A literatura recente sugere que a fadiga mental piora o desempenho de atletas durante testes contrarrelógio (TT) de ciclismo. Assim o objetivo deste estudo foi verificar se a cafeína poderia reverter ou bloquear os efeitos negativos da fadiga mental em um contrarrelógio de 20km (TT20km). Métodos: Doze ciclistas treinados, com experiência em TT há pelo menos 2 anos, e nível de performance > 3 (34.3 ± 6.2 anos; 179.3 ± 5.1 cm; 77.6 ± 6.8 kg; 13.8 ± 4.5 % de gordura corporal; 58.9 ± 6.2 ml.kg-1.min-1; 367.0 ± 32.5 WPEAK), realizaram cinco visitas ao laboratório: 1) PRELIMINAR: para seleção dos sujeitos e familiarização com os instrumentos; 2) CONTROLE: foram realizadas três contrações voluntárias isométrica máxima (CVM), cujo maior torque encontrado entre elas definirá o valor de 70% para contração voluntária isométrica submáxima (CVIS) nas sessões seguintes. Posteriormente a CVIS, foi realizado o TT20km sem manipulação cognitiva ou suplementação; 3) FADIGA MENTAL (FM): execução do teste de atenção sustentada (RVIP), CVIS e TT20km respectivamente; 4) PLACEBO: ingestão da cápsula de placebo (FM + PLA) em seguida teste de RVIP, CVIS e TT20km; 5) CAFEÍNA: ingestão de cafeína (FM + CAF), consequentemente realizaram o teste de RVIP, CVIS e o TT20km). A atividade cerebral do córtex pré-frontal e córtex motor primário foi analisada por meio de eletroencefalografia (EEG) registrada antes e depois do teste RVIP. Igualmente, EEG do córtex pré-frontal e motor primário foi registrada durante uma contração voluntária isométrica submáxima, realizada antes do TT20km. Para as análises de comparações entre pré e pós tarefa cognitiva de atenção sustentada utilizou-se um teste T-student. Para as comparações múltiplas analisou-se por modelo misto entre a condição e a distância no TT20km, quando necessário o teste de Bonferroni foi utilizado. Resultados: CAF melhorou o desempenho em ciclistas mentalmente fatigados em ~ 1.8 % para FM e ~ 1.7 % para PLA (p = 0.00) e aumentou ~ 4.4 % para FM e ~ 3.6 % do que o placebo de WMEAN em FM + CAF (p = 0,00). A ativação cortical aumentou em ~ 4.8 % nas ondas teta de EEG após teste RVIP em FM e reduziu em FM + CAF ~ 8.8 % e FM + PLA ~ 4.8%. A razão entre PSE e WMEAN foi menor em FM + CAF do que nas outras condições (p = 0.01). Os ciclistas apresentaram maior motivação nos primeiros 2 km em FM + CAF comparado a FM e FM + PLA (p = 0.02) e maior afeto nos últimos 2 km em FM e FM + CAF do que FM + PLA (p = 0.01). Uma menor ativação cortical durante a CVIS e uma maior eficiência neuromuscular foi identificada na condição FM + CAF (p = 0.03). Conclusão: A CAF bloqueou os efeitos negativos da fadiga mental no CPF, melhorou o desempenho, diminuiu a PSE durante TT20km e aumentou a eficiência neuromuscular / Recent literature suggests that mental fatigue worsens the performance of athletes during time trial (TT) cycling tests. Thus, the aim of this study was to verify if caffeine could reverse or block the negative effects of mental fatigue in a TT of 20km (TT20km). Methods: Twelve trained cyclists with experience in TT for at least 2 years, and performance level > 3 (34.3 ± 6.2 years, 179.3 ± 5.1 cm, 77.6 ± 6.8 kg, 13.8 ± 4.5 % body fat 58.9 ± 6.2 ml .kg-1.min-1; 367.0 ± 32.5 WPEAK), carried out five visits at laboratory: 1) PRELIMINARY: for selection of subjects and familiarization with the instruments; 2) CONTROL: three maximal isometric voluntary contractions (CVM) were performed, the highest torque found between them will define the value of 70% for voluntary isometric submaximal contraction (CVIS) in the following sessions. After the CVIS, the TT20km will be performed without cognitive manipulation or supplementation; 3) MENTAL FATIGUE (FM): execution of the sustained attention test (RVIP), CVIS and TT20km respectively; 4) PLACEBO: placebo capsule intake (FM + PLA) then RVIP, CVIS and TT20km test; 5) CAFFEINE: caffeine intake (FM + CAF), consequently performed the RVIP, CVIS and TT20km tests). Brain activity of the prefrontal cortex and primary motor cortex will be analyzed by electroencephalography (EEG) recorded before and after the RVIP test. Likewise, EEG of the prefrontal cortex and primary motor will be recorded during a submaximal isometric voluntary contraction, performed before TT20km. For the analysis of comparisons between pre and post cognitive task of sustained attention was used a T-student test. For the multiple comparisons, the mixed model was analyzed for the condition and the distance in the TT20km, and the best matrix was identified for each case, when necessary the Bonferroni test was used. Results: CAF improved performance in mentally fatigued cyclists at ~ 1.8 % for FM and ~ 1.7 % for PLA (p = 0.00) and increased ~ 4.4% for FM and ~ 3.6% than WMEAN on FM + CAF (p = 0.00). Cortical activation increased by ~ 4.8 % in the theta EEG waves after RVIP test in FM and reduced in FM + CAF ~ 8.8 % and FM + PLA ~ 4.8 %. The ratio of RPE to WMEAN was lower in FM + CAF than in other conditions (p = 0.01). The ciclists started the TT20km more motivated in first 2 km (p = 0.02) and finished with more pleasure in the last 2km in FM and FM + CAF than in FM + PLA (p = 0.01). Lower cortical activation during CVIS and greater neuromuscular efficiency was identified in the FM + CAF condition (p = 0.03). Conclusion: CAF blocked the negative effects of mental fatigue on CPF, improved performance, decreased PSE over TT20km and increased neuromuscular efficiency

