Physical Activity and Cognitive Performance in Early Childhood: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Growing evidence suggests that physical activity (PA) could improve cognitive performance in youths, but whether these effects occur from early childhood remains unclear. OBJECTIVE: To summarize evidence on the effects of PA interventions on cognitive performance in early childhood. METHODS: We performed a systematic search in PubMed, Scopus, Web of Science and PsycINFO (from inception to 6 September 2023) for randomized controlled trials assessing the effects of PA interventions (≥ 3 weeks) on cognitive-related outcomes in early childhood (3-6 years). We conducted a random-effects meta-analysis when five or more studies assessed a given outcome. The potential moderating role of participant (e.g., age) and intervention characteristics (e.g., duration, volume, intensity, cognitive engagement) was also assessed. RESULTS: We found a total of 24 studies (N = 3483 children) that were deemed to be of overall fair methodological quality. PA interventions were supervised and lasted between 3 and 24 weeks. The most common session duration was 30 min, with a frequency of two sessions per week. Pooled analyses revealed that PA interventions have positive effects on all analysed outcomes, including attention (standardized mean difference (SMD) = 0.49, 95% confidence interval (CI) 0.18-0.79, p = 0.002), inhibition (SMD = 0.45, 95% CI 0.06-0.84, p = 0.022), working memory (SMD = 0.50, 95% CI 0.18-0.82, p = 0.002), cognitive flexibility (SMD = 0.39, 0.15-0.62, p = 0.002) and vocabulary (SMD = 1.18, 0.19-2.16, p = 0.019). Sensitivity analyses confirmed the benefits in all cases except for inhibition (p = 0.062). No consistent differences were found relating to any moderator variable. CONCLUSIONS: Although further research is warranted, our findings suggest that PA interventions may improve cognitive performance in early childhood, particularly in the domains of attention, inhibition, working memory, cognitive flexibility and vocabulary. These findings might support the implementation of PA interventions from early childhood. PROSPERO REGISTRATION: CRD42021249319.

Shaping Graphene Superconductivity with Nanometer Precision.

Graphene holds great potential for superconductivity due to its pure 2D nature, the ability to tune its carrier density through electrostatic gating, and its unique, relativistic-like electronic properties. At present, still far from controlling and understanding graphene superconductivity, mainly because the selective introduction of superconducting properties to graphene is experimentally very challenging. Here, a method is developed that enables shaping at will graphene superconductivity through a precise control of graphene-superconductor junctions. The method combines the proximity effect with scanning tunnelling microscope (STM) manipulation capabilities. Pb nano-islands are first grown that locally induce superconductivity in graphene. Using a STM, Pb nano-islands can be selectively displaced, over different types of graphene surfaces, with nanometre scale precision, in any direction, over distances of hundreds of nanometres. This opens an exciting playground where a large number of predefined graphene-superconductor hybrid structures can be investigated with atomic scale precision. To illustrate the potential, a series of experiments are performed, rationalized by the quasi-classical theory of superconductivity, going from the fundamental understanding of superconductor-graphene-superconductor heterostructures to the construction of superconductor nanocorrals, further used as "portable" experimental probes of local magnetic moments in graphene.

Observation of Yu-Shiba-Rusinov States in Superconducting Graphene.

When magnetic atoms are inserted inside a superconductor, the superconducting order is locally depleted as a result of the antagonistic nature of magnetism and superconductivity. Thereby, distinctive spectral features, known as Yu-Shiba-Rusinov states, appear inside the superconducting gap. The search for Yu-Shiba-Rusinov states in different materials is intense, as they can be used as building blocks to promote Majorana modes suitable for topological quantum computing. Here, the first observation of Yu-Shiba-Rusinov states in graphene, a non-superconducting 2D material, and without the participation of magnetic atoms, is reported. Superconductivity in graphene is induced by proximity effect brought by adsorbing nanometer-scale superconducting Pb islands. Using scanning tunneling microscopy and spectroscopy the superconducting proximity gap is measured in graphene, and Yu-Shiba-Rusinov states are visualized in graphene grain boundaries. The results reveal the very special nature of those Yu-Shiba-Rusinov states, which extends more than 20 nm away from the grain boundaries. These observations provide the long-sought experimental confirmation that graphene grain boundaries host local magnetic moments and constitute the first observation of Yu-Shiba-Rusinov states in a chemically pure system.

Quantum Confinement of Dirac Quasiparticles in Graphene Patterned with Sub-Nanometer Precision.

