The role of heart rate on the associations between body composition and heart rate variability in children with overweight/obesity : the ActiveBrains project

Background: Heart rate variability (HRV) is negatively associated with body mass index and adiposity in several populations. However, less information is available about this association in children with overweight and obesity, especially severe/morbid obesity, taking into consideration the dependence of HRV on heart rate (HR). Objectives: (1) to examine associations between body composition measures and HRV, (2) to study differences in HRV between children with overweight and severe/morbid obesity; and (3) to test whether relationships and differences tested in objectives 1 and 2, respectively are explained by the dependency of HRV on HR. Methods: A total of 107 children with overweight/obesity (58% boys, 10.03 +/- 1.13 years) participated in this study. Body composition measures were evaluated by Dual-energy X-ray absorptiometry (DXA). HRV parameters were measured with Polar RS800CXR (R). Results: Body composition measures were negatively associated with HRV indicators of parasympathetic activity (beta values ranging from -0.207 to -0.307, all p 0.05). Conclusion: All associations between adiposity/obesity and HRV could be explained by HR, suggesting a key confounding role of HR in HRV studies in children with weight disturbances

Levels of Physical Activity at Age 10 Years and Brain Morphology Changes from Ages 10 to 14 Years

Importance: Physical activity may promote healthy brain development in children, but previous research was predominantly cross-sectional and included small samples, providing limited knowledge. Objective:To investigate the longitudinal associations of physical activity with brain morphology changes. Design, Setting, and Participants: A 4-year longitudinal population-based cohort study in Rotterdam, the Netherlands, embedded in Generation R, a cohort from fetal life onward. From the women enrolled during pregnancy, children who had repeated measures of brain structure at ages 10 (range 8 to 12) years and 14 (range 13 to 15) years were included. Data were collected from March 2013 to November 2015 (baseline) and from October 2016 to January 2020 (follow-up). Data were analyzed from April to December 2022. Exposure: At age 10 years, both the child and their primary caregiver reported the child's levels of physical activity with regard to sport participation, outdoor play, and total physical activity. Primary analyses were based on an average multi-informant report. Main outcomes and measures: Brain morphology was quantified by magnetic resonance imaging. Hypothesized regions of interest were the bilateral amygdala and hippocampal volumes. Global brain measures were studied to test the specificity of the hypothesis. Results: Data were available for 1088 children (566 girls [52%]; 693 [64%] Dutch). Their mean (SD) age at baseline was 10.1 (0.6) years. For amygdala volume change, positive associations with multi-informant reports of total physical activity (β = 2.6; 95% CI, 0.3-4.9) were found. Total physical activity was associated with hippocampal volume increases only when reported by the child (β = 3.1; 95% CI, 0.4-5.8). No robust associations with global brain measures were found. Conclusions and relevance: In this cohort study of 1088 children, more physical activity at 10 years was consistently associated with an increase in amygdala volume in children aged 10 to 14 years. Physical activity and increases in hippocampal volume were found using child reports of physical activity only. These findings suggest physical activity in late childhood was prospectively associated with volumetric changes in specific subcortical structures, but not to global brain development, from late childhood to early adolescence. These findings may inform the design of future public health interventions to best facilitate neurodevelopment with physical activity..</p

The effects of an exercise intervention on neuroelectric activity and executive function in children with overweight/obesity:The ActiveBrains randomized controlled trial

Objective: To investigate whether a 20-week aerobic and resistance exercise program induces changes in brain current density underlying working memory and inhibitory control in children with overweight/obesity. Methods: A total of 67 children (10.00 ± 1.10 years) were randomized into an exercise or control group. Electroencephalography (EEG)-based current density (μA/mm2) was estimated using standardized low-resolution brain electromagnetic tomography (sLORETA) during a working memory task (Delayed non-matched-to-sample task, DNMS) and inhibitory control task (Modified flanker task, MFT). In DNMS, participants had to memorize four stimuli (Pokemons) and then select between two of them, one of which had not been previously shown. In MFT, participants had to indicate whether the centered cow (i.e., target) of five faced the right or left. Results: The exercise group had significantly greater increases in brain activation in comparison with the control group during the encoding phase of DNMS, particularly during retention of second stimuli in temporal and frontal areas (peak t = from 3.4 to 3.8, cluster size [k] = from 11 to 39), during the retention of the third stimuli in frontal areas (peak t = from 3.7 to 3.9, k = from 15 to 26), and during the retention of the fourth stimuli in temporal and occipital areas (peak t = from 2.7 to 4.3, k = from 13 to 101). In MFT, the exercise group presented a lower current density change in the middle frontal gyrus (peak t = −4.1, k = 5). No significant change was observed between groups for behavioral performance (p ≥ 0.05). Conclusion: A 20-week exercise program modulates brain activity which might provide a positive influence on working memory and inhibitory control in children with overweight/obesity.</p

Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites

OBJECTIVE: Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and inflammation that promote lesion initiation. The transcription factor HIF1α (hypoxia-inducible factor 1α) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1α activation and the contribution of this noncanonical pathway to lesion initiation. APPROACH AND RESULTS: Quantitative polymerase chain reaction and en face staining revealed that HIF1α was expressed preferentially at low shear stress regions of porcine and murine arteries. Low shear stress induced HIF1α in cultured EC in the presence of atmospheric oxygen. The mechanism involves the transcription factor nuclear factor-κB that induced HIF1α transcripts and induction of the deubiquitinating enzyme Cezanne that stabilized HIF1α protein. Gene silencing revealed that HIF1α enhanced proliferation and inflammatory activation in EC exposed to low shear stress via induction of glycolysis enzymes. We validated this observation by imposing low shear stress in murine carotid arteries (partial ligation) that upregulated the expression of HIF1α, glycolysis enzymes, and inflammatory genes and enhanced EC proliferation. EC-specific genetic deletion of HIF1α in hypercholesterolemic apolipoprotein E-defecient mice reduced inflammation and endothelial proliferation in partially ligated arteries, indicating that HIF1α drives inflammation and vascular dysfunction at low shear stress regions. CONCLUSIONS: Mechanical low shear stress activates HIF1α at atheroprone regions of arteries via nuclear factor-κB and Cezanne. HIF1α promotes atherosclerosis initiation at these sites by inducing excessive EC proliferation and inflammation via the induction of glycolysis enzymes

Levels of ADAM10 are reduced in Alzheimer's disease CSF

BACKGROUND: The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of the amyloid precursor protein. This study assesses whether ADAM10 is present in cerebrospinal fluid (CSF), and whether it has potential as a biomarker for Alzheimer’s disease (AD). METHODS: ADAM10 was characterized in human CSF samples by immunoprecipitation and western blotting using antibodies specific for different domains of the protein and by ultracentrifugation in sucrose density gradients. Samples from AD patients (n = 20) and age-matched non-AD controls (n = 20) were characterized for classical CSF biomarkers, Aβ42, T-tau, or P-tau by ELISA, and assayed for soluble ADAM10 levels by western blotting. RESULTS: We found that ADAM10 is present in human CSF as several distinct species: an immature form retaining the prodomain (proADAM10; ~ 80 kDa), a mature unprocessed full-length form (ADAM10f; ~ 55 kDa), and a truncated large soluble form released from the membrane (sADAM10; ~ 50 kDa). Fractionation by ultracentrifugation on sucrose density gradients showed that the ADAM10f and sADAM10 species form large complexes. Immunoblotting revealed a significant decrease in ADAM10f and sADAM10 in AD CSF compared to control CSF, while proADAM10 levels remained unaltered. CONCLUSIONS: Several forms of ADAM10 are present in CSF, mainly assembled as high-molecular weight complexes. The determination of the levels of mature forms of CSF-ADAM10 may be useful as a biomarker for AD

A transient homotypic interaction model for the influenza A virus NS1 protein effector domain

Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins

From Heisenberg matrix mechanics to EBK quantization: theory and first applications

Despite the seminal connection between classical multiply-periodic motion and Heisenberg matrix mechanics and the massive amount of work done on the associated problem of semiclassical (EBK) quantization of bound states, we show that there are, nevertheless, a number of previously unexploited aspects of this relationship that bear on the quantum-classical correspondence. In particular, we emphasize a quantum variational principle that implies the classical variational principle for invariant tori. We also expose the more indirect connection between commutation relations and quantization of action variables. With the help of several standard models with one or two degrees of freedom, we then illustrate how the methods of Heisenberg matrix mechanics described in this paper may be used to obtain quantum solutions with a modest increase in effort compared to semiclassical calculations. We also describe and apply a method for obtaining leading quantum corrections to EBK results. Finally, we suggest several new or modified applications of EBK quantization.Comment: 37 pages including 3 poscript figures, submitted to Phys. Rev.

