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1
Coles, S. K. "Controls of the locomotor system in the rat." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233493.
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Avor, John Kweku. "Application of sensor fusion to human locomotor system." To access this resource online via ProQuest Dissertations and Theses @ UTEP, 2009. http://0-proquest.umi.com.lib.utep.edu/login?COPT=REJTPTU0YmImSU5UPTAmVkVSPTI=&clientId=2515.
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Kramer, Patricia Ann. "Locomotor energetics and limb length in hominid bipedality /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/6428.
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Jia, Yan. "Computer simulation of the lamprey spinal cord locomotor system." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610128.
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Lu, Tung-Wu. "Geometric and mechanical modelling of the human locomotor system." Thesis, University of Oxford, 1997. https://ora.ox.ac.uk/objects/uuid:789d619c-f32e-4efa-9935-6ec8ce82ece4.
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A critical review of studies related to the modelling of the human locomotor system is given. Kinematic and dynamic modelling and analysis of the pelvis-leg apparatus as an ensemble of four rigid body segments are described. Experiments were performed on two patients with custom-made instrumented massive proximal femoral prostheses implanted after tumour resection. Telemetered axial forces transmitted along the prostheses, together with kinematic, force plate and electromyographic data, were recorded synchronously during level walking, single and double leg stance, and isometric tests of the hip muscles. A sagittal plane model of the locomotor system, with an anatomical model of the knee joint, was developed from an existing model and used for a comparative study of methods for the calculation of the internal forces. A three-dimensional computer graphics-based animated model of the locomotor system was developed, with the hip as a ball-and-socket joint, the knee as a parallel spatial mechanism and the ankle as a two-hinge complex. Thirty-four muscles or muscle groups were included. A method for the determination of the orientation of multi-joint systems from surface markers was developed to take account of measurement errors including skin movement artefacts. Both the 2D and 3D models of the locomotor system were evaluated and validated quantitatively with the telemetered femoral axial forces. It is concluded that (a) a significant part of the bending moments along limbs are transmitted by a combination of tensile forces in muscles and compressive forces in bones so that moments transmitted by the bones are much less than the limb moments, (b) bi-articular muscles play a major role in modulating forces in bones, (c) appropriate simulation of muscle forces is important in experimental or theoretical studies of load transmission along bones, (d) computer graphics-based modelling and animation are important tools in bridging the gap between clinical users and biomechanists.
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Zwart, Maarten Frans. "Structural and functional plasticity in the Drosophila larval locomotor circuit." Thesis, University of Cambridge, 2012. https://www.repository.cam.ac.uk/handle/1810/252285.
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Jackson, Adam Wesley. "Organization of brain and spinal cord locomotor networks in larval lamprey." Diss., Columbia, Mo. : University of Missouri-Columbia, 2006. http://hdl.handle.net/10355/4481.
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Thesis (Ph.D.)--University of Missouri-Columbia, 2006.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on April 27, 2009) Vita. Includes bibliographical references.
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Yunusov, Temur. "Characterisation of cholinergic interneurons in the larval locomotor network of Drosophila." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607841.
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Gilbert, Mathew Alan. "Optimising visuo-locomotor interactions in a motion-capture virtual reality rehabilitation system." Thesis, University of York, 2013. http://etheses.whiterose.ac.uk/3986/.
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This thesis presents the research-driven design and development of Stromohab: A motion-capture virtual-reality locomotion simulator for the research and rehabilitation of gait disorders following stroke. Software and hardware components are designed, developed and tested to facilitate and motivate patients in rehabilitative interactive avatar-based locomotor tasks. The system is then used to investigate systematically on healthy volunteers the known problem of distance underestimation in virtual environments by testing and analysing all combinations of cross-planar translation of leg movement to avatar actuated movement in a virtual environment. Specific performance deficits in the sagittal plane are confirmed and compared to those from coronal and transverse motion. Potential improvements of adding in isolation monocular cues for perspective, illumination, or size, and binocular cues from 3D stereo anaglyphs, are investigated, leading to a proposed movement model and scaling solution that both explains and resolves the observed deficit empirically in a practical locomotor task. Overall, the findings demonstrate the importance for the design and application of virtual environment interfaces of quantifying the underlying mechanisms in order to ensure accurate and controlled reproduction of a user’s movement. These would be of particular significance in medical rehabilitation for neurological patients, for whom consideration of cognitive load and the potential for improper re-adaptation when returning to real world environments can be critical. It is envisaged that this study will be useful to technologists, clinicians and other professionals who apply the rapidly developing, increasingly accessible and beneficial motion capture and virtual reality technologies to medicine and related applications.
