfunction, among others. While GDF15 signaling through its recently identified hindbrain-specific receptor GDNF family receptor alpha-like (GFRAL) has been proposed to be involved in the metabolic stress response, its endocrine role under chronic stress conditions is still poorly understood. Mitochondrial dysfunction is characterized by the impairment of oxidative phosphorylation (OXPHOS), leading to inefficient functioning of mitochondria and consequently, to mitochondrial stress. Importantly, mitochondrial dysfunction is among the pathologies to most robustly induce GDF15 as a cytokine in the circulation. The overall aim of this thesis was to elucidate the role of the GDF15-GFRAL pathway under mitochondrial stress conditions. For this purpose, a mouse model of skeletal muscle-specific mitochondrial stress achieved by ectopic expression of uncoupling protein 1 (UCP1), the HSA-Ucp1-transgenic (TG) mouse, was employed. As a consequence of mitochondrial stress, TG mice display a metabolic remodeling consisting of a lean phenotype, an improved glucose metabolism, an increased metabolic flexibility and a metabolic activation of white adipose tissue. Making use of TG mice crossed with whole body Gdf15-knockout (GdKO) and Gfral-knockout (GfKO) mouse models, this thesis demonstrates that skeletal muscle mitochondrial stress induces the integrated stress response (ISR) and GDF15 in skeletal muscle, which is released into the circulation as a myokine (muscle-induced cytokine) in a circadian manner. Further, this work identifies GDF15-GFRAL signaling to be responsible for the systemic metabolic remodeling elicited by mitochondrial stress in TG mice. Moreover, this study reveals a daytime-restricted anorexia induced by the GDF15-GFRAL axis under muscle mitochondrial stress, which is, mechanistically, mediated through the induction of hypothalamic corticotropin releasing hormone (CRH). Finally, this work elucidates a so far unknown physiological outcome of the GDF15-GFRAL pathway: the induction of anxiety-like behavior. In conclusion, this study uncovers a muscle-brain crosstalk under skeletal muscle mitochondrial stress conditions through the induction of GDF15 as a myokine that signals through the hindbrain-specific GFRAL receptor to elicit a stress response leading to metabolic remodeling and modulation of ingestive- and anxiety-like behavior.

Research on problem solving offers insights into how humans process task-related information and which strategies they use (Newell and Simon, 1972; Öllinger et al., 2014). Problem solving can be defined as the search for possible changes in one's mind (Kahneman, 2003). In a recent study, Adams et al. (2021) assessed whether the predominant problem solving strategy when making changes involves adding or subtracting elements. In order to do this, they used several examples of simple problems, such as editing text or making visual patterns symmetrical, either in naturalistic settings or on-line. The essence of the authors' findings is a strong preference to add rather than subtract elements across a diverse range of problems, including the stabilizing of artifacts, creating symmetrical patterns, or editing texts. More specifically, they succeeded in demonstrating that “participants were less likely to identify advantageous subtractive changes when the task did not (vs. did) cue them to consider subtraction, when they had only one opportunity (vs. several) to recognize the shortcomings of an additive search strategy or when they were under a higher (vs. lower) cognitive load” (Adams et al., 2021, p. 258). Addition and subtraction are generally defined as de-contextualized mathematical operations using abstract symbols (Russell, 1903/1938). Nevertheless, understanding of both symbols and operations is informed by everyday activities, such as making or breaking objects (Lakoff and Núñez, 2000; Fischer and Shaki, 2018). The universal attribution of “addition bias” or “subtraction neglect” to problem solving activities is perhaps a convenient shorthand but it overlooks influential framing effects beyond those already acknowledged in the report and the accompanying commentary (Meyvis and Yoon, 2021). Most importantly, while Adams et al.'s study addresses an important issue, their very method of verbally instructing participants, together with lack of control over several known biases, might render their findings less than conclusive. Below, we discuss our concerns that emerged from the identified biases, namely those regarding the instructions and the experimental materials. Moreover, we refer to research from mathematical cognition that provides new insights into Adams et al.'s findings.

Children’s physical fitness development and related moderating effects of age and sex are well documented, especially boys’ and girls’ divergence during puberty. The situation might be different during prepuberty. As girls mature approximately two years earlier than boys, we tested a possible convergence of performance with five tests representing four components of physical fitness in a large sample of 108,295 eight-year old third-graders. Within this single prepubertal year of life and irrespective of the test, performance increased linearly with chronological age, and boys outperformed girls to a larger extent in tests requiring muscle mass for successful performance. Tests differed in the magnitude of age effects (gains), but there was no evidence for an interaction between age and sex. Moreover, “physical fitness” of schools correlated at r = 0.48 with their age effect which might imply that "fit schools” promote larger gains; expected secular trends from 2011 to 2019 were replicated.

Computation of the instantaneous phase and amplitude via the Hilbert Transform is a powerful tool of data analysis. This approach finds many applications in various science and engineering branches but is not proper for causal estimation because it requires knowledge of the signal’s past and future. However, several problems require real-time estimation of phase and amplitude; an illustrative example is phase-locked or amplitude-dependent stimulation in neuroscience. In this paper, we discuss and compare three causal algorithms that do not rely on the Hilbert Transform but exploit well-known physical phenomena, the synchronization and the resonance. After testing the algorithms on a synthetic data set, we illustrate their performance computing phase and amplitude for the accelerometer tremor measurements and a Parkinsonian patient’s beta-band brain activity.

Background Coronavirus disease (COVID-19) has a severe impact on all aspects of patient care. Among the numerous biomarkers of potential validity for diagnostic and clinical management of COVID-19 are biomarkers at the interface of iron metabolism and inflammation. Methods The follow-up study included 54 hospitalized patients with laboratory-confirmed COVID-19 with a moderate and severe/critical form of the disease. Iron deficiency specific biomarkers such as iron, ferritin, transferrin receptor, hepcidin, and zinc protoporphyrin (ZnPP) as well as relevant markers of inflammation were evaluated twice: in the first five days when the patient was admitted to the hospital and during five to 15 days; and their validity to diagnose iron deficiency was further assessed. The regression and Receiver Operating Characteristics (ROC) analyses were performed to evaluate the prognosis and determine the probability for predicting the severity of the disease in the first five days of COVID-19. Results Based on hemoglobin values, anemia was observed in 21 of 54 patients. Of all iron deficiency anemia-related markers, only ZnPP was significantly elevated (P<0.001) in the anemic group. When patients were grouped according to the severity of disease, slight differences in hemoglobin or other anemia-related parameters could be observed. However, the levels of ZnPP were significantly increased in the severely ill group of patients. The ratio of ZnPP to lymphocyte count (ZnPP/L) had a discrimination power stronger than the neutrophil to lymphocyte count ratio (N/L) to determine disease severity. Additionally, only two markers were independently associated with the severity of COVID-19 in logistic regression analysis; D-dimer (OR (5.606)(95% CI 1.019–30.867)) and ZnPP/L ratio (OR (74.313) (95% CI 1.081–5108.103)). Conclusions For the first time ZnPP in COVID-19 patients were reported in this study. Among all iron-related markers tested, ZnPP was the only one that was associated with anemia as based on hemoglobin. The increase in ZnPP might indicate that the underlying cause of anemia in COVID-19 patients is not only due to the inflammation but also of nutritional origin. Additionally, the ZnPP/L ratio might be a valid prognostic marker for the severity of COVID-19.