Finger-counting to relieve working memory in children with developmental coordination disorder: Insights from behavioral and 3D motion analysis.

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Contribution of finger gnosia and fine motor skills to early numerical and arithmetic abilities: New insights from 3D motion analyses

peer reviewedFinger gnosia and fine motor skills (FMS) are assumed to play a key role in the development of arithmetic abilities, but their contribution to early numerical skills (i.e., enumeration skills and cardinality) has received little attention so far. The purpose of this study was to investigate the predictive value of finger gnosia and FMS to enumeration, cardinal, and arithmetical abilities and how these different dimensions contribute to arithmetic development. Three- to five-year-old preschoolers were asked to perform tasks assessing enumeration, cardinality, and early arithmetic, as well as finger gnosia and FMS. FMS, involving either static or dynamic fine finger movement, were examined using a 3D motion analyses. Using hierarchical regression, FMS were found to be the best predictor of both cardinality and early arithmetic skills, while finger gnosia did not predict the additional variance of arithmetic performance when FMS and age were considered in the regression model. Moreover, neither finger gnosia nor FMS were significant predictors of enumeration. Mediation analyses indicated that knowledge of the cardinal principle fully mediates the relationship between FMS and arithmetic skills, suggesting that FMS contribute to cardinal principle knowledge development, which would be a gateway to more complex arithmetical processing

Recent Duplication and Functional Divergence in Parasitic Nematode Levamisole-Sensitive Acetylcholine Receptors

Helminth parasites rely on fast-synaptic transmission in their neuromusculature to experience the outside world and respond to it. Acetylcholine plays a pivotal role in this and its receptors are targeted by a wide variety of both natural and synthetic compounds used in human health and for the control of parasitic disease. The model, Caenorhabditis elegans is characterized by a large number of acetylcholine receptor subunit genes, a feature shared across the nematodes. This dynamic family is characterized by both gene duplication and loss between species. The pentameric levamisole-sensitive acetylcholine receptor has been characterized from C. elegans, comprised of five different subunits. More recently, cognate receptors have been reconstituted from multiple parasitic nematodes that are found to vary in subunit composition. In order to understand the implications of receptor composition change and the origins of potentially novel drug targets, we investigated a specific example of subunit duplication based on analysis of genome data for 25 species from the 50 helminth genome initiative. We found multiple independent duplications of the unc-29, acetylcholine receptor subunit, where codon substitution rate analysis identified positive, directional selection acting on amino acid positions associated with subunit assembly. Characterization of four gene copies from a model parasitic nematode, Haemonchus contortus, demonstrated that each copy has acquired unique functional characteristics based on phenotype rescue of transgenic C. elegans and electrophysiology of receptors reconstituted in Xenopus oocytes. We found evidence that a specific incompatibility has evolved for two subunits co-expressed in muscle. We demonstrated that functional divergence of acetylcholine receptors, driven by directional selection, can occur more rapidly than previously thought and may be mediated by alteration of receptor assembly. This phenomenon is common among the clade V parasitic nematodes and this work provides a foundation for understanding the broader context of changing anthelmintic drug targets across the parasitic nematodes

Action of Carvacrol on Parascaris sp. and Antagonistic Effect on Nicotinic Acetylcholine Receptors

Parascaris sp. is the only ascarid parasitic nematode in equids and one of the most threatening infectious organisms in horses. Only a limited number of compounds are available for treatment of horse helminthiasis, and Parascaris sp. worms have developed resistance to the three major anthelmintic families. In order to overcome the appearance of resistance, there is an urgent need for new therapeutic strategies. The active ingredients of herbal essential oils are potentially effective antiparasitic drugs. Carvacrol is one of the principal chemicals of essential oil from Origanum, Thymus, Coridothymus, Thymbra, Satureja and Lippia herbs. However, the antiparasitic mode of action of carvacrol is poorly understood. Here, the objective of the work was to characterize the activity of carvacrol on Parascaris sp. nicotinic acetylcholine receptor (nAChR) function both in vivo with the use of worm neuromuscular flap preparations and in vitro with two-electrode voltage-clamp electrophysiology on nAChRs expressed in Xenopus oocytes. We developed a neuromuscular contraction assay for Parascaris body flaps and obtained acetylcholine concentration-dependent contraction responses. Strikingly, we observed that 300 µM carvacrol fully and irreversibly abolished Parascaris sp. muscle contractions elicited by acetylcholine. Similarly, carvacrol antagonized acetylcholine-induced currents from both the nicotine-sensitive AChR and the morantel-sensitive AChR subtypes. Thus, we show for the first time that body muscle flap preparation is a tractable approach to investigating the pharmacology of Parascaris sp. neuromuscular system. Our results suggest an intriguing mode of action for carvacrol, being a potent antagonist of muscle nAChRs of Parascaris sp. worms, which may account for its antiparasitic potency

Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from Trichuris muris

From MDPI via Jisc Publications RouterHistory: accepted 2021-07-16, pub-electronic 2021-07-20Publication status: PublishedFunder: Wellcome Trust; Grant(s): Z10661/Z/18/ZFunder: Wellcome Trust Centre for Cell Matrix Research; Grant(s): Z03128/Z/16/ZThe human whipworm, Trichuris trichiura, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxantel. We recently identified a novel ACR-16-like subunit from the pig whipworm, T. suis which gave rise to a functional acetylcholine receptor (nAChR) preferentially activated by oxantel. However, there is no ion channel described in the mouse model parasite T. muris so far. Here, we have identified the ACR-16-like and ACR-19 subunits from T. muris, and performed the functional characterization of the receptors in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. We found that the ACR-16-like subunit from T. muris formed a homomeric receptor gated by acetylcholine whereas the ACR-19 failed to create a functional channel. The subsequent pharmacological analysis of the Tmu-ACR-16-like receptor revealed that acetylcholine and oxantel were equally potent. The Tmu-ACR-16-like was more responsive to the toxic agonist epibatidine, but insensitive to pyrantel, in contrast to the Tsu-ACR-16-like receptor. These findings confirm that the ACR-16-like nAChR from Trichuris spp. is a preferential drug target for oxantel, and highlights the pharmacological difference between Trichuris species

Functional validation of novel levamisole resistance marker S168T in Haemonchus contortus

Recently, a S168T variant in the acetylcholine receptor subunit ACR-8 was associated with levamisole resistance in the parasitic helminth Haemonchus contortus. Here, we used the Xenopus laevis oocyte expression system and two-electrode voltage-clamp electrophysiology to measure the functional impact of this S168T variant on the H. contortus levamisole-sensitive acetylcholine receptor, L-AChR-1.1. Expression of the ACR-8 S168T variant significantly reduced the current amplitude elicited by levamisole compared to acetylcholine, with levamisole changing from a full to partial agonist on the recombinant L-AChR. Functional validation of the S168T mutation on modulating levamisole activity at the receptor level highlights its critical importance as both a mechanism and a marker of levamisole resistance

Gastrointestinal strongyles of ruminants : mechanisms of anthelmintic resistance and consequences on their management

The management of gastrointestinal strongyle infestations in ruminants relies mostly on anthelmintics. Only three chemical families are available, and gastrointestinal strongyles resistance is increasing. The resistance mechanisms are relatively well known for benzimidazoles (involving one gene with two alleles), whereas the genetic determinism of the resistance to macrocyclic lactones or imidazothiazoles (levamisole) is still poorly understood, but probably involves multigenic regulation. A double approach (candidate genes and transcriptomic) is proposed for levamisole resistance and the first results are presented. It is very important to understand resistance mechanisms to reduce their occurrences. Examples with benzimidazoles are presented to describe interactions between the type of genetic mechanism and the speed with which resistance appears and expands, the efficacy of selective pressure by treatments, and the role of refugia.La gestion des infestations du tube digestif par les strongles chez les ruminants est essentiellement assurée par les traitements anthelminthiques. Seules trois familles chimiques sont disponibles et des phénomènes de résistance à ces produits sont apparus chez les strongles gastro-intestinaux. Les mécanismes de résistance concernant la famille des benzimidazoles sont relativement bien établis (un gène avec deux allèles est impliqué), alors que pour la famille des lactones macrocycliques ou celle des imidazothiazoles (lévamisole), les déterminismes génétiques, encore peu connus, sont sans doute multigéniques. Une double approche (« gènes candidats » et transcriptomique) est proposée pour le lévamisole et les premiers résultats sont présentés. La compréhension des mécanismes d'action est très importante pour tenter de réduire l'apparition de résistance. Des exemples concernant les benzimidazoles sont utilisés pour décrire l'interaction entre le type de mécanisme de résistance et la vitesse d'apparition et de diffusion de la résistance, l'efficacité des pressions sélectives par les traitements et le rôle des refuges

The plant apoplasm is an important recipient compartment for nematode secreted proteins

Similarly to microbial pathogens, plant-parasitic nematodes secrete into their host plants proteins that are essential to establish a functional interaction. Identifying the destination of nematode secreted proteins within plant cell compartment(s) will provide compelling clues on their molecular functions. Here the fine localization of five nematode secreted proteins was analysed throughout parasitism in Arabidopsis thaliana. An immunocytochemical method was developed that preserves both the host and the pathogen tissues, allowing the localization of nematode secreted proteins within both organisms. One secreted protein from the amphids and three secreted proteins from the subventral oesophageal glands involved in protein degradation and cell wall modification were secreted in the apoplasm during intercellular migration and to a lower extent by early sedentary stages during giant cell formation. Conversely, another protein produced by both subventral and dorsal oesophageal glands in parasitic stages accumulated profusely at the cell wall of young and mature giant cells. In addition, secretion of cell wall-modifying proteins by the vulva of adult females suggested a role in egg laying. The study shows that the plant apoplasm acts as an important destination compartment for proteins secreted during migration and during sedentary stages of the nematode

Intérêt du modèle C. elegans

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Les nématodes, amis ou ennemis ?

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