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Bauman, Jay Morris. "Injury compensation reveals implicit goals that guide locomotor coordination." Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/51737.
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Locomotion persists despite changes in external and internal circumstances. Motor responses to gait impairment exhibit commonalities across various taxa and types of injury, yet we lack a systematic understanding of compensation strategies. The objective of this dissertation is to uncover principles governing implicit goals within the control of locomotion. I propose that coordination of injured locomotion will demonstrate that these goals follow a hierarchical organization of the neuromuscular system. Accurate quantification of gait deficits in rodents demands sophisticated measurement techniques. I utilize X-ray technology to examine intralimb and interlimb coordination after unilateral injury in rats. My findings indicate that compensation to injury involves the coordination of lower-order motor elements to preserve the pre-injury behaviors of higher-order elements. Specifically I present evidence that preservation of limb angle and limb length are critical task goals that transcend injury states and afferent sensory feedback conditions. Broadening my investigation to include interlimb coordination revealed that task goals may change to satisfy the goals of a higher hierarchical level. This work is a necessary precursor to study locomotor coordination and injury compensation in more complex rodent injury models such as self-reinnervation, sciatic nerve, and spinal cord injury. These results could also translate to clinical gait rehabilitation through future protocols that address motor patterns of the entire limb over the behavior of individual joints.
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Clotten, Felix [Verfasser], Carmen [Gutachter] Wellmann, and Ansgar [Gutachter] Büschges. "Descending Control in a Locomotor System / Felix Clotten ; Gutachter: Carmen Wellmann, Ansgar Büschges." Köln : Universitäts- und Stadtbibliothek Köln, 2019. http://d-nb.info/1213896940/34.
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Hudson, Penny Elena. "The structural and functional specialisation of locomotion in the cheetah (Acinonyx Jubatus)." Thesis, Royal Veterinary College (University of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572138.
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Somera, Junior Renato. "Estratégia de ensino anatômico a violonistas para prevenção de lesões do aparelho locomotor." Faculdade de Medicina de São José do Rio Preto, 2012. http://bdtd.famerp.br/handle/tede/182.
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Previous issue date: 2012-11-27Introduction: Acoustic Guitar players represent the most part of the instrumentalists and their activities involve repetitive efforts or static posture, which makes them likely candidates to develop labor disease, most times due to absolute lack of information. The objective of this study was to prepare an illustrative manual of the locomotor system, specifically directed to guitarists, for injury prevention. Method: 61 guitarists (students, professors, semi-professionals and professionals) in the city of São José do Rio Preto SP were taken into consideration, with the application of a questionnaire in order to estimate knowledge on bones, muscles and joints intrinsically associated with the praxis of guitar musical performances. As results, 83.5 % of the respondents had no specific anatomical knowledge, 62.3 % received no orientation on the best physical postures to perform the guitar; 63.93 % do not effect prior stretching for upper limbs or other body regions; 50.82 % do not practice muscle warming before the practice, and 52.46 % do not make pauses during the activity. Body areas that were constantly used during practice with the guitar encompassed right wrist (70.49%), left wrist (59.01%), right hand (63.93%) and left hand (50.81%). Spearman's correlation was used to estimate the relation between discomfort and hours of daily practice with guitar and it indicated positive correlation of low degree on right (r=0.3536) and left wrists (r=0.3226) and on the left hand (r=0.3431). Production of Illustrated Manual of Human Anatomy specific to the Locomotor System promotes teaching strategy to prevent injuries, traumas or musculoskeletal origin pathologies of guitarists, from complete beginners to instrumentalists.