A osteoporose é um enfraquecimento progressivo dos ossos, que ficam cada vez mais sujeitos a fraturas. Embora possa acometer ambos os sexos, ela é mais freqüente nas mulheres após a menopausa devido à diminuição dos hormônios femininos, os estrógenos. É uma doença que avança lentamente, sem sintomas, geralmente sem ser percebida até que aconteça uma fratura. Uma vez instalada a osteoporose, tem que se evitar maior perda óssea para prevenir fraturas. O objetivo deste trabalho é analisar o quadro de instalação de osteopenia em ossos corticais de ratas ovariectomizadas. Foi utilizado um modelo de osteopenia em 29 ratas Wistar ovarectomizadas com massa corpórea de 250 gramas. Os animais foram divididos em 6 grupos experimentais e eutanaziados em períodos diferentes: o primeiro grupo foi eutanaziado 30 dias após a cirurgia, que corresponde ao tempo de início da osteopenia, e a partir daí, os demais grupos foram eutanaziados numa seqüência de 15 dias até o 105º dia. A avaliação do quadro de instalação foi realizada através de medidas antropométricas e de propriedades mecânicas dos fêmures (ensaio de flexão de três pontos). Cada um dos itens obtidos foram comparados utilizando-se o programa GraphPad InStat 3. O teste t-Student foi aplicado para checar a variação do peso corporal com p < 0,05. Aplicaram-se os testes ANOVA e Student-Newmam-Keuls com coeficiente de variação também menor que 5% para os demais itens analisados. Observou-se um aumento significativo no comprimento dos fêmures durante o primeiro mês de experimento, assim como na carga máxima aplicada. Os resultados obtidos neste estudo sugerem que a ovariectomia é um fator que não causa grandes alterações mecânicas e geométricas na região cortical dos fêmures de ratas no período analisado / Osteoporosis is a progressive weakness of bones, which are more and more subjects to fractures. Although it happens to men and women, it is more frequent in postmenopausal women due to a decrease of female hormones. It is a disease without symptoms and it is usually noticed only after a fracture. Once the osteoporosis is installed, a bigger bone loss must be avoided in order to prevent a fracture. This study aims to analyze the osteopenia installation process in cortical bones of ovariectomized rats. An osteopenia model was used in 29 ovariectomized Wistar female rats with body weight of 250 g. Animals were divided in 6 experimental groups, the first group was sacrificed 30 days after the surgery and, the other groups, every 15 days on until the 105th day. The evaluation of installation process was made through anthropometrics and mechanical proprieties of femur (three-point bending test). Program GraphPad InStat 3 was used in order to compare the observed items. T-student test was used to check the body weight variation with p < 0,05 and tests ANOVA and Student-Newmam-Keuls were applied to the other items (p < 0,05). A significant increase in femur length and in maximum bending load were obtained. The found results in this research suggest that ovariectomy is a factor that does not cause significant mechanical and geometric alterations on cortical region of femurs in female rats during the analyzed period

[EN] Cortical bone tissue is the responsible of giving support and structure to vertebrates. For that reason, understanding and analyzing its behavior is needed from each different hierarchical level that composes it. The lower the structural scale is, the greater the complexity and scarcity of studies in literature. These studies are relevant for understanding, preventing and solving important health problems that affect human beings. From a mechanical point of view is interesting to evaluate and apply engineering numerical tools to analyze complex materials as biological tissues, increasing the state of the art in different disciplines that can be applied in numerous fields as material science, biomechanics, numerical methods, medicine and more. In this Thesis the mechanical behavior of cortical bone at microstructural level is analyzed, with finite element models of its basic structure, the osteon. The microstructure of osteons, composed of mineralized collagen fibrils in layers with different orientations disposed concentrically around blood vessels is considered in the models for the calculation of elastic properties and failure criteria definition. For obtaining elastic properties, the use of micromechanical finite element models is considered, with heterogeneous