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Introduction Tilting the human body in different positions during both rest and exercise provides an opportunity to investigate circulatory reflex responses and hemodynamic adjustments in response to orthostatic stress (OS; [...], It was hypothesized that faster cardiorespiratory kinetics during exercise are associated with higher orthostatic tolerance. Cardiorespiratory kinetics of 14 healthy male subjects (30 [+ or -] 4 years, 179 [+ or -] 8 cm, 79 [+ or -] 8 kg) were tested on a cycle ergometer during exercise with changing work rates of 30 and 80 W. Pulmonary oxygen uptake ([??][O.sub.2pulm]) was measured breath-by-breath and heart rate (HR), mean arterial blood pressure (MAP), and total peripheral resistance (TPR) were measured beat-to-beat. Muscular oxygen uptake ([??][O.sub.2musc]) was estimated from HR and [??][O.sub.2pulm]. Kinetic parameters were determined by time-series analysis, using cross-correlation functions ([CCF.sub.max](x)) between the parameter and the work rate. Cardiovascular regulations of MAP, HR, and TPR during orthostatic stress were measured beat-to-beat on a tilt seat. Changes between the minima and maxima during the 6[degrees] head-down tilt and the 90[degrees] head-up tilt positions were calculated for each parameter ([[DELTA].sub.tilt-up]). [CCF.sub.max] ([??][O.sub.2musc]) correlated significantly with [DELTA][TPR.sub.tilt-up] (r = 0.790, p [less than or equal to] 0.001). [CCF.sub.max](HR) was significantly correlated with [DELTA][HR.sub.tilt-up] (r = -0.705, p = 0.002) and the amplitude in HR from 30 to 80 W ([r.sub.SP] = -0.574, p = 0.016). The observed correlations between cardiorespiratory regulation in response to exercise and orthostatic stress during rest might allow for a more differential analysis of the underlying mechanisms of orthostatic intolerance in, for example, patient groups. Key words: cardiovascular regulation, orthostatic stress, cardiorespiratory kinetics, tilting experiments, exercise, physical fitness, orthostatic tolerance. Nous avons pose l'hypothese selon laquelle la cinetique cardiorespiratoire plus rapide pendant l'exercice physique est associee avec une plus grande tolerance orthostatique. Nous avons etudie la cinetique cardiorespiratoire chez 14 sujets de sexe masculin en bonne sante (30 [+ or -] 4 ans, 179 [+ or -] 8 cm, 79 [+ or -] 8 kg) a l'aide d'une bicyclette ergometrique pendant un exercice physique avec des rythmes de travail variables de 30 et 80 W. Nous avons mesure le taux d'absorption de l'oxygene par les poumons ([??][O.sub.2pulm]) respiration par respiration et la frequence cardiaque (FC), la tension arterielle moyenne (TAM) et la resistance peripherique totale (RPT) battement par battement. Nous avons estime le taux d'absorption de l'oxygene par les muscles ([??][O.sub.2musc]) a partir de la FC et de la [??][O.sub.2pulm]. Nous avons etabli les parametres cinetiques par une analyse chronologique a l'aide de fonctions de correlation croisees ([FCC.sub.max](x)) entre le parametre et le rythme de travail. Nous avons mesure la regulation cardiovasculaire de la TAM, de la FC et de la RPT pendant un stress orthostatique battement par battement sur un siege basculant. Nous avons calcule les variations de chacun des parametres entre les minimums et les maximums pendant les positions de basculement tete vers le bas de 6[degrees] et basculement tete vers le haut de 90[degrees] (Abasc-haut). La [FCC.sub.max] ([??][O.sub.2musc]) etait nettement proportionnelle a la [DELTA][RPT.sub.basc-haut] (r = 0,790; p [less than or equal to] 0,001). La [FCC.sub.max](FC) etait nettement inversement proportionnelle a la [DELTA][FC.sub.basc-haut] (r = -0,705; p = 0,002), ainsi qu'a l'amplitude de la FC de 30 a 80 W ([r.sub.SP] = -0,574; p = 0,016). Les correlations observees entre la regulation cardiorespiratoire en reaction a l'exercice physique et l'orthostatisme au repos pourraient permettre de proceder a une etude plus differentielle des modes d'action sous-jacents de l'intolerance a l'orthostatisme, par exemple aupres de groupes de patients. [Traduit par la Redaction] Mots-cles : regulation cardiovasculaire, stress orthostatique, cinetique cardiorespiratoire, experiences de basculement, exercice physique, forme physique, tolerance orthostatique.