Introdução: Violonistas representam a maioria dos instrumentistas e suas atividades envolvem esforços repetitivos ou postura estática, o que assim os torna prováveis candidatos a desenvolver doença laboral, a maioria das vezes por absoluta falta de informação. O objetivo do presente estudo foi elaborar manual ilustrativo do aparelho locomotor, especificamente direcionado a violonistas, para prevenção de lesões. Método: Foram considerados 61 violonistas (estudantes, docentes, semi-profissionais e profissionais) da cidade de São José do Rio Preto SP, com aplicação de questionário a fim de estimar conhecimento referente a ossos, músculos e articulações intrinsecamente associados à práxis de execuções musicais de violão. Como resultados, 83,5% dos respondentes não tinham conhecimento anatômico específico; 62,3% não receberam orientação sobre as melhores posturas físicas para executar o violão; 63,93% mencionam não efetuar alongamento prévio dos membros superiores ou de outras regiões corporais; 50,82% não praticam aquecimento muscular antes da prática, e 52,46% não efetuam pausas durante a atividade. Áreas corporais constantemente utilizadas durante a prática com o violão englobaram pulso direito (70,49%), pulso esquerdo (59,01%), mão direita (63,93%) e mão esquerda (50,81%). Correlação de Spearman foi usada para estimar relação entre desconforto e horas de prática diária com violão indicou correlação positiva de grau baixo nos pulsos direito (r=0,3536) e esquerdo (r=0,3226) e na mão esquerda (r=0,3431). Confecção de Manual Ilustrado de Anatomia Humana específica ao Aparelho Locomotor promove estratégia de ensino para prevenir lesões, traumas ou patologias de origem musculoesquelética a violonistas, desde iniciantes até instrumentistas.
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McGregor, Lisa. "Locomotor morphology of Anolis, comparative investigations of the design and function of the subdigital adhesive system." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0021/MQ49643.pdf.
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Bigordà, Sagué Albert. "Diseño y validación de una aplicación informática de sospecha de patología del aparato locomotor en el hombro." Doctoral thesis, Universitat de Lleida, 2017. http://hdl.handle.net/10803/405802.
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S'exposa una demora significativa per accedir a tractament de fisioteràpia en els afectats per dolor d'espatlla. Es proposa millorar-la amb el disseny i validació d'una aplicació informàtica autoadministrada per a la sospita de patologia. Es van reclutar usuaris amb dolor de més de 6 setmanes d'evolució en serveis de rehabilitació i traumatologia. S'ha realitzat una revisió bibliogràfica, una prova de viabilitat, una revisió per avaluadors experts segons la metodologia Delphi, una prova pilot amb anàlisi de la fiabilitat i una prova de validació en 250 pacients. Els valors de validesa van ésser: CP+ 7,8 i CP- 0,1 per a la radiculopatia; CP+ 4,1 i CP- 0,4 per a l’artrosi glenohumeral; CP+ 15,5 i CP- 0,2 per a la inestabilitat; CP+ 17,2 i CP- 0,2 per a la ruptura massiva del manegot rotador; CP+ 6,2 i CP- 0,2 per a la retracció capsular; CP+ 4,0 i CP- 0,3 per al síndrome subacromial; i CP+ 2,5 i CP- 0,6 per a l’artropatia acromioclavicular. S'ha obtingut un coeficient de Kappa del 0,67 i una mitja de correcta classificació del 84% per a un mateix pacient. Els factors que van influir negativament en la precisió van ser la ruptura massiva del manegot rotador, l'artropatia acromioclavicular, una edat superior a 55 anys i una intensitat del dolor (EVA) superior a 8 (p> 0,05). S'exposa una bona fiabilitat, una acceptable validesa per a algunes patologies, però una insuficient capacitat per a sospitar la totalitat del quadre clínic en un mateix pacient.Se expone una demora significativa para acceder a tratamiento de fisioterapia en los aquejados por dolor de hombro. Se propone mejorarla con el diseño y validación de una aplicación informática autoadministrada para la sospecha de patología. Se reclutaron usuarios con dolor de más de 6 semanas de evolución en servicios de rehabilitación y traumatología. Se ha realizado una revisión bibliográfica, una prueba de factibilidad, una revisión por evaluadores expertos según la metodología Delphi, una prueba piloto con análisis de la fiabilidad y una prueba de validación en 250 pacientes. Los valores de validez fueron: CP+ 7,8 y CP- 0,1 para la radiculopatía, CP+ 4,1 y CP- 0,4 para la artrosis glenohumeral, CP+ 15,5 y CP- 0,2 para la inestabilidad, CP+ 17,2 y CP- 0,2 para la rotura masiva del manguito rotador, CP+ 6,2 y CP- 0,2 para la retracción capsular, CP+ 4,0 y CP- 0,3 para el síndrome subacromial, y CP+ 2,5 y CP- 0,6 para la artropatía acromioclavicular. Se ha obtenido un coeficiente Kappa del 0,67 y una media de correcta clasificación del 84% para un mismo paciente. Los factores que influyeron negativamente en la precisión fueron la rotura masiva del manguito rotador, la artropatía acromioclavicular, una edad superior a 55 años y una intensidad del dolor (EVA) superior a 8 (p>0,05). Se expone una buena fiabilidad y una aceptable validez para algunas patologías, pero una insuficiente capacidad para la sospecha de la totalidad del cuadro clínico en un mismo paciente.
