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Game-based learning is supposed to motivate learners. However, to what degree does motivation driven by interest in playing an instructional game affect learning outcomes compared to motivation driven by interest in the very learning process? This is not known. In this study with a unique design and intervention, young adults (N = 128; a heterogeneous sample) learned how to control an electro-mechanical device in a 40-minute-long learning session integrated into a 2-hour-long educational live action role-playing game (edu-LARP). Edu-LARPs are supposedly engaging games where players take part in team role-playing by physically enacting characters in a fictional universe. In our edu-LARP, players had to understand how the to-be-learned device worked in order to win the game. Departing from typical game-based learning research, learning- and playing-related variables were assessed for each learner separately (i.e., a within-subject design). Affective-motivational factors related to playing (rather than learning) predicted learning outcomes in a positive, but considerably weaker, way compared to learning-related, affective-motivational factors. Developed interest in LARP-like games was primarily related to enjoying the game rather than better learning outcomes; whereas, developed interest in the instructional domain was primarily related to enjoyment of learning and better learning outcomes. Overall, autonomous motivation to play was connected to higher learning outcomes, but this connection was weak.

The effects of neomycin on human neutrophils (PMN) were studied with respect to the generation of leukotrienes, the involvement of guanine triphosphate binding proteins (G proteins) and the polymerization of actin. Incubation of neutrophils with neomycin induced the generation of low amounts of leukotrienes. Co-incubation of neutrophils with neomycin and the direct G-protein activator sodium fluoride (NaF) resulted in an enhanced leukotriene formation at 0.5 mM neomycin and an inhibition at a concentration of 10 mM. Simultaneous incubation with neomycin and formyl-methionyl-leueyl-phenylalanine (FLMP) did not affect the FMLP-induced leukotriene formation. However, pretreatment of neutrophils with 10 mM neomycin followed by the addition of NaF or FMLP resulted in an enhanced generation of leukotrienes. Crude membrane fractions of PMN incubated with neomycin at different concentrations showed an enhanced (0.5 mM) as well as a reduced (10 mM) guanine triphosphatase activity. Furthermore, incubation of neutrophils with neomycin above a concentration of 0.5 mM led to the depolymerization of actin. The presented results show inhibitory and stimulatory effects of neomycin on various cell functions, which may reflect differences in transmembrane signalling. [ABSTRACT FROM AUTHOR]

Human polymorphonuclear granulocytes (PMN) and platelets were pre-activated with a receptor- mediated stimulus [formyl-methionyl-leucyl-phenylalanine (FMLP) or thrombin, respectively] and subsequently incubate with sodium fluoride (NaF). We investigated various cell responses, such as chemiluminescence by PMN, platelet aggregation and the release of lipid mediators [i.e. leukotriene 84 (LTH4) and its co-oxidation products from neutrophils and 12-hydroxy-eicosatetraenoic acid (12- HETE) from platelets]. As a marker of G protein involvement, the binding of [3H]guanylylimidodi- phosphate (Gpp (NH) p) to the membrane fractions of stimulated cells was determined. PMN pre-stimulated with FMLP showed a synergistically enhanced generation of leukotrienes returning to control values with the time of preincubation. Platelets preliminary treated with thrombin followed by incubation with NaF resulted in a sub-additive and time-independent mediator generation. Neither chemiluminescence by PMN nor platelet aggregation showed a similar pattern compared to the mediator release: PMN preincubated with FMLP followed by NaF resulted in a second chemiluminescence response; the aggregation of platelets which were preincubated with thrombin was partially inhibited by the addition of NaF. Membrane fractions isolated from FMLP-pre- stimulated neutrophils showed a pattern in [3H]Gpp (NH) p-binding capacity that was comparable to the respective leukotriene release. With thrombin-prestimulated platelets, no similarities between Gpp (NH) p binding, aggregation or 12-HETE generation were observed. The sequential activation of different cell populations using the same kind of stimulation lead to different cell responses, indicating the diversity of G proteins and their control mechanisms. [ABSTRACT FROM AUTHOR]