Purpose: Heart rate (HR), pulmonary and muscle oxygen uptake ([Formula: see text]O2pulm, [Formula: see text]O2musc) kinetics after changes of work rate (WR) indicate regulatory characteristics related to aerobic metabolism. We analysed whether the kinetics of HR, [Formula: see text]O2pulm and [Formula: see text]O2musc are slowed after missions to the International Space Station (ISS). The changes of the kinetics were correlated with [Formula: see text]O2peak data.Methods: 10 astronauts [4 females, 6 males, age: 48.0 ± 3.8 years, height: 176 ± 7 cm, mass: 74.5 ± 15.9 kg (mean ± SD)] performed an incremental test to determine [Formula: see text]O2peak (before missions on L-110 days, after return on R+1/+10/+36 days), and a cardio-respiratory kinetics test (CRKT) with randomized 30-80 W WR changes to determine HR, [Formula: see text]O2pulm and [Formula: see text]O2musc kinetics by time-series analysis (L-236/-73, R+6/+21). Kinetics were summarized by maximum and related lag of cross-correlation function (CCFmax, CCFlag) of WR with the analysed parameter.Results: Statistically, significant changes were also found for CCFmax([Formula: see text]O2musc) between L-236 and R+6 (P = 0.010), L-236 and R+21 (P = 0.030), L-72 and R+6 (P = 0.043). Between pre-to-post mission change in [Formula: see text]O2peak and CCFmax(HR), a correlation was shown (r SP = 0.67, P = 0.017).Conclusion: The [Formula: see text]O2musc kinetics changes indicate aerobic detraining effects which are present up to 21 days following space flight. The correlations between changes in [Formula: see text]O2peak and HR kinetics illustrate the key role of cardiovascular regulation in [Formula: see text]O2peak. The addition of CRKT to ISS flight is recommended to obtain information regarding the potential muscular and cardiovascular deconditioning. This allows a reduction in the frequency of higher intensity testing during flight. [ABSTRACT FROM AUTHOR]

During non-steady-state exercise, dynamic changes in pulmonary oxygen uptake (VO₂pulm) are dissociated from skeletal muscle VO₂ (VO₂musc) by changes in lung and venous O₂ concentrations (CvO₂), and the dynamics and distribution of cardiac output (CO) between active muscle and remaining tissues (Qrem). Algorithms can compensate for fluctuations in lung O₂ stores, but the influences of CO and CvO₂ kinetics complicate estimation of VO₂musc from cardio-pulmonary measurements. We developed an algorithm to estimate VO₂musc kinetics from VO₂pulm and heart rate (HR) during exercise. 17 healthy volunteers (28 ± 7 years; 71 ± 12 kg; 7 females) performed incremental exercise using recumbent cycle ergometry (VO₂peak 52 ± 8 ml min(-1) kg(-1)). Participants completed a pseudo-random binary sequence (PRBS) test between 30 and 80 W. VO₂pulm and HR were measured, and CO was estimated from HR changes and steady-state stroke volume. VO₂musc was derived from a circulatory model and time series analyses, by solving for the unique combination of venous volume and the perfusion of non-exercising tissues that provided close to mono-exponential VO₂musc kinetics. Independent simulations showed that this approach recovered the VO₂musc time constant (τ) to within 7% (R(2) = 0.976). Estimates during PRBS were venous volume 2.96 ± 0.54 L; Qrem 3.63 ± 1.61 L min(-1); τHR 27 ± 11 s; τVO₂musc 33 ± 8 s; τVO₂pulm 43 ± 14 s; VO₂pulm time delay 19 ± 8 s. The combination of stochastic test signals, time series analyses, and a circulatory model permitted non-invasive estimates of VO₂musc kinetics. Large kinetic dissociations exist between muscular and pulmonary VO₂ during rapid exercise transients. [ABSTRACT FROM AUTHOR]