There is a significant delay in accessing physiotherapy treatment for those patients with shoulder pain. It is proposed to improve it with the design and validation of a self-administered computer application for suspected pathology. Patients with pain for more than six weeks in rehabilitation and traumatology services were recruited. A bibliographic review, a feasibility test, a review by expert evaluators according to the Delphi methodology, a pilot test with reliability analysis and a validation test in 250 patients were carried out. Validity values were: LR+ 7,8 and LR- 0,1 for radiculopathy; LR+ 4,1 and LR- 0,4 for glenohumeral osteoarthritis; LR+ 15,5 and LR- 0,2 for instability; LR+ 17,2 and LR- 0,2 for massive rotator cuff tear; LR+ 6,2 and LR- 0,2 for capsular retraction; LR+ 4,0 and LR- 0,3 for subacromial syndrome; and LR+ 2,5 and LR- 0,6 for acromioclavicular arthropathy. A kappa coefficient of 0,67 and an average of correct classification for the same patient of 84% were obtained. Factors that negatively influenced precision were massive rupture of the rotator cuff, acromioclavicular arthropathy, age over 55 years and pain intensity (VAS) over 8 (p> 0,05). The result were good reliability and acceptable validity, but insufficient capacity to suspect whole clinical state in the same patient.
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Blümel, Marcus [Verfasser], and Ansgar [Akademischer Betreuer] Büschges. "Locomotor system simulations and muscle modeling of the stick insect (Carausius morosus) / Marcus Blümel. Gutachter: Ansgar Büschges." Köln : Universitäts- und Stadtbibliothek Köln, 2011. http://d-nb.info/1037851374/34.
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Mozerle, Angelise. "Inventário de avaliação do sistema locomotor de pacientes da reabilitação cardiopulmonar e metabólica." Universidade do Estado de Santa Catarina, 2009. http://tede.udesc.br/handle/handle/435.
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Previous issue date: 2009-06-15Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
It is generally thought that a significant number of individuals who participate in Cardiopulmonary and Metabolic Rehabilitation Programs (CPMR) are also affected by changes in their locomotor system, partly due to the natural aging process. Such changes must be detected, to prevent musculoskeletal complications, to enhance adherence to treatment and to improve the benefits of physical exercises. As far as we know, an instrument specially developed to identify locomotor system conditions in patients referred to CPMR programs is lacking, at this moment. Thus, the Locomotor System Assessment Inventory (IASL Inventário de Avaliação do Sistema Locomotor) was developed, comprising the following stages: the instrument s creation, the theoretical validation of items through a content and semantic analysis and also by means of analytical procedures, aiming to identify locomotor conditions, specially those causing pain; to check if the identified conditions bear a relation with the physical exercises, and to allow the patient s screening for complete medical clearance, clearance with some reserve and no medical clearance before a specialized opinion. A group of 103 individuals who were participating in CPMR programs was assessed. The group comprised 33 male participants (32%) and 70 female participants (68%) ages 36 to 84, with 47 participants (45.6) diagnosed with a locomotor condition, 39 (37.9%) under a specific treatment (drug treatment, physiotherapy, and surgery), 33 (32%) taking some pain killer for locomotor symptoms, and 10 individuals (9.7%) stating that at some point their physicians had advised them against physical exercises. It is worth mentioning that 48 subjects (46.6%) reported some pain, and in 14 of these subjects (13.6%), physical exercises exacerbated their symptoms. In our opinion, patients with these conditions would require na expert opinion, before being allowed to resume their exercises.<0} IASL was developed as a 6-question test, with yes or no answers. The internal validity of the instrument was checked by Cronbach's alpha showed that for items 1, 2,3 and 5 of Cronbach's alpha coefficient for being more than satisfactory 0.70 (alpha 0.80) and items 4 and 6 received moderate alpha (alpha 0.61).