composition for both mineralized collagen fibrils (at nanostructural level) and lamellar level (at sub-microstructural level). The failure analysis for realistic geometries is applied after comparing different models that involve, on one hand the growth of microcracks with contact conditions and on the other, degradation of elastic material properties by user subroutines of the finite element code, the latter being the one that brings better results from a computational cost viewpoint. Therefore an interesting alternative is here presented that can be used to evaluate the damage propagation at three-dimensional level, which with other methods as X-FEM can be computationally unaffordable. Composite materials failure criteria are applied to osteon analysis and the results are related with experimental tests from bibliography, showing the relevance of shear stresses between lamellae for failure initiation and propagation. In a two-dimensional study it is also shown the important role of osteocyte lacunae in the failure initiation, what is interesting from a cellular mechanotransduction approach. / [ES] El tejido óseo cortical es el encargado de dar soporte y estructura a los vertebrados. Existe por tanto una necesidad de conocer y analizar mecánicamente su comportamiento desde los distintos niveles jerárquicos que lo componen, siendo mayor la complejidad y más escasos los estudios disponibles en la literatura cuanto más pequeña es la escala estructural que se analiza. Estos estudios son relevantes para comprender, prevenir y solucionar problemas de salud importantes que afectan al ser humano. Desde el punto de vista mecánico es interesante evaluar y aplicar herramientas numéricas ingenieriles para el análisis de materiales más complejos como son los biológicos, incrementando el estado del arte en distintas disciplinas que pueden ser aplicadas en numerosos campos como la ciencia de los materiales, la biomecánica, los métodos numéricos o la medicina, entre otras. En esta Tesis se analiza el comportamiento mecánico del hueso cortical a nivel microestructural, donde se modela mediante el método de los elementos finitos su unidad básica, la osteona. Para la obtención de las propiedades elásticas se considera en los modelos la microestructura compuesta por capas de colágeno mineralizado con diferentes orientaciones, dispuestas de manera concéntrica alrededor de los canales vasculares. Se incluye además la utilización de modelos micromecánicos de elementos finitos que tienen en cuenta la composición heterogénea tanto para el nivel del fibrilo de colágeno mineralizado (nivel nanoestructural) como para el nivel de lamela (nivel sub microestructural). El análisis del fallo para geometrías realistas se aplica tras comparar varios modelos que involucran por un lado el crecimiento de grietas mediante condiciones de contacto y por otro, degradación de las propiedades elásticas del material mediante subrutinas de usuario del código de elementos finitos, siendo este último el que mejores resultados presenta desde el punto de vista del coste computacional. De esta manera se presenta una alternativa interesante que permite evaluar la propagación del daño a nivel tridimensional, lo que con otros métodos como el X-FEM puede ser computacionalmente inabordable. Se aplican criterios de fallo utilizados para materiales compuestos en ingeniería estructural a las osteonas y los resultados se relacionan con los de los ensayos experimentales disponibles en la bibliografía, mostrando la relevancia de las tensiones de cortadura entre lamelas para la iniciación y propagación del daño. En un estudio bidimensional, también se muestra la participación importante en la fase de inicio de daño de las lagunas de osteocitos lo que es interesante desde un enfoque de mecanotransducción celular. / [CAT] El teixit ossi cortical és l'encarregat de donar suport i estructura als vertebrats. Existeix per tant una necessitat de conèixer i analitzar mecànicament el seu comportament des dels diferents nivells jeràrquics que ho componen, sent major la complexitat i més escassos els estudis disponibles en la literatura com més xicoteta és l'escala estructural que s'analitza. Aquests estudis són rellevants per a comprendre, prevenir i solucionar problemes de salut importants que afecten a l'ésser humà. Des del punt de vista mecànic és interessant avaluar i aplicar eines numèriques ingenieriles per a l'anàlisi de materials més complexos com són els biològics, incrementant l'estat de l'art en diferents disciplines que poden ser aplicades en nombrosos camps com la ciència dels materials, la biomecànica, els mètodes numèrics o la medicina, entre altres. En aquesta Tesi s'analitza el comportament mecànic de l'os cortical a nivell microestructural, on es modela mitjançant el mètode dels elements finits la seua unitat bàsica, la osteona. Per a l'obtenció de les propietats elàstiques es considera en els models la microestructura composta per capes de