Incubation of human polymorphonuclear granulocytes, monocytes and platelets with sodium fluoride (NaF) results in a time- and dose-dependent generation of leukotrienes and 12-HETE, respectively. This release was not influenced by pretreatment with pertussis toxin or cholera toxin. The mediators are detectable after a lag phase of about 5–10 min. Inactivation of LTB4 by the neutrophils via omega-oxidation into 20-hydroxy-LTB4 and 20-carboxy-LTB4 is inhibited by NaF. In combination with other cell stimuli, NaF showed modulatory effects, such as an enhanced formation of the lenkotrienes when FMLP, opsonized zymosan, PMA, and arachidonic acid were applied as stimuli. Prestimulation of cells with NaF causes an increased [3H]guanylylimidodiphosphate binding to isolated membrane preparations, indicating an enhanced exchange rate for GDP to GTP. Our data demonstrate that a direct activation of GTP-binding proteins results in the generation of the inflammatory mediators and provides evidence for the involvement of the signal-transduction pathway. [ABSTRACT FROM AUTHOR]

Rotations of schoolchildren were considered as a non-pharmacological intervention in the COVID-19 pandemic. This study investigates the impact of different rotation and testing schedules.We built an agent-based model of interactions among pupils and teachers based on a survey in an elementary school in Prague, Czechia. This model contains 624 schoolchildren and 55 teachers and about 27 thousands social contacts in 10 layers. The layers reflect different types of contacts (classroom, cafeteria, etc.) in the survey. On this multi-graph structure we run a modified SEIR model of covid-19 infection. The parameters of the model are calibrated on data from the outbreak in the Czech Republic in spring 2020. Weekly rotations of in-class and distance learning are an effective preventative measure in schools reducing the spread of covid-19 by 75-81% . Antigen testing twice a week or PCR once a week significantly reduces infections even when using tests with a lower sensitivity. The structure of social contacts between pupils and teachers strongly influences the transmission. While the density of contact graphs for older pupils is 1.5 times higher than for younger pupils, the teachers' network is an order of magnitude denser. Teachers moreover act as bridges between groups of children, responsible for 14-18% of infections in the secondary school compared to 8-11% in the primary school. Weekly rotations with regular testing are a highly effective non-pharmacological intervention for the prevention of covid-19 spread in schools and a way to keep schools open during an epidemic., (© 2023. The Author(s).)

Learning grammar requires practice and practicing grammar can be boring. We examined whether an instructional game with intrinsically integrated game mechanics promotes this practice: compared to rote learning through a quiz. We did so "in the field." Tens of thousands children visited, in their leisure time, a public website with tens of attractive online games for children during a 6-week-long period. Of these children, 11,949 picked voluntarily our grammar training intervention. Thereafter, unbeknown to them, they were assigned either to the game or the quiz condition. By means of learning analytics, we examined variables related to participants' persistence and performance. The results showed large participant drop-out before completing the first level in both conditions (42.2%), confirming the boringness of the topic. More children completed at least one level in the game compared to the quiz (61.8 vs. 53.6%). However, more children completed the intervention (all six levels) with the quiz (6.0 vs. 4.3%). In the game, children answered fewer questions correctly (36.3 vs. 47.4) and made more errors compared to the quiz (16.1 vs. 13.1). These findings suggest that even if a game initially catches user attention, it may not hold it. Plus, even if it is a minimalistic game with intrinsic integration of learning and playing, it may be distractive. We conclude that persistence in practicing grammar may be driven by other means than by a game's shooting mechanics; for instance, by a desire to learn the topic and a feeling of achievement or by quizzing mechanics., Competing Interests: KV declares a potential conflict of interest because she is employed by Czech TV, which is a public institution engaged (also) in development of educational games. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brom, Kolek, Lukavský, Děchtěrenko and Volná.)

Instructional quizzes are frequently used in educational games. When they present correct answers after learners have responded, these quizzes can be used on their own for teaching new factual and conceptual knowledge (no additional learning materials are needed). In games, these quizzes are often unrelated to gameplay: gameplay can be viewed as a reward for answering quiz questions. This has been criticized in game-based learning literature as a "chocolate-covered-broccoli" approach. However, is it really a bad approach? Theories offer conflicting predictions concerning the instructional efficiency of in-game quizzes relative to bare quizzes (i.e., not embedded in games) and empirical literature is lacking. Here, we present a within-subject design study ( N = 69), in which 10-12-year-olds learn from both an in-game quiz and a bare quiz and undergo immediate and 2-3 weeks delayed post-test on the quiz questions. A modest difference in learning outcomes favoring the bare quiz was found in the immediate post-tests ( d = 0.46), but not in the 2-3 weeks delayed post-tests ( d = 0.09). Children enjoyed the game more than the bare quiz ( d z = 0.65) and 59 preferred the game in the free-choice period. The findings suggest that both a bare quiz and a quiz within a game have their place at the table for useful educational interventions: the bare quiz should be preferred in schooling contexts; whereas, the game in leisure time situations as a voluntary activity. In the latter case, it should be considered how the game and the quiz are integrated., Competing Interests: KV declares a potential conflict of interest, as she was employed by Czech Television, which is a public institution engaged (also) in development of educational games. The remaining authors declare the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jičínská, Sedláčková, Kolek, Tetourová, Volná, Lukavský and Brom.)