Supõe-se que parcela significativa dos participantes dos Programas de Reabilitação Cardiopulmonar e Metabólica (RCPM) apresente alterações do sistema locomotor, em parte decorrentes do processo natural do envelhecimento, que devem ser detectadas, no intuito de evitar complicações músculo esqueléticas, aumentar a aderência ao tratamento e aprimorar os resultados decorrentes dos exercícios físicos. Não é do nosso conhecimento um instrumento desenvolvido especialmente para identificar problemas do sistema locomotor em indivíduos encaminhados aos programas de RCPM. Foi desenvolvido o Inventário de Avaliação do Sistema Locomotor (IASL) de acordo com os seguintes passos: construção do instrumento, validação teórica dos itens por meio de análise de conteúdo e análise semântica, e por meio de procedimentos analíticos, com os objetivos de identificar problemas do sistema locomotor, em especial os dolorosos; verificar se os problemas identificados apresentam relação com o exercício físico; possibilitando a triagem dos pacientes, ou seja, liberação sem restrições, liberação com restrições e não liberação antes de parecer especializado. Foram avaliados por meio do IASL 103 indivíduos participantes de programas de RCPM, sendo 33 homens (32%) e 70 mulheres (68%), com idades entre 36 e 84 anos, dos quais 47 (45,6%) responderam ter recebido diagnóstico de problema do sistema locomotor, 39 (37,9%) receberam tratamento específico para o sistema locomotor (farmacológico, fisioterapia e cirurgia), 33 (32%) esporadicamente fazem uso de medicamentos devido sintomas do sistema locomotor e 10 indivíduos (9,7%) responderam que em algum momento o médico proibiu algum tipo de exercício físico. Ressalte-se que 48 indivíduos (46,6%) relataram sentir dor, que piorava com o exercício em 14 (13,6%) deles, o que segundo a nossa proposta exigiria parecer de especialista para prosseguimento no programa de exercícios. O IASL foi construído com 6 questões com respostas dicotômicas. A validade interna do instrumento foi verificada através do alfa de Cronbach que apresentou para os itens 1, 2,3 e 5 coeficiente de alfa de Cronbach satisfatório por serem maiores que 0,70 (alfa 0,80) e os itens 4 e 6 receberam alfa moderado (alfa 0,61).
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Rodríguez, Nuevo Aida. "OPA1 deficiency drives muscle inflammation = La deficiència d'OPA1 resulta en inflamació muscular." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/586046.
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Opa1 is a mitochondrial dynamics protein responsible for the fusion of the inner mitochondrial membrane, the maintenance of cristae morphology, and involved in mitochondrial DNA stability. In this study we have explored the origin of the effects of Opa1 deficiency in skeletal muscle, as well as the cellular mechanisms that give rise to the primary responses derived from its deficiency in the muscle context. Chronic treatment with an anti-inflammatory compound rescued the growth defects that suffer mice defective of Opa1 in skeletal muscle, observed in previous studies. These results indicate that inflammation is the primary cause of this growth impairment. The analysis of the origin of this inflammation allows us to describe that it is a NF- κB activation-mediated, local, primary and autonomous process of the muscle cell. At the intracellular level, the data show that the deficiency of Opa1 generates mitochondrial network fragmentation and disarrangement, and a reduction in the oxidative capacity of the electron transport chain of the mitochondria. These observations were made both in muscle cells and in skeletal muscle, which correlates with a dysfunctionality of the mitochondrial fusion as well as of the morphogenesis of the cristae of the organelle. Likewise, the loss of Opa1 function in muscle cells results in a 50% reduction in the mitochondrial DNA content, accompanied by a comparable reduction on TFAM protein levels. Confocal microscopy analysis show a reduction in the number of mitochondrial DNA nucleoids per cell, as well as an enhancement of the relative area of each nucleoids, which has been described as mitochondrial DNA stress. Given the features of mitochondrial DNA, owing to the past of mitochondria as free living bacteria, it has a powerful immunogenic capacity as a damage associated molecular pattern. From the two main pathways with potential to detect misplaced mitochondrial DNA and induce NF-κB activation, we discarded cGAS activation due to the fact that mitochondrial DNA is not detected in the cytosol and that cGAS deficiency is unable to normalize the expression of NF-κB target genes. Given the absence of the molecule in the cytosolic fraction, we analyzed the functionality of mitophagy. Although in Opa1 loss-of-function cells mitophagy initiates normally, the completion of the mitophagic process is impaired, probably resulting in an accumulation of undegraded mitochondrial components, which has been reported that can produce an intracellular inflammatory response. Studies of the location of mitochondrial DNA indicate that all nucleoids are found in mitochondria-containing compartments. In addition, more than half are located in
