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MiR-219a-5p Enriched Extracellular Vesicles Induce OPC Differentiation and EAE Improvement More Efficiently Than Liposomes and Polymeric Nanoparticles.
Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs have been postulated as a promising tool to induce oligodendrocyte precursor cell differentiation and therefore remyelination. Herein, DSPC liposomes and PLGA nanoparticles were studied for miR-219a-5p encapsulation, release and remyelination promotion. In parallel, they were compared with biologically engineered extracellular vesicles overexpressing miR-219a-5p. Interestingly, extracellular vesicles showed the highest oligodendrocyte precursor cell differentiation levels and were more effective than liposomes and polymeric nanoparticles crossing the blood-brain barrier. Finally, extracellular vesicles were able to improve EAE animal model clinical evolution. Our results indicate that the use of extracellular vesicles as miR-219a-5p delivery system can be a feasible and promising strategy to induce remyelination in multiple sclerosis patients.
Against the microfoundation hegemony: cooperation in biology, business and economics.
We use recent insights from evolutionary biology and the principle of biological relativity to reveal the remarkable parallels between forms of cooperation in biology, business and economics. The principle of biological relativity states that there is no privileged level of causation. The creation of higher levels of organisation and regulation constrains the components of co-operation in a form of downward causation. The upward and downward forms of causation are not equivalent. Downward causation is an organising principle arising from the ordered creation of the 'initial' and 'boundary' conditions experienced by the lower level components. But the existence of the lower level components is also the necessary condition for the creation of the higher-level constraints. Very similar processes are at work in corporations. The restrictions imposed by the legal form of the corporation bind investors to the provision of permanent capital in a similar way to that of fusion of organisms in biological processes, creating a form of symbiogenesis. The higher order conditions imposed on the agents of the firm provide an organising principle and the existence of the lower level agents is a necessary condition for the creation of the higher-level constraints. Furthermore, the process of entry into new business environments resembles that of symbiosis or symbiogenesis in that the interaction is asymmetric; the subsequent process is dynamic, resulting in super-additivity. The dynamic processes can create higher levels of organisation, such as new business models involving cooperation between businesses, corporations, regulators and governments. These in turn constrain the entities forming the new process.
Corrigendum: Ion Channel Targeted Mechanisms of Anti-arrhythmic Chinese Herbal Medicine Xin Su Ning.
[This corrects the article DOI: 10.3389/fphar.2019.00070.].
Sleep homeostasis reflects temporally integrated local cortical neuronal activity
<jats:title>Abstract</jats:title><jats:p>The homeostatic regulation of sleep manifests as a relative constancy of its daily amount and intensity. Theoretical descriptions of this phenomenon define “Process S”, a variable with dynamics dependent only on sleep-wake history, whose levels are reflected in electroencephalogram (EEG) slow wave activity (0.5 – 4 Hz) during sleep. Here we developed novel mathematical models of Process S in mice, assuming that its dynamics are a function of the deviation of cortical neuronal firing rates from a locally defined set-point, crucially without explicit knowledge of sleep-wake state. Our results suggest that Process S tracks global sleep-wake history through an integration of local cortical neuronal activity levels over time. We posit that, instead of reflecting sleep-wake-dependent changes in specific variables and serving their homeostatic regulation, Process S may be a time-keeping mechanism which enables individuals to obtain a species-specific and ecologically-relevant quantity of sleep, even in the absence of external temporal information.</jats:p>
Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism.
Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms.