Abstract Background Retinotectal map formation develops via topographically specific guidance and branching of retinal axons in their target area. This process is controlled, in part, by reverse signalling of ephrinAs expressed on retinal axons. As glycosylphosphatidylinositol-anchored molecules, ephrinAs require transmembrane co-receptors to exert this function, for which the two neurotrophin receptors, p75NTR and TrkB, were recently proposed. Results We show here that the ligands for these receptors, the brain-derived neurotrophic factor precursor (proBDNF) and its processed form, BDNF, respectively, control the branching of retinal axons antagonistically, which they mediate by inducing the corresponding neurotrophin receptor-ephrinA complexes. Moreover, scavenging proneurotrophins, by adding antibodies specific for the pro-domain of proBNDF or a soluble extracellular domain of p75NTR, abolish repellent ephrinA reverse signalling in the stripe assay. Conclusions This indicates that retinal cells secrete proneurotrophins, inducing the ephrinA-p75NTR interaction and enabling repellent axon guidance. The antagonistic functions of proBDNF and BDNF raise the possibility that topographic branching is controlled by local control of processing of proneurotrophins.

Abstract Background In the developing hindbrain, cranial motor axon guidance depends on diffusible repellent factors produced by the floor plate. Our previous studies have suggested that candidate molecules for mediating this effect are Slits, Netrin-1 and Semaphorin3A (Sema3A). It is unknown to what extent these factors contribute to floor plate-derived chemorepulsion of motor axons, and the downstream signalling pathways are largely unclear. Results In this study, we have used a combination of in vitro and in vivo approaches to identify the components of floor plate chemorepulsion and their downstream signalling pathways. Using in vitro motor axon deflection assays, we demonstrate that Slits and Netrin-1, but not Sema3A, contribute to floor plate repulsion. We also find that the axon pathways of dorsally projecting branchiomotor neurons are disrupted in Netrin-1 mutant mice and in chick embryos expressing dominant-negative Unc5a receptors, indicating an in vivo role for Netrin-1. We further demonstrate that Slit and Netrin-1 signalling are mediated by Rho-kinase (ROCK) and myosin light chain kinase (MLCK), which regulate myosin II activity, controlling actin retrograde flow in the growth cone. We show that MLCK, ROCK and myosin II are required for Slit and Netrin-1-mediated growth cone collapse of cranial motor axons. Inhibition of these molecules in explant cultures, or genetic manipulation of RhoA or myosin II function in vivo causes characteristic cranial motor axon pathfinding errors, including the inability to exit the midline, and loss of turning towards exit points. Conclusions Our findings suggest that both Slits and Netrin-1 contribute to floor plate-derived chemorepulsion of cranial motor axons. They further indicate that RhoA/ROCK, MLCK and myosin II are components of Slit and Netrin-1 signalling pathways, and suggest that these pathways are of key importance in cranial motor axon navigation.

Neuronal network formation is facilitated by recognition between synaptic cell adhesion molecules at the cell surface. Alternative splicing of cell adhesion molecules provides additional specificity in forming neuronal connections. For the teneurin family of cell adhesion molecules, alternative splicing of the EGF-repeats and NHL domain controls synaptic protein-protein interactions. Here we present cryo-EM structures of the compact dimeric ectodomain of two teneurin-3 isoforms that harbour the splice insert in the EGF-repeats. This dimer is stabilised by an EGF8-ABD contact between subunits. Cryo-EM reconstructions of all four splice variants, together with SAXS and negative stain EM, reveal compacted dimers for each, with variant-specific dimeric arrangements. This results in specific trans-cellular interactions, as tested in cell clustering and stripe assays. The compact conformations provide a structural basis for teneurin homo- and heterophilic interactions. Altogether, our findings demonstrate how alternative splicing results in rearrangements of the dimeric subunits, influencing neuronal recognition and likely circuit wiring., (© 2024. The Author(s).)

A biological understanding of the apparent sex bias in autism is lacking. Here we have identified Cntnap2 KO mice as a model system to help better understand this dimorphism. Using this model, we observed social deficits in juvenile male KO mice only. These male-specific social deficits correlated with reduced spine densities of Layer 2/3 and Layer 5 pyramidal neurons in the Anterior Cingulate Cortex, a forebrain region prominently associated with the control of social behaviour. Furthermore, in male KO mice, microglia showed an increased activated morphology and phagocytosis of synaptic structures compared to WT mice, whereas no differences were seen in female KO and WT mice. Our data suggest that sexually dimorphic microglial activity may be involved in the aetiology of ASD, disrupting the development of neural circuits that control social behaviour by overpruning synapses at a developmentally critical period., (© 2023. Springer Nature Limited.)