late endosomes. Approximately the same portion is localized in compartments also positive for TLR9. We assessed the importance of this two key components, mitochondrial DNA and TLR9, in the development of the inflammatory response by ablating one or the other and assessing the normalization of NF-κB target gene expression. Indeed, reduction of mitochondrial DNA copy number to a residual 5% rescued the expression pro-inflammatory genes. Moreover, treatment with TLR9 antagonist also restored NF-κB target genes expression and extracellular concentration of IL-6. In parallel to these data, TLR9 depletion can as well normalize inflammatory genes expression. The data compiled in this study indicate that Opa1 deficiency results in mitochondrial dysfunction together with mitochondrial DNA stress. The mitophagy machinery of the cell is able to identify this damage and restrain the damaged mitochondria into mito-autophagosome that, by a mechanism that still needs further investigation, is re-routed to the endosomal pathway. In late endosomes mtDNA can interact with TLR9 which in turn results in activation of NF-κB pro-inflammatory pathway resulting, eventually, in the secretion of cytokines that may potentially cause the growth defects observed in the skeletal muscle specific Opa1 deficient mouse model.La proteïna Opa1 és una GTPasa de dinàmica mitocondrial responsable de la fusió de la membrana mitocondrial interna, del manteniment de la morfologia de les crestes mitocondrials, i relacionada amb l’estabilitat de l’ADN mitocondrial. En aquest estudi explorem l’origen dels efectes de la deficiència d’Opa1 en múscul esquelètic, així com els mecanismes cel·lulars que donen lloc a les respostes primàries derivades de la deficiència en el context muscular. Les dades obtingudes durant el transcurs d’aquesta tesi doctoral identifiquen la inflamació com la causa dels defectes de creixements, observats en estudis anteriors, que pateixen els animals deficients d’Opa1 en múscul esquelètic. L’anàlisi de la procedència d’aquesta inflamació permet descriure que es tracta d’un procés local, primari i autònom de la cèl·lula muscular. A nivell intracel·lular, les dades mostres que la deficiència d’Opa1 genera una desestructuració de la xarxa mitocondrial, i una reducció en la capacitat oxidativa de la cadena de transport d’electrons del mitocondri, tant en cèl·lules com en múscul esquelètic, el que es correlaciona amb una disfuncionalitat tant de la fusió mitocondrial com de l’estructuració de les crestes de l’orgànul. Així mateix, la pèrdua de funció d’Opa1 en cèl·lules musculars comporta una reducció del 50% en el contingut d’ADN mitocondrial, com també presència d’estrès de l’ADN mitocondrial. L’anàlisi de la funcionalitat de la mitofàgia en aquestes condicions indica una correcta iniciació però una manca de finalització, resultant en una acumulació de material mitocondrial no degradat, el que ha estat reportat que pot produir una resposta inflamatòria intracel·lular. Estudis de la localització del ADN mitocondrial indiquen la seva absència en el citosol, contràriament la totalitat de nucleoides es troben en compartiments mitocondrials. A més, més de la meitat es localitzen en endosomes tardans on també colocalitzen amb el receptor TLR9. L’absència de ADN mitocondrial o de TLR9 són suficients per cancel·lar la resposta inflamatòria, pel que podem afirmar que és el TLR9 el que detecta l’ADN mitocondrial i engega la resposta inflamatòria que donarà lloc a la producció de citocines i potencialment als defectes observats en el model animal.
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Cage, Mary Pauline. "Molecular characterization of mesocorticolimbic brain regions in DBA/2J mice sensitized to the locomotor activating effects of ethanol /." Abstract, 24-page preview and downloadable full-text (PDF format) available to VCU users at:, 2005. http://wwwlib.umi.com/cr/vcu/fullcit?p3196511.
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Rich, Megan Elizabeth. "The role of the oxytocin system in the pathophysiology of schizophrenia-like behavior." Kent State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=kent1429200996.
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Segalés, Dalmau Jessica. "Efectes de la proteïna Mitofusina 2 sobre el metabolisme muscular." Doctoral thesis, Universitat de Barcelona, 2011. http://hdl.handle.net/10803/83914.