Unstable binocular control in dyslexic children
Le contrôle binoculaire instable chez les enfants mauvais lecteurs Dans ce texte nous passons en revue les arguments favorables à l'hypotébe suivant laquelle de nombrew mauvais lecteurs ont un contrôle binoculaire instable et suivant laquelle cette instabilité est une cause de leurs problémes de lecture. Nous avons consideré comme mauvais lecteurs les enfants dont le résultat en lecture était inférieur de deux téarts‐types a leurs scores standardisés dans les tests de l'Echelle d'Habileté Britannique. Nous avons utilisé le Test de Dunlop (TD) pour montrer que plus des deux tiers des enfants mauvais lecteurs ont un contrôle binoculaire instable. Celui‐ci va de pair avec une perturbation du contrôle des mouvements de convergence visuelle et une fixation binoculaire instable lors de l'observation de petites cibles en un point proche. Ces résultats ont été maintenant confirmés par plusieurs autres chercheurs. I1 y a beaucoup de controverses sur la question de savoir si les lecteurs ordinaires ont également un contrôle binoculaire instable. La plupart de ceux qui ont travaillé sur ce point sont d'accord pour dire que un quart seulement des enfants ordinaires manifestent un contrôle binoculaire instable dans le TD et s'accordent pour dire qu'après l'augmentation de stabilité binoculaire qui se produit avec l'âge, les enfants instables dans le TD sont de plus mauvais lecteurs que ceux qui présentent des réponses stables. Nous avons également été en mesure de montrer que les enfants qui ont un contrôle binoculaire instable dans le TD ont un sens limité de la direction visuelle de telle sorte qu'ils ont tendance à mal localiser des cibles non‐linguistiques tels que de petits points. Leur instabilité binoculaire semble aussi être associée avec une acuité réduite pour le relief. Les enfants présentant un contrôle binoculaire instable dans le TD commettent des erreurs caractéristiques sous forme de non‐mots quand ils essaient de lire. L'oeil semble presenter à leur esprit un fouillis visuel qu'ils décodent oralement sous forme de non‐mots. De façon a prouver que les associations décrites ci‐dessus sont de nature causale, que l'instabilité binoculaire cause une confusion visuelle et donc des difficult de lecture, et qu'il ne s'agit donc pas d'un épiphénoméne, nous avons comparé le contrôle binoculaire des mauvais lecteurs non seulement avec des contrôles appariés par l'âge, mais aussi avec des enfants plus jeunes du même âge de lecture que les mauvais lecteurs. La stabilité binoculaire des enfants ordinaires plus jeunes a toujours été supérieure. L'appariement par l'âge de lecture écarte la possibilité que l' apprentissage de la lecture soit ce qui stabilise le contrôle binoculaire plutôt que l'inverse. Les jeunes enfants ont lu au même niveau que les mauvais lecteurs et néanmoins leur contrôle binoculaire était déjà supérieur. Notre proposition la plus discutable est peut étre que l'amélioration de la stabilité binoculaire au moyen d'un traitement approprié des enfants par occlusion de l'oeil gauche améliore leur lecture. II n'y a pas d'argument permettant de dire qu'une occlusion monoculaire améliore la stabilité binoculaire des jeunes mauvais lecteurs, mais notre conclusion que ceci aide beaucoup d'enfants à apprendre A lire a étéénergiquement mis en cause. Nous avons trouvé que l'importance des gains en lecture dépendait du niveau de lecture au départ. Néanmoins, dans l'analyse de covariance, l'interaction du gain en stabilité binoculaire avec l'âge initial de lecture a été très significative. Ainsi y a‐t'il peu de doute que ceux qui ont acquis un contrôle binoculaire stable ont amélioré beaucoup plus leur lecture que les autres. Nous en concluons qu'un contrôle binoculaire instable peut étre une cause potentielle de difficulté de lecture chez les enfants et que les aider à améliorer leur contrôle binoculaire les aide à apprendre à lire. Toutefois corriger l'instabilité binoculaire ne ‘traite’ pas la mauvaise lecture. De nombreux mauvais lecteurs ont également des difficultés phonologiques et ont besoin d'une aide technique spécialisée. Copyright © 1993, Wiley Blackwell. All rights reserved
Auditory temporal processing in developmental dyslexics
Developmental dyslexia is usually considered to result from a high level cognitive/linguistic deficit. Butit is possiblethat the phonological difficulties that most display may in part be due to impaired auditory perception. This study investigates the ability of adult dyslexics, screened for normal hearing sensitivity, to perform a non-speech auditory task. The test (FM rate difference limen) was designed to be analogous to visual motion sensitivity at which dyslexics are worse than controls. Subjects were identified as dyslexic by educational psychologists using standard criteria. Their persistentreading difficulties were confirmed using single real word and non-word reading tests. The 12 dyslexics not only made more errors than 12 matched controls in both tests but also took longer to complete the lists. When we ranked all 24 subjects on their word and non-word reading performance there was a strong correlation between them (r =0.813; p< 0.001). There were no significant differences between dyslexics and controls in hearing 1 KHz pure tones; but the dyslexics were significantly worse at detecting changes in the rate of modulation of frequency modulated tones (their FM rate difference limen was larger; t = 3.04, p < 0.005); and their FM depth difference limen was also worse (t =3.55, p < 0.005). The rank of all the subjects on these tests correlated with their reading performance (r ® 0.5, p <0.05). Results support the hypothesis that dyslexics have impaired development of neuronal systems responsible for processing the timing of auditory frequency changes. As in the visual system this function may be mediated by magnocellular neurones. © 1995, Taylor & Francis Group, LLC. All rights reserved.
Differences in eye movements and reading problems in dyslexic and normal children.