Quantum confinement of graphene Dirac-like electrons in artificially crafted nanometer structures is a long sought goal that would provide a strategy to selectively tune the electronic properties of graphene, including bandgap opening or quantization of energy levels. However, creating confining structures with nanometer precision in shape, size, and location remains an experimental challenge, both for top-down and bottom-up approaches. Moreover, Klein tunneling, offering an escape route to graphene electrons, limits the efficiency of electrostatic confinement. Here, a scanning tunneling microscope (STM) is used to create graphene nanopatterns, with sub-nanometer precision, by the collective manipulation of a large number of H atoms. Individual graphene nanostructures are built at selected locations, with predetermined orientations and shapes, and with dimensions going all the way from 2 nm up to 1 µm. The method permits the patterns to be erased and rebuilt at will, and it can be implemented on different graphene substrates. STM experiments demonstrate that such graphene nanostructures confine very efficiently graphene Dirac quasiparticles, both in 0D and 1D structures. In graphene quantum dots, perfectly defined energy bandgaps up to 0.8 eV are found that scale as the inverse of the dot's linear dimension, as expected for massless Dirac fermions.

Feasibility of the Internet Attachment-Based Compassion Therapy in the General Population: Protocol for an Open-Label Uncontrolled Pilot Trial.

BACKGROUND: Compassion-based interventions delivered over the internet are showing promising results for the promotion of psychological health and well-being. Several studies have highlighted their feasibility, acceptance, and preliminary efficacy. However, this is an incipient field of research, and to the best of our knowledge, there are no data available from Spanish-speaking countries. OBJECTIVE: The aim of this study is to investigate the feasibility, acceptance, and preliminary efficacy of the Internet Attachment-Based Compassion Therapy (iABCT), a web-based version of the Attachment-Based Compassion Therapy, in Spanish speakers from the general population. METHODS: This feasibility study features a single-arm, uncontrolled, within-group design with an embedded qualitative and quantitative process evaluation at baseline, immediately after the intervention and at the 3-month follow-up. A minimum of 35 participants from the general population will be allocated to iABCT. Feasibility measures will include attrition rate, patterns of use of the web-based system, and participants' acceptability, usability, and opinion. The primary outcome was measured using the Pemberton Happiness Index. Secondary outcomes were measured using the Compassion Scale, Self-Compassion Scale, Forms of Self-Criticizing/Attacking and Self-Reassuring Scale-Short form, Five Facets of Mindfulness Questionnaire, Relationships Questionnaire, General Health Questionnaire, Non-Attachment Scale, International Positive and Negative Affect Schedule Short Form, Purpose-In-Life Test, and difficulties regarding the practice of compassion (Compassion Practice Quality Questionnaire). Mixed models will be used to evaluate primary and secondary outcome measures. A qualitative content analysis of the participants' qualitative responses will also be performed. RESULTS: Enrollment started in February 2020 and will be finished in April 2020. Data analysis will start in October 2020. CONCLUSIONS: To our knowledge, this study will, for the first time, show data on the feasibility, acceptability, and preliminary efficacy of web-based compassion (and self-compassion) training-that is, the adapted iABCT-in Spanish speakers from the general population. Further aspects of their implementation (ie, facilitators, barriers, and unwanted effects) and mechanisms of change will be investigated. This study will allow the revision and fine-tuning of the developed intervention, study design, and planning procedures, as well as the initiation of a future randomized controlled trial. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03918746. Registered on April 17, 2019. Protocol version 1, 6 March 2019. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/16717.

Cholinesterase and phenyl valerate-esterase activities sensitive to organophosphorus compounds in membranes of chicken brain.

Some effects of organophosphorus compounds (OPs) esters cannot be explained by action on currently recognized targets acetylcholinesterase or neuropathy target esterase (NTE). In previous studies, in membrane chicken brain fractions, four components (EPα, EPß, EPγ and EPδ) of phenyl valerate esterase activity (PVase) had been kinetically discriminated combining data of several inhibitors (paraoxon, mipafox, PMSF). EPγ is belonging to NTE. The relationship of PVase components and acetylcholine-hydrolyzing activity (cholinesterase activity) is studied herein. Only EPα PVase activity showed inhibition in the presence of acetylthiocholine, similarly to a non-competitive model. EPα is highly sensitive to mipafox and paraoxon, but is resistant to PMSF, and is spontaneously reactivated when inhibited with paraoxon. In this papers we shows that cholinesterase activities showed inhibition kinetic by PV, which does not fit with a competitive inhibition model when tested for the same experimental conditions used to discriminate the PVase components. Four enzymatic components (CP1, CP2, CP3 and CP4) were discriminated in cholinesterase activity in the membrane fraction according to their sensitivity to irreversible inhibitors mipafox, paraoxon, PMSF and iso-OMPA. Components CP1 and CP2 could be related to EPα as they showed interactions between substrates and similar inhibitory kinetic properties to the tested inhibitors.