Purpose: Kinetics of cardiorespiratory parameters (CRP) in response to work rate (WR) changes are evaluated by pseudo-random binary sequences (PRBS testing). In this study, two algorithms were applied to convert responses from PRBS testing into appropriate impulse responses to predict steady states values and responses to incremental increases in exercise intensity., Methods: 13 individuals (age: 41 ± 9 years, BMI: 23.8 ± 3.7 kg m -2 ), completing an exercise test protocol, comprising a section of randomized changes of 30 W and 80 W (PRBS), two phases of constant WR at 30 W and 80 W and incremental WR until subjective fatigue, were included in the analysis. Ventilation ([Formula: see text]), O 2 uptake ([Formula: see text]), CO 2 output ([Formula: see text]) and heart rate (HR) were monitored. Impulse responses were calculated in the time domain and in the frequency domain from the cross-correlations of WR and the respective CRP., Results: The algorithm in the time domain allows better prediction for [Formula: see text] and [Formula: see text], whereas for [Formula: see text] and HR the results were similar for both algorithms. Best predictions were found for [Formula: see text] and HR with higher (3-4%) 30 W steady states and lower (1-4%) values for 80 W. Tendencies were found in the residuals between predicted and measured data., Conclusion: The CRP kinetics, resulting from PRBS testing, are qualified to assess steady states within the applied WR range. Below the ventilatory threshold, [Formula: see text] and HR responses to incrementally increasing exercise intensities can be sufficiently predicted., (© 2021. The Author(s).)

Introduction: Adequate cardiorespiratory fitness is of utmost importance during spaceflight and should be assessable via moderate work rate intensities, e.g., using kinetics parameters. The combination of restricted sleep, and defined physical exercise during a 45-day simulated space mission is expected to slow heart rate (HR) kinetics without changes in oxygen uptake ([Formula: see text]) kinetics., Methods: Overall, 14 crew members (9 males, 5 females, 37 ± 7 yrs, 23.4 ± 3.5 kg m -2 ) simulated a 45-d-mission to an asteroid. During the mission, the sleep schedule included 5 nights of 5 h and 2 nights of 8 h sleep. The crew members were tested on a cycle ergometer, using pseudo-random binary sequences, changing between 30 and 80 W on day 8 before (MD-8), day 22 (MD22) and 42 (MD42) after the beginning and day 4 (MD + 4) following the end of the mission. Kinetics information was assessed using the maxima of cross-correlation functions (CCF max ). Higher CCF max indicates faster responses., Results: CCF max (HR) was significantly (p = 0.008) slower at MD-8 (0.30 ± 0.06) compared with MD22 (0.36 ± 0.06), MD42 (0.38 ± 0.06) and MD + 4 (0.35 ± 0.06). Mean HR values during the different work rate steps were higher at MD-8 and MD + 4 compared to MD22 and MD42 (p < 0.001)., Discussion: The physical training during the mission accelerated HR kinetics, but had no impact on mean HR values post mission. Thus, HR kinetics seem to be sensitive to changes in cardiorespiratory fitness and may be a valuable parameter to monitor fitness. Kinetics and capacities adapt independently in response to confinement in combination with defined physical activity and sleep., (© 2021. The Author(s).)

Interstitial axon branching is an essential step during the establishment of neuronal connectivity. However, the exact mechanisms on how the number and position of branches are determined are still not fully understood. Here, we investigated the role of Arl8B, an adaptor molecule between lysosomes and kinesins. In chick retinal ganglion cells (RGCs), downregulation of Arl8B reduces axon branch density and shifts their location more proximally, while Arl8B overexpression leads to increased density and more distal positions of branches. These alterations correlate with changes in the location and density of lysosomes and autophagosomes along the axon shaft. Diminishing autophagy directly by knock-down of atg7, a key autophagy gene, reduces branch density, while induction of autophagy by rapamycin increases axon branching, indicating that autophagy plays a prominent role in axon branch formation. In vivo , local inactivation of autophagy in the retina using a mouse conditional knock-out approach disturbs retino-collicular map formation which is dependent on the formation of interstitial axon branches. These data suggest that Arl8B plays a principal role in the positioning of axon branches by spatially controlling autophagy, thus directly controlling formation of neural connectivity in the brain. SIGNIFICANCE STATEMENT The formation of interstitial axonal branches plays a prominent role in numerous places of the developing brain during neural circuit establishment. We show here that the GTPase Arl8B controls density and location of interstitial axon branches, and at the same time controls also density and location of the autophagy machinery. Upregulation or downregulation of autophagy in vitro promotes or inhibits axon branching. Local disruption of autophagy in vivo disturbs retino-collicular mapping. Our data suggest that Arl8B controls axon branching by controlling locally autophagy. This work is one of the first reports showing a role of autophagy during early neural circuit development and suggests that autophagy in general plays a much more prominent role during brain development than previously anticipated., (Copyright © 2020 the authors.)