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Els mitocondris són orgànuls citoplasmàtics que tenen un paper fonamental en múltiples processos biològics com l’oxidació de substrats i la producció d’ATP, la senyalització cel•lular, l’apoptosi, el control del cicle cel•lular i l’homeòstasi del calci. Els mitocondris són orgànuls dinàmics, que pateixen canvis de morfologia regulats per processos de fusió i de fissió. Existeix un equilibri entre ambdós processos que és indispensable per a la correcta funció mitocondrial. Les proteïnes que participen directament en la fusió mitocondrial en mamífers són les mitofusines (Mfn1 i Mfn2), localitzades a la membrana mitocondrial externa i OPA1, situada a la membrana mitocondrial interna. Diferents estudis han demostrat que la proteïna Mfn2, a més de promoure la fusió dels mitocondris, també està implicada en la interacció entre els mitocondris i el reticle endoplasmàtic i que participa en la regulació del cicle cel•lular i del metabolisme mitocondrial. Per altra banda, l’expressió de Mfn2 es troba disminuïda en múscul esquelètic en situacions de resistència a la insulina, com l’obesitat o la diabetis de tipus 2, que a la vegada es caracteritzen per una alterada activitat mitocondrial. En base a aquestes observacions, l’objectiu principal de la present tesi doctoral ha estat estudiar els efectes de la modulació de l’expressió de Mfn2 sobre el metabolisme i la bioenergètica mitocondrial en múscul esquelètic. Amb aquest propòsit hem expressat una forma truncada de Mfn2 (hMfn2Δ614-757) o bé hem reprimit l’expressió de Mfn2 endògena en el model cel•lular C2C12 i en múscul esquelètic de ratolí. Per dur a terme aquest objectiu hem generat 3 models de ratolí diferents: el model d’expressió transitòria de la forma hMfn2Δ614-757; el model de repressió transitòria de Mfn2 i el ratolí knockdown de Mfn2. Els dos primers models han estat generats mitjançant la tècnica de l’electrotransferència d’ADN en múscul esquelètic.
La sobreexpressió de la forma hMfn2Δ614-757 en cèl•lules C2C12 diferenciades incrementa el consum d’oxigen mitocondrial en situació basal i també en desacoblar la cadena de transport d’electrons de la síntesi d’ATP, suggerint una major capacitat respiratòria dels miotubs que expressen la hMfn2Δ614-757. En múscul esquelètic de ratolí, l’expressió d’aquesta forma de Mfn2 causa una estimulació de la taxa d’oxidació de glucosa així com un increment de la Respiratory Control Ratio (RCR). La inducció del metabolisme mitocondrial observada en sobreexpressar la forma hMfn2Δ614-757 no és deguda a un augment de la massa mitocondrial, sinó a un increment en l’expressió i l’activitat d’alguns dels complexes de la cadena respiratòria mitocondrial.
La repressió de Mfn2 en miotubs C2C12 produeix un increment en la respiració no associada a la producció d’ATP o proton leak i una disminució en el potencial de membrana mitocondrial. Aquests resultats indiquen que la repressió de Mfn2 provoca el desacoblament de la cadena de transport d’electrons i la síntesi d’ATP, suggerint una disminució de l’eficiència de la fosforilació oxidativa. Els músculs dels ratolins knockdown de Mfn2 presenten una reducció de la taxa d’oxidació de glucosa i de la Respiratory Control Ratio. A més, la repressió de Mfn2 disminueix l’activitat del complex IV de la cadena respiratòria. En conjunt aquests resultats suggereixen que la disminució de l’expressió de Mfn2 origina una disfunció del sistema de transport electrònic mitocondrial.
També cal remarcar que els ratolins knockdown de Mfn2 presenten una major susceptibilitat a desenvolupar resistència a la insulina en resposta a l’envelliment o a una dieta rica en greixos. La disfunció mitocondrial i l’augment en la producció d’espècies reactives d’oxigen (ROS) observats en el múscul esquelètic d’aquests ratolins podrien explicar aquesta major susceptibilitat.Mitochondria are cellular organelles that play a fundamental role in many cellular functions, such as substrates oxidation, ATP production, apoptosis and calcium economy. Mitochondria are dynamic organelles that can fuse and divide; the balance between both processes is crucial for a correct mitochondrial function. The most relevant proteins described to date involved in the regulation of mitochondrial fusion are mitofusins 1 and 2 (Mfn1 and Mfn2, respectively) and OPA1. Substantial data indicates that Mfn2 is also a key regulator of cell cycle and mitochondrial metabolism. On the other hand, Mfn2 expression is reduced in skeletal muscle of obese subjects and type 2 diabetic patients, situations characterized by altered mitochondrial activity. Based on these observations, the main objective of this thesis was the study of the metabolic role of Mfn2 in skeletal muscle. We have studied the metabolic effects caused by the manipulation of Mfn2 expression in mice skeletal muscle in vivo. By means of DNA electrotransfer technologies, we have expressed a truncated Mfn2 mutant in skeletal muscle and we have also repressed endogenous Mfn2 expression with microRNAs. We have also generated a skeletal muscle Mfn2 knockout mouse model (Mfn2 KO). The expression of truncated Mfn2 mutant in tibialis stimulated glucose oxidation and increased the Respiratory Control Ratio (RCR). It also increased the expression of subunits Cox4 of OXPHOS complex IV and Atp5a1 of complex V. We observed these metabolic effects in absence of changes in mitochondrial content. The repression of Mfn2 in mice skeletal muscle caused a marked reduction in the expression of subunit Cox4 of OXPHOS complex IV, accompanied with a 20% of decrease in COX activity. In this case we neither observed differences in mitochondrial content. Skeletal muscle from Mfn2 KO mice showed a decrease in glucose oxidation and in the RCR. In addition, Mfn2 KO mice showed a higher susceptibility to develop insulin resistance in response to aging or a high fat diet. Mitochondrial dysfunction and the increased ROS production observed in skeletal muscle of these mice could explain this higher susceptibility.