Hydrolyzing activities of phenyl valerate sensitive to organophosphorus compounds paraoxon and mipafox in human neuroblastoma SH-SY5Y cells.

The molecular targets of best known neurotoxic effects associated to acute exposure to organophosphorus compounds (OPs) are serine esterases located in the nervous system, although there are other less known neurotoxic adverse effects associated with chronic exposure to OPs whose toxicity targets are still not identified. In this work we studied sensitivity to the non-neuropathic OP paraoxon and to the neuropathic OP mipafox of phenyl valerate esterases (PVases) in intact and lysed human neuroblastoma SH-SY5Y cells. The main objective was to discriminate different unknown pools of esterases that might be potential targets of chronic effects from those esterases already known and recognized as targets to these acute neurotoxicity effects. Two components of PVases of different sensitivities were discriminated for paraoxon in both intact and lysed cells; while the two components inhibitable by mipafox were found only for intact cells. A completely resistant component to paraoxon of around 30% was found in both intact and lysed cells; while a component of slightly lower amplitude (around 20%) completely resistant to mipafox was also found for both preparations (intact and lysed cells). The comparison of the results between the intact cells and the lysed cells suggests that the plasma membrane could act as a barrier that reduced the bioavailability of mipafox to PVases. This would imply that the discrimination of the different esterases should be made in lysed cells. However, those studies which aim to determine the physiological role of these esterases should be necessarily conducted in intact cultured cells.

Author Correction: The effect of foreign language in fear acquisition.

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The effect of foreign language in fear acquisition.

Emotions are at the core of human nature. There is evidence that emotional reactivity in foreign languages compared to native languages is reduced. We explore whether this emotional distance could modulate fear conditioning, an essential mechanism for the understanding and treatment of anxiety disorders. A group of participants was verbally informed (either in a foreign or in a native language) that two different stimuli could be either cueing the potential presence of a threat stimulus or its absence. We registered pupil size and electrodermal activity and calculated the difference in psychophysiological responses to conditioned and to unconditioned stimuli. Our findings provided evidence that verbal conditioning processes are affected by language context in this paradigm. We report the first experimental evidence regarding how the use of a foreign language may reduce fear conditioning. This observation opens the avenue to the potential use of a foreign language in clinical contexts.

Effects of mipafox, paraoxon, chlorpyrifos and its metabolite chlorpyrifos-oxon on the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells.

Chlorpyrifos (CPS) is an organophosphorus compound (OP) capable of causing well-known cholinergic and delayed syndromes through the inhibition of acetylcholinesterase and Neuropathy Target Esterase (NTE), respectively. CPS is also able to induce neurodevelopmental toxicity in animals. NTE is codified by the Pnpla6 gene and plays a central role in differentiation and neurodifferentiation. We tested, in D3 mouse embryonic stem cells under differentiation, the effects of the NTE inhibition by the OPs mipafox, CPS and its main active metabolite chlorpyrifos-oxon (CPO) on the expression of genes Vegfa, Bcl2, Amot, Nes and Jun, previously reported to be under- or overexpressed after Pnpla6 silencing in this same cellular model. Mipafox did not significantly alter the expression of such genes at concentrations that significantly inhibited NTE. However, CPS and CPO at concentrations that caused NTE inhibition at similar levels to mipafox statistically and significantly altered the expression of most of these genes. Paraoxon (another OP with capability to inhibit esterases but not NTE) caused similar effects to CPS and CPO. These findings suggest that the molecular mechanism for the neurodevelopmental toxicity induced by CPS is not based on NTE inhibition, and that other unknown esterases might be potential targets of neurodevelopmental toxicity.

Expression of biomarker genes of differentiation in D3 mouse embryonic stem cells after exposure to different embryotoxicant and non-embryotoxicant model chemicals.