col·làgen mineralitzat amb diferents orientacions, disposades de manera concèntrica al voltant dels canals vasculars. S'inclou a més la utilització de models micromecànics d'elements finits que tenen en compte la composició heterogènia tant per al nivell del fibril de col·làgen mineralitzat (nivell nanoestructural) com per al nivell de lamela (nivell submicroestructural). L'anàlisi de la fallada per a geometries realistes s'aplica després de comparar diversos models que involucren d'una banda el creixement de clavills mitjançant condicions de contacte i per un altre, degradació de les propietats elàstiques del material mitjançant subrutines d'usuari del codi d'elements finits, sent aquest últim el que millors resultats presenta des del punt de vista del cost computacional. D'aquesta manera es presenta una alternativa interessant que permet avaluar la propagació del dany a nivell tridimensional, la qual cosa amb altres mètodes com el X-FEM pot ser computacionalment inabordable. S'apliquen criteris de fallada utilitzats per a materials compostos en enginyeria estructural a les osteones i els resultats es relacionen amb els de els assajos experimentals disponibles en la bibliografia, mostrant la rellevància de les tensions de cisallament entre lameles per a la iniciació i propagació del dany. En un estudi bidimensional, també es mostra la participació important en la fase d'inici de dany de les llacunes d'osteòcits el que és interessant des d'un enfocament de mecanotransducción cel·lular. / Arango Villegas, C. (2016). Study of the mechanical behavior of cortical bone microstructure by the finite element method [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/67570 / TESIS

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18180号 / 医博第3900号 / 新制||医||1004(附属図書館) / 31038 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 金子 武嗣, 教授 渡邉 大 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

On utilise en IRM clinique T2, T1 et la densité de protons comme biomarqueurs de diagnostic et de suivi. Cependant, seuls les tissus à T2 long sont visibles par IRM classique. La séquence UTE (Ultra-short TE) a été récemment développée pour des études quantitatives de l’os cortical. Nous avons dans une première étape confronté des mesures de porosité de l’os cortical par IRM-UTE et par microtomographie par rayonnement synchrotron, car la porosité est un paramètre déterminant de la qualité osseuse. L’étude a été menée sur 38 échantillons de diaphyses fémorales humaines en collaboration avec une équipe du B2OA (UMR7052). La porosité par IRM-UTE à 4.7 T (TE = 51 µs) est entre 18 et 43% (moyenne 30%). La porosité par microtomographie (résolution spatiale : 6.5 µm) est entre 3 et 27% (moyenne 14%). Aucune corrélation n’a pu être observée entre les deux mesures. Une importante dispersion a été observée sur les valeurs de T1 entre les échantillons, que nous proposons d’attribuer à des effets de transfert d’aimantation (MT) entre les protons de l’eau liée au collagène et les protons des terminaisons méthylène du collagène. Pour confirmer cette interprétation, nous avons dans une seconde étape confronté plusieurs méthodes d’évaluation de la relaxation longitudinale dans des échantillons d’os bovin. Les mesures réalisées par différentes séquences (inversion-récupération, saturation hors-résonance, saturation par répétition de binomiales et angle de bascule variable) confirment des effets de MT importants. Les méthodes les plus robustes pour évaluer les paramètres sont la saturation hors-résonance et par répétition de binomiales, ce qui suggère leur utilisation pour de futures applications in vivo. / Longitudinal and transverse relaxations are quantitative tools used in MRI for diagnosis and follow up. However only tissues with long T2 can be detected with MRI. Quantitative evaluation of cortical bone porosity is now feasible with UTE.In this work, porosity measurements from UTE in human cortical bone samples were compared with those from micro-computed tomography (µCT). 38 human cortical bone samples (upper diaphysis) were examined in collaboration with a team from B2OA (UMR7052). Porosity from UTE (TE = 51 µs) was between 18% and 43% (mean 30%) and from µCT (spatial resolution = 6.5 µm) between 3% and 27% (mean 14%). No correlation could be established between the two measurements. T1 values from few samples were dispersed; a possible explanation could be the magnetization transfer (MT) between collagen-bound water protons and collagen methylene protons.For a quantitative interpretation of this phenomenon, 11 bovine cortical bone samples were examined. Several sequences (inversion-recovery, off-resonance saturation, repeated binomial excitations, variable flip angle) were implemented at 4.7 T to assess MT parameters. The aim was to compare which method may provide accurate parameter estimation. Off-resonance saturation and repeated binomial excitation seem to be more suitable for in vivo MT quantification.