Associations of physical activity and screen time with white matter microstructure in children from the general population

Physical activity and sedentary behaviors have been linked to a variety of general health benefits and problems. However, few studies have examined how physical activity during childhood is related to brain development, with the majority of work to date focusing on cardio-metabolic health. This study examines the association between physical activity and screen time with white matter microstructure in the general pediatric population. In a sample of 2532 children (10.12 ± 0.58 years; 50.04% boys) from the Generation R Study, a population-based cohort in Rotterdam, the Netherlands, we assessed physical activity and screen time using parent-reported questionnaires. Magnetic resonance imaging of white matter microstructure was conducted using diffusion tensor imaging. Total physical activity was positively associated with global fractional anisotropy (β = 0.057, 95% CI = 0.016, 0.098, p = 0.007) and negatively associated with global mean diffusivity (β = −0.079, 95% CI = −0.120, −0.038, p 0.05). This study provides new evidence that physical activity is modestly associated with white matter microstructure in children. In contrast, complementing other recent evidence on cognition, screen time was not associated with white matter microstructure. Causal inferences from these modest associations must be interpreted cautiously in the absence of longitudinal data. However, these data still offer a promising avenue for future work to explore to what extent physical activity may promote healthy white matter development

Effects of an exercise program on cardiometabolic and mental health in children with overweight or obesity: a secondary analysis of a randomized clinical trial

Importance: Childhood obesity is a risk factor associated with type 2 diabetes, cardiovascular disease, and mental disorders later in life. Investigation of the parallel effects of a defined exercise program on cardiometabolic and mental health in children with overweight or obesity may provide new insights on the potential benefits of exercise on overall health. Objective: To investigate the effects of a 20-week exercise program on cardiometabolic and mental health in children with overweight or obesity. Design, Setting, and Participants: This secondary analysis of a parallel-group randomized clinical trial was conducted in Granada, Spain, from November 1, 2014, to June 30, 2016. Data analyses were performed between February 1, 2020, and July 14, 2022. Children with overweight or obesity aged 8 to 11 years were eligible, and the study was performed in an out-of-school context. Intervention: The exercise program included 3 to 5 sessions/wk (90 min/session) of aerobic plus resistance training for 20 weeks. The wait-list control group continued with their usual routines. Main Outcomes and Measures: Cardiometabolic outcomes as specified in the trial protocol included body composition (fat mass, fat-free mass, and visceral adipose tissue), physical fitness (cardiorespiratory, speed-agility, and muscular), and traditional risk factors (waist circumference, blood lipid levels, glucose levels, insulin levels, and blood pressure). Cardiometabolic risk score (z score) was calculated based on age and sex reference values for levels of triglycerides, inverted high-density lipoprotein cholesterol, and glucose, the mean of systolic and diastolic blood pressure, and waist circumference. An additional cardiometabolic risk score also included cardiorespiratory fitness. Mental health outcomes included an array of psychological well-being and ill-being indicators. Results: The 92 participants included in the per-protocol analyses (36 girls [39%] and 56 boys [61%]) had a mean (SD) age of 10.0 (1.1) years. The exercise program reduced the cardiometabolic risk score by approximately 0.38 (95% CI, -0.74 to -0.02) SDs; decreased low-density lipoprotein cholesterol level by -7.00 (95% CI, -14.27 to 0.37) mg/dL (to convert to mmol/L, multiply by 0.0259), body mass index (calculated as weight in kilograms divided by height in meters squared) by -0.59 (95% CI, -1.06 to -0.12), fat mass index by -0.67 (95% CI, -1.01 to -0.33), and visceral adipose tissue by -31.44 (95% CI, -58.99 to -3.90) g; and improved cardiorespiratory fitness by 2.75 (95% CI, 0.22-5.28) laps in the exercise group compared with the control group. No effects were observed on mental health outcomes. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, an aerobic plus resistance exercise program improved cardiometabolic health in children with overweight or obesity but had no effect on mental health. Trial Registration: ClinicalTrials.gov Identifier: NCT02295072.This project was supported with grants DEP2013-47540, DEP2016-79512-R, DEP2017-91544-EXP, and RYC-2011-09011 from the Spanish Ministry of Economy and Competitiveness and the Fondo Europeo de Desarrollo Regional (FEDER) and by grant PID2020-120249RB-I00 from the MCIN/AEI /10.13039/501100011033. Additional funding was obtained from the Andalusian Operational Programme supported with grant B-CTS-355-UGR18 from the European Regional Development Fund (FEDER in Spanish). Dr Cardenas-Sanchez is supported by grant FJC2018-037925-I from the Spanish Ministry of Science and Innovation and by a grant from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement No 101028929. Dr Migueles is supported by grant FPU15/02645 from the Spanish Ministry of Education, Culture and Sport, and grant 2012–00036 from the Swedish Research Council for Health, Working Life and Welfare. Dr Torres-Lopez is supported by grant FPU17/04802 from the Spanish Ministry of Science, Innovation and Universities. Dr Rodriquez-Ayllon was funded by grant DEP2017-91544-EXP from the Ramón Areces Foundation. Additional support was obtained from grant ALICIAK-2018 from the Alicia Koplowitz Foundation, University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence, Unit of Excellence on Exercise, Nutrition and Health, the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades; and grant DEP2005-00046/ACTI from the EXERNET Research Network on Exercise and Health in Special Populations. This research was supported by grant CB22/03/00058 from the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea–European Regional Development Fund