There is a necessity to develop in vitro methods for testing embryotoxicity (Romero et al., 2015) [1]. We studied the progress of D3 mouse embryonic stem cells differentiation exposed to model embryotoxicants and non-embryotoxicants chemicals through the expression of biomarker genes. We studied a set of 16 different genes biomarkers of general cellular processes (Cdk1, Myc, Jun, Mixl, Cer and Wnt3), ectoderm formation (Nrcam, Nes, Shh and Pnpla6), mesoderm formation (Mesp1, Vegfa, Myo1e and Hdac7) and endoderm formation (Flk1 and Afp). We offer dose response in order to derive the concentration causing either 50% or 200% of expression of the biomarker gene. These records revealed to be a valuable end-point to predict in vitro the embryotoxicity of chemicals (Romero et al., 2015) [1].

RNA transcripts for the quantification of differentiation allow marked improvements in the performance of embryonic stem cell test (EST).

Embryonic stem cell test (EST) is an in vitro validated assay for testing embryotoxicity. The EST needs improvements before being used for regulatory purposes, but also needs technical simplification for use in high throughput screenings. We propose the quantification in alterations of the differentiation of D3 monolayer cells cultures through the expression of biomarker genes in a shorter (5-day) and technically simpler (we use only monolayer cultures) test. We have defined a set of sixteen different genes biomarkers of ectoderm (Nrcam, Nes, Shh and Pnpla6), endoderm formation (Flk1 and Afp), mesoderm formation (Mesp1, Vegfa, Myo1e and Hdac7) and general cellular processes (Cdk1, Myc, Jun, Mixl, Cer and Wnt3). These, together with alterations in the viability of D3 and 3T3 cells and the prediction model of a classic EST, enhance the features of EST determinations to 100% concordance between in vivo-in vitro predictions with a set of seven different chemicals used in the validation of a classic EST. In conclusion, the proposed changes implemented in the classic EST confer it more reliability, speed and technical simplicity, which brings the EST closer to high throughput processes and regulatory purposes.

Organophosphorus pesticide chlorpyrifos and its metabolites alter the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells in a comparable way to other model neurodevelopmental toxicants.

There are discrepancies about whether chlorpyrifos is able to induce neurodevelopmental toxicity or not. We previously reported alterations in the pattern of expression of biomarker genes of differentiation in D3 mouse embryonic stem cells caused by chlorpyrifos and its metabolites chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol. Now, we reanalyze these data comparing the effects on these genes with those caused in the same genes by retinoic acid, valproic acid, and penicillin-G (model compounds considered as strong, weak, and non-neurodevelopmental toxicants, respectively). We also compare the effects of chlorpyrifos and its metabolites on the cell viability of D3 cells and 3T3 mouse fibroblasts with the effects caused in the same cells by the three model compounds. We conclude that chlorpyrifos and its metabolites act, regarding these end-points, as the weak neurodevelopmental toxicant valproic acid, and consequently, a principle of caution should be applied avoiding occupational exposures in pregnant women. A second independent experiment run with different cellular batches coming from the same clone obtained the same result as the first one.

Adrenocortical and behavioural response to chronic restraint stress in neurokinin-1 receptor knockout mice.

Brain substance P and its receptor (neurokinin-1, NK1) have a widespread brain distribution and are involved in an important number of behavioural and physiological responses to emotional stimuli. However, the role of NK1 receptors in the consequences of exposure to chronic stress has not been explored. The present study focused on the role of these receptors in the hypothalamic-pituitary-adrenal (HPA) response to daily repeated restraint stress (evaluated by plasma corticosterone levels), as well as on the effect of this procedure on anxiety-like behaviour, spatial learning and memory in the Morris water maze (MWM), a hippocampus-dependent task. Adult null mutant NK1-/- mice, with a C57BL/6J background, and the corresponding wild-type mice showed similar resting corticosterone levels and, also, did not differ in corticosterone response to a first restraint. Nevertheless, adaptation to the repeated stressor was faster in NK1-/- mice. Chronic restraint modestly increased anxiety-like behaviour in the light-dark test, irrespective of genotype. Throughout the days of the MWM trials, NK1-/- mice showed a similar learning rate to that of wild-type mice, but had lower levels of thigmotaxis and showed a better retention in the probe trial. Chronic restraint stress did not affect these variables in either genotype. These results indicate that deletion of the NK1 receptor does not alter behavioural susceptibility to chronic repeated stress in mice, but accelerates adaptation of the HPA axis. In addition, deletion may result in lower levels of thigmotaxis and improved short-term spatial memory, perhaps reflecting a better learning strategy in the MWM.