La recherche en biomécanique des chocs est une nécessité pour améliorer la sécurité dans les transports. Pour une meilleure évaluation des critères lésionnels lors des simulations de crash, le manque de représentativité des modèles EF du thorax humain pourrait être comblé par une démarche de personnalisation aussi bien au niveau géométrique que mécanique. Cette thèse se base sur l’étude de 18 sujets humains post-mortem. A partir des données d’imagerie, les différentes dimensions des côtes sont analysées. La corrélation de ces paramètres aboutit à la prédiction de 192 dimensions à partir d’un unique paramètre d’entrée. A une échelle inférieure, un protocole innovant a permis de coupler des informations microstructurales issues d’un μCT avec la forme extérieure des côtes. 2 hémi-thorax ont été micro-scannés afin de générer une cartographie complète des épaisseurs d’os cortical. Une stratégie a été mise en place pour proposer un algorithme prédisant l’intégralité de cette géométrie locale d’après un seul tronçon de côte. La pertinence de cette personnalisation a été évaluée par une étude de sensibilité sur des modèles EF. Les résultats d’essais de traction sur os cortical montrent un comportement différent entre les éprouvettes prélevées sur la table interne ou externe des côtes. Une caractérisation précise de la structure interne de l’os cortical, couplé à des essais de micro-traction in-situ, a pu apporter des éléments de réponse sur cette différence. Unalgorithme de personnalisation a été aussi proposé pour les propriétés mécaniques, complétant ainsi la démarche d’adapter les modèles EF du thorax à chaque individu afin d’améliorer leur biofidélité. / For a better assessment of injury criteria on the human thorax, realistic numerical simulations need accurate geometrical characterization and an understanding of the mechanical behavior of the rib. Thelack of representation of the FE models of the human thorax could be filled by a personalization of these two aspects. This thesis is based on the study of 18 post-mortem human subjects. From medical data (CT-scans), the different dimensions of the ribs were analyzed. The correlation of the measurements led to the prediction of 192 dimensions from a single input parameter. At a lower scale, an innovative protocol enabled us to combine microstructural information obtained from a μCT with the external shape of the ribs. 2 hemi-thoraxes were scanned to generate a complete map of the thickness of cortical bone and cross-section area evolution. A strategy was implemented to provide an algorithm, predicting this entire local geometry from a single rib’s sample. The relevance of this customization was evaluated by a sensitivity analysis on FE models. The results of tensile tests on cortical bone showed different behaviors between the samples harvested from the inner or outer side of the rib. A precise characterization of the internal structure of the cortical bone, coupled with in-situ micro-tensile device, revealed certain answers about this difference. An algorithm is also proposed topersonalize the mechanical properties, completing the approach of adapting the FE models of the thorax of each individual to improve their biofidelity.