INTRODUCTION: Changes in gravity or body position provoke changes in hydrostatic pressure in the arterial system and in venous return. Potential asymmetries between left (Q LV ) and right ventricular (Q RV ) cardiac output during transient gravity changes were investigated. It was hypothesized that blood volume is temporarily stored in the pulmonary vessels, with amount and duration depending on the level and directions of gravity. METHODS: Eight healthy, male subjects (32 ± 3 yr, 182 ± 7 cm, 82 ± 6 kg) were tested on a tilt seat (TS), in a long arm human centrifuge (laHC), and during parabolic flights (PF). The gravitational changes during PF were reconstructed by changing gravity in a laHC and different body positions on a TS. All participants were tested in the seated, resting position. Heart rate and blood pressure were recorded continuously and Q LV was calculated, applying the Modelflow Algorithm. Gas exchange was measured breath-by-breath. Q RV was calculated from these data according to the Fick Principle. Four sequences were superimposed and analyzed by ANOVA with the factors Time, Ventricle (Q RV , Q LV ), and Mode (TS, PF, laHC). RESULTS: After reductions in gravity Q RV and Q LV were transiently desynchronized. ANOVA showed no main effect for Mode, but significant changes were found for Time and Ventricle and all interactions. DISCUSSION: Phases of reduced gravity seem to lead to transiently increased storage of blood volume inside the pulmonary vascular system. A more detailed understanding of these mechanisms might help to describe the compliance of the pulmonary vascular system in diseases of the pulmonary circulation. Hoffmann U, Koschate J, Appell Coriolano H-J, Drescher U, Thieschäfer L, Dumitrescu D, Werner A. Adaptation of systemic and pulmonary circulation to acute changes in gravity and body position . Aerosp Med Hum Perform. 2019; 90(8):688-695.

Purpose: Fast muscular oxygen uptake ([Formula: see text]) kinetics are limiting factors for high exercise capacities. It is hypothesized that [Formula: see text] and heart rate (HR) kinetics would be faster in individuals, performing long-distance endurance training (CONT) compared with athletes performing predominantly interval-based sports (INT)., Methods: 17 subjects (INT: n = 7, 24 ± 5 years, 183 ± 7 cm, 85 ± 10 kg, 6 ± 3 h of training per week, CONT: n = 10, 37 ± 7 years, 175 ± 9 cm, 69 ± 10 kg, 6 ± 3 h of training per week) completed a treadmill work rate (WR) protocol with pseudo-randomized WR changes with velocities of 6.5 and 9.5 km h -1 . [Formula: see text]O 2musc and the respective kinetics were estimated from the measured pulmonary oxygen uptake and HR combined with a circulatory model. Kinetics information were calculated using time series analysis. Higher maxima of the cross-correlation function (CCF) of WR and the respective parameter ([Formula: see text], HR) indicate faster kinetics responses., Results: The kinetics of HR (INT: 0.23 ± 0.04 vs. CONT: 0.42 ± 0.18; P = 0.001), [Formula: see text]O 2pulm (0.30 ± 0.05 vs. 0.53 ± 0.20; P = 0.005) and [Formula: see text]O 2musc (0.31 ± 0.06 vs. 0.53 ± 0.16; P = 0.005) were significantly slower in INT compared with the CONT athletes., Conclusions: It seems that at least in the long-term CONT exercise, training without the need of changing intensities is favorable for fast [Formula: see text]O 2 and HR kinetics compared with INT exercise including frequently changing intensities.