Background: Cardiopulmonary bypass (CPB) during cardiac surgery impairs microcirculatory perfusion and is paralleled by vascular leakage. The endothelial angiopoietin/Tie2 system controls microvascular leakage. This study investigated whether targeting Tie2 with the angiopoietin-1 mimetic vasculotide reduces vascular leakage and preserves microcirculatory perfusion in a rat CPB model., Methods: Rats were subjected to 75 min of CPB after treatment with vasculotide or phosphate buffered solution as control or underwent a sham procedure. Microcirculatory perfusion and leakage were assessed with intravital microscopy (n=10 per group) and Evans blue dye extravasation (n=13 per group), respectively. Angiopoietin-1, -2, and Tie2 protein and gene expression were determined in plasma, kidney, and lung., Results: CPB immediately impaired microcirculatory perfusion [5 (4-8) vs 10 (7-12) vessels per recording, P=0.002] in untreated CPB rats compared with sham, which persisted after weaning from CPB. CPB increased circulating angiopoeietin-1, -2, and soluble Tie2 concentrations and reduced Tie2 messenger ribonucleic acid (mRNA) expression in kidney and lung. Moreover, CPB increased Evans blue dye leakage in kidney [12 (8-25) vs 7 (1-12) μg g -1 , P=0.04] and lung [and 23 (13-60) vs 6 (4-16) μg g -1 , P=0.001] compared with sham. Vasculotide treatment preserved microcirculatory perfusion during and after CPB. Moreover, vasculotide treatment reduced Evans blue dye extravasation in lung compared with CPB control [18 (6-28) μg g -1 vs 23 (13-60) μg g -1 , P=0.04], but not in kidney [10 (3-23) vs 12 (8-25) μg g -1 , P=0.38]. Vasculotide did not affect circulating or mRNA expression of angiopoietin-1, -2, and Tie2 concentrations compared with untreated CPB controls., Conclusions: Treatment with the angiopoietin-1 mimetic vasculotide reduced pulmonary vascular leakage and preserved microcirculatory perfusion during CPB in a rat model., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Rationale: Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay and increases mortality and healthcare costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown., Objectives: To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal atrophy by displacing the diaphragm in the caudal direction and reducing the length of fibers., Methods: We studied structure and function of diaphragm fibers of mechanically ventilated critically ill patients and mechanically ventilated rats with normal and increased titin compliance., Measurements and Main Results: PEEP causes a caudal movement of the diaphragm, both in critically ill patients and in rats, and this caudal movement reduces fiber length. Diaphragm fibers of 18-hour mechanically ventilated rats (PEEP of 2.5 cm H 2 O) adapt to the reduced length by absorbing serially linked sarcomeres, the smallest contractile units in muscle (i.e., longitudinal atrophy). Increasing the compliance of titin molecules reduces longitudinal atrophy., Conclusions: Mechanical ventilation with PEEP results in longitudinal atrophy of diaphragm fibers, a response that is modulated by the elasticity of the giant sarcomeric protein titin. We postulate that longitudinal atrophy, in concert with the aforementioned cross-sectional atrophy, hampers spontaneous breathing trials in critically ill patients: during these efforts, end-expiratory lung volume is reduced, and the shortened diaphragm fibers are stretched to excessive sarcomere lengths. At these lengths, muscle fibers generate less force, and diaphragm weakness ensues.