It has been suggested that eye movement abnormalities seen in dyslexics are attributable to their language problems. In order to investigate this claim, we studied eye movements in dyslexic children, during several non-reading tasks. Dyslexic children were compared to normal and backward readers on measures of fixation, vergence amplitude, saccade and smooth pursuit. The results were compared to the children's phonological ability. Dyslexic children (n = 26) had significantly worse eye movement stability during fixation of small targets than normal children (n = 39). Vergence amplitudes were lower for dyslexics than for controls. A qualitative assessment of saccadic eye movements revealed that dyslexics exhibit fixation instability at the end of saccades. Assessment of smooth pursuit revealed poor smooth pursuit in the dyslexic group, particularly when pursuing a target moving from left to right. Dyslexic children also performed significantly worse than normal children on a test of phonological awareness (Pig Latin). Eye movement results were studied in the light of the findings on phonological awareness: dyslexics with small vergence amplitudes also always have poor phonemic awareness. However, poor fixation control is found in dyslexics with or without poor phonological ability. The backward reading children performed similar to the dyslexics on all tests, suggesting that the deficiencies observed in this study are not specific to children with dyslexia. The problems experienced by the children (revealed by a questionnaire) are in agreement with those measured in terms of eye movement recordings and phonemic awareness. Sex, handedness, IQ or the presence of attention deficit disorder (ADD) did not appear to influence the children's performances on any of the eye movement tasks. The presence of oculomotor abnormalities in a non-reading task strongly suggests that the underlying deficit in the control of eye movements seen in dyslexics is not caused by language problems alone.
Is the cerebellum a smith predictor?
The motor system may use internal predictive models of the motor apparatus to achieve better control than would be possible by negative feedback. Several theories have proposed that the cerebellum may form these predictive representations. In this article, we review these theories and try to unify them by reference to an engineering control model known as a Smith Predictor. We suggest that the cerebellum forms two types of internal model. One model is a forward predictive model of the motor apparatus (e.g., limb and muscle), providing a rapid prediction of the sensory consequences of each movement. The second model is of the time delays in the control loop (due to receptor and effector delays, axonal conductances, and cognitive processing delays). This model delays a copy of the rapid prediction so mat it can be compared in temporal register with actual sensory feedback from the movement. The result of this comparison is used both to correct for errors in performance and as a training signal to learn the first model. We discuss evidence that the cerebellum could form both of these models and suggest that the cerebellum may hold at least two separate Smith Predictors. One, in the lateral cerebellum, would predict the movement outcome in visual, egocentric, or peripersonal coordinates. Another, in the intermediate cerebellum, would predict the consequences in motor coordinates. Generalization of the Smith Predictor theory is discussed in light of cerebellar involvement in nonmotor control systems, including autonomic functions and cognition. © 1982 Taylor & Francis Group, LLC.
Correction: identification of candidate genes for dyslexia susceptibility on chromosome 18.
[This corrects the article on p. e13712 in vol. 5.].
Representation of Color
Color is an important part of our visual experience. The swirls of blues, yellows, and greens in Van Gogh's Starry Night affect a viewer in a way that a black-and-white rendition cannot. Color vision allows us to find a green bell pepper among red ones and predict how good it will taste. This article describes briefly the aspects of light that are most important for color vision, the processing of color information in the retina and thalamus, and color processing in the cerebral cortex. Also, some of the recent computational modelling approaches of color processing are discussed at the end.
Movement decoding using neural synchronization and inter-hemispheric connectivity from deep brain local field potentials.
OBJECTIVE: Correlating electrical activity within the human brain to movement is essential for developing and refining interventions (e.g. deep brain stimulation (DBS)) to treat central nervous system disorders. It also serves as a basis for next generation brain-machine interfaces (BMIs). This study highlights a new decoding strategy for capturing movement and its corresponding laterality from deep brain local field potentials (LFPs). APPROACH: LFPs were recorded with surgically implanted electrodes from the subthalamic nucleus or globus pallidus interna in twelve patients with Parkinson's disease or dystonia during a visually cued finger-clicking task. We introduce a method to extract frequency dependent neural synchronization and inter-hemispheric connectivity features based upon wavelet packet transform (WPT) and Granger causality approaches. A novel weighted sequential feature selection algorithm has been developed to select optimal feature subsets through a feature contribution measure. This is particularly useful when faced with limited trials of high dimensionality data as it enables estimation of feature importance during the decoding process. MAIN RESULTS: This novel approach was able to accurately and informatively decode movement related behaviours from the recorded LFP activity. An average accuracy of 99.8% was achieved for movement identification, whilst subsequent laterality classification was 81.5%. Feature contribution analysis highlighted stronger contralateral causal driving between the basal ganglia hemispheres compared to ipsilateral driving, with causality measures considerably improving laterality discrimination. SIGNIFICANCE: These findings demonstrate optimally selected neural synchronization alongside causality measures related to inter-hemispheric connectivity can provide an effective control signal for augmenting adaptive BMIs. In the case of DBS patients, acquiring such signals requires no additional surgery whilst providing a relatively stable and computationally inexpensive control signal. This has the potential to extend invasive BMI, based on recordings within the motor cortex, by providing additional information from subcortical regions.