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Hosseininejad, Justin. "Design and Implementation of a Custom Force Pole Assembly for the Measurement of Primate Locomotor Kinetics." Youngstown State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1377357570.
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Brown, Russell W., Marla K. Perna, Daniel M. Noel, Jamie D. Whittemore, Julia Lehmann, and Meredith L. Smith. "Amphetamine Locomotor Sensitization and Conditioned Place Preference in Adolescent Male and Female Rats Neonatally Treated with Quinpirole." Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etsu-works/6341.
Full textAbstract:
Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D₂-like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats.
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Rovira, i. Berger Mireia. "Skeletal muscle and cardiac adaptations to swimming-induced exercise in adult zebrafish = Adaptacions del múscul esquelètic i cardiac a l'exercici per natació induïda en el peix zebra adult." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/402623.
Full textAbstract:
In mammals, regular exercise is related to important benefits for health by protecting from the development of cardiovascular diseases, stimulating the immune system by providing anti- inflammatory effects and maintaining glucose homeostasis, that is particularly relevant in diabetes. In the present study, the model species zebrafish (Danio rerio) has been used to investigate the physiological response to swimming-induced exercise. After four weeks of a swimming training protocol, we have observed a significant increase of the fiber area and increased capilarization of fast skeletal muscle. These cellular changes are accompanied by a transcriptomic response involving differentially regulated genes and pathways relevant for muscle growth, development, contraction, oxidative metabolism and angiogenesis. Also, mTOR signaling pathway, typically related to processes of muscular hypertrophy and in exercise in mammals, was activated concomitantly with an increase of expression of markers for cell proliferation. The activity of AMPK, a kinase that regulates multiple cellular processes including muscle glucose uptake or mitochondrial biogenesis, was increased by exercise, in conjunction with expression of pgc1a. These results suggest an adaptation towards a more oxidative metabolism of the fast skeletal muscle, similar to mammals. Also, a dynamic regulation of several “myokines" in the zebrafish fast muscle was observed over the training period. In mammals, muscle cells have the capacity to express factors of the immune system under certain stimuli. After stimulation with E.coli lipopolysaccharide, a notable expression of immune and muscle developmental genes has been observed in the fast muscle of previously exercised zebrafish. Nevertheless, survival of exercised zebrafish after an in vivo challenge with P. aeruginosa was not improved, suggesting that exercise did not stimulate zebrafish immune function under the tested conditions. Remarkably, zebrafish has the capacity to regenerate the heart completely after a cardiac injury. The results of this study suggests that exercise improves cardiac regeneration in view of the significant recovery of cardiac function and increased proliferation of cardiomyocytes that coincides with the induction of a specific transcriptomic response. In conclusion, this study shows that exercise in adult zebrafish promotes muscular and cardiac adaptations at the cellular and molecular level, and that these results can contribute to our knowledge of muscular, metabolic and cardiovascular diseases.En mamífers l'exercici s'ha relacionat amb importants efectes fisiològics com protecció contra malalties cardiovasculars, estimulació del sistema immunitari proporcionant defenses antiinflamatòries, i el manteniment homeostàtic de la glucosa sobretot en casos de diabetis on es veu augmentada la sensibilitat a la insulina. En aquest estudi s'ha utilitzat l'espècie model Danio rerio, peix zebra, i mitjançant un protocol de natació s'ha induït l'exercici. Al cap de quatre setmanes de natació s'ha observat un augment significatiu de l'àrea de les fibres musculars i capil·larització del múscul esquelètic. Aquests canvis cel