Background: The mechanisms causing increased endothelial permeability after cardiopulmonary bypass (CPB) have not been elucidated. Using a bioassay for endothelial barrier function, we investigated whether endothelial hyperpermeability is associated with alterations in plasma endothelial activation and adhesion markers and can be attenuated by the use of pulsatile flow during CPB., Methods: Patients undergoing cardiac surgery were randomized to non-pulsatile (n=20) or pulsatile flow CPB (n=20). Plasma samples were obtained before (pre-CPB) and after CPB (post-CPB), and upon intensive care unit (ICU) arrival. Changes in plasma endothelial activation and adhesion markers were determined by enzyme-linked immunosorbent assay. Using electric cell-substrate impedance sensing of human umbilical vein endothelial monolayers, the effects of plasma exposure on endothelial barrier function were assessed and expressed as resistance., Results: Cardiopulmonary bypass was associated with increased P-selectin, vascular cell adhesion molecule-1, and von Willebrand factor plasma concentrations and an increase in the angiopoietin-2 to angiopoietin-1 ratio, irrespective of the flow profile. Plasma samples obtained after CPB induced loss of endothelial resistance of 21 and 23% in non-pulsatile and pulsatile flow groups, respectively. The negative effect on endothelial cell barrier function was still present with exposure to plasma obtained upon ICU admission. The reduction in endothelial resistance after exposure to post-CPB plasma could not be explained by CPB-induced haemodilution., Conclusion: The change in the plasma fingerprint during CPB is associated with impairment of in vitro endothelial barrier function, which occurs irrespective of the application of a protective pulsatile flow profile during CPB., Clinical Trial Registration: NTR2940., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

There is ample experimental evidence describing changes of tonotopic organisation in the auditory cortex due to environmental factors. In order to uncover the underlying mechanisms, we designed a large-scale computational model of the auditory cortex. The model has up to 100 000 Izhikevich's spiking neurons of 17 different types, almost 21 million synapses, which are evolved according to Spike-Timing-Dependent Plasticity (STDP) and have an architecture akin to existing observations. Validation of the model revealed alternating synchronised/desynchronised states and different modes of oscillatory activity. We provide insight into these phenomena via analysing the activity of neuronal subtypes and testing different causal interventions into the simulation. Our model is able to produce experimental predictions on a cell type basis. To study the influence of environmental factors on the tonotopy, different types of auditory stimulations during the evolution of the network were modelled and compared. We found that strong white noise resulted in completely disrupted tonotopy, which is consistent with in vivo experimental observations. Stimulation with pure tones or spontaneous activity led to a similar degree of tonotopy as in the initial state of the network. Interestingly, weak white noise led to a substantial increase in tonotopy. As the STDP was the only mechanism of plasticity in our model, our results suggest that STDP is a sufficient condition for the emergence and disruption of tonotopy under various types of stimuli. The presented large-scale model of the auditory cortex and the core simulator, SUSNOIMAC, have been made publicly available.

Objectives: Cognitive deficit is considered to be a characteristic feature of schizophrenia disorder. A similar cognitive dysfunction was demonstrated in animal models of schizophrenia. However, the poor comparability of methods used to assess cognition in animals and humans could be responsible for low predictive validity of current animal models. In order to assess spatial abilities in schizophrenia and compare our results with the data obtained in animal models, we designed a virtual analog of the Morris water maze (MWM), the virtual Four Goals Navigation (vFGN) task., Methods: Twenty-nine patients after the first psychotic episode with schizophrenia symptoms and a matched group of healthy volunteers performed the vFGN task. They were required to find and remember four hidden goal positions in an enclosed virtual arena. The task consisted of two parts. The Reference memory (RM) session with a stable goal position was designed to test spatial learning. The Delayed-matching-to-place (DMP) session presented a modified working memory protocol designed to test the ability to remember a sequence of three hidden goal positions., Results: Data obtained in the RM session show impaired spatial learning in schizophrenia patients compared to the healthy controls in pointing and navigation accuracy. The DMP session showed impaired spatial memory in schizophrenia during the recall of spatial sequence and a similar deficit in spatial bias in the probe trials. The pointing accuracy and the quadrant preference showed higher sensitivity toward the cognitive deficit than the navigation accuracy. Direct navigation to the goal was affected by sex and age of the tested subjects. The age affected spatial performance only in healthy controls., Conclusions: Despite some limitations of the study, our results correspond well with the previous studies in animal models of schizophrenia and support the decline of spatial cognition in schizophrenia, indicating the usefulness of the vFGN task in comparative research.