No description available.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23774号 / 医博第4820号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 高橋 淳, 教授 井上 治久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Les malformations du développement cortical (MDC) résultent d’altérations au niveau de différentes étapes de la corticogénèse telles que la prolifération, la migration et la différenciation neuronale et sont généralement associées à des épilepsies pharmaco-résistantes et à des déficiences intellectuelles sévères. Les causes génétiques des MDC restent encore inconnues dans de nombreux cas, nous avons donc réalisé le séquençage de l’exome entier de nombreux patients présentant des MDC et les analyses ont permis de mettre en évidence l’implication des gènes KIF2A et NEDD4L dans les MDC. Dans le cadre de ma thèse, nous proposons de focaliser sur les conséquences cellulaires et neurodéveloppementales résultant des mutations dans les gènes KIF2A et NEDD4L retrouvées chez les patients atteints de MDC. KIF2A code pour une kinésine-13 qui a pour fonction de réguler la dynamique des microtubules (MT) via son activité MT dépolymérase ATP-dépendante aux niveaux des extrémités des MT. L’approche basée sur la technique d’électroporation in utero nous a permis de mettre en évidence le rôle crucial joué par KIF2A dans la régulation de la neurogénèse, la migration neuronale et le positionnement des neurones dans le cortex. En particulier, nos données révèlent que l’expression des mutants KIF2A responsables de MDC entraîne une augmentation du nombre de cellules à l’état de progéniteurs qui est conséquente à un allongement du temps passé dans le cycle cellulaire. Nos premières données cellulaires et au cours du développement montrent que l’expression des mutants KIF2A induit des altérations dans l’intégrité du fuseau mitotique, dans la progression mitotique et également une localisation anormale de KIF2A au niveau du cil primaire. NEDD4L code pour une E3 ubiquitine ligase qui joue un rôle dans l’ubiquitination de nombreux substrats permettant la régulation de leur dégradation et de leur localisation subcellulaire. Dans un premier temps, nos données cellulaires ont montré que les mutants associées à des MDC ont une sensibilité accrue pour la dégradation par le protéasome. De plus, l’approche d’électroporation in utero a permis de montrer que l’expression des mutants NEDD4L ainsi qu’un excès de NEDD4L WT dérégulent la neurogenèse, le positionnement des neurones et le processus de translocation terminal. Des études complémentaires, incluant le traitement à la rapamycine, ont révélé qu’un excès de NEDD4L WT mène à la dérégulation des voies de signalisations mTORC1 et Dab1 tandis que l’expression des mutants est associée à une dérégulation des voies mTORC1 et Akt. L’ensemble de ces résultats renforce donc dans un premier temps l’importance des protéines liées aux MT dans le développement cortical en décrivant le rôle crucial de la kinésine KIF2A dans des mécanismes tels que la dynamique de migration neuronale et dans la régulation du cycle cellulaire des progéniteurs neuronaux. D’autre part, nous fournissons également de nouvelles données permettant de mieux comprendre le rôle critique de NEDD4L dans la régulation des voies mTOR et de leurs contributions dans le développement cortical. / Malformations of cortical development (MCD) result from alterations in different stages of corticogenesis such as proliferation, migration and neuronal differentiation, and are generally associated with drug-resistant epilepsy and severe intellectual disabilities. The genetics causes of MCD remain largely unknown, we have thus performed the whole-exome sequencing of many patients with MCD and reported the identification of multiple pathogenic missense mutations in KIF2A and NEDD4L genes. Within the frame of my thesis project, we propose to focus on the cellular and neurodevelopmental consequences resulting from KIF2A and NEDD4L mutations shown to be involved in MCD. KIF2A is a member of the kinesin-13 family, which rather than regulating cargos transport along microtubules (MT), regulates MT dynamics by depolymerizing MTs. The in utero electroporation approach allowed us to highlight the crucial role of KIF2A in the regulation neurogenesis, neuronal migration and the neuronal positioning in the cortex. Particularly, our data show that the expression of the KIF2A mutants involved in MDC lead to an increase in the number of cells in proliferative state which is a consequence of a prolonged time spent in the cell cycle. Our first cellular data and during development show that the expression of pathogenic KIF2A mutations induce alterations in the mitotic spindle integrity, in the mitotic progression and also an abnormal localization of KIF2A in the primary cilium. NEDD4L encodes a member of the NEDD4 family of HECT-type E3 ubiquitin ligases known to regulate the turnover and function of a number of proteins involved in fundamental cellular pathways and processes. Firstly, cellular and expression data showed sensitivity of MCD-associated mutants to proteasome degradation. Moreover, the in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while MCD-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these results reinforce the importance of MT-related proteins in cortical development describing the crucial role of KIF2A kinesin in mechanisms such as neuronal migration dynamics and neuronal progenitor’s cell cycle regulation. On the other hand, we also provide new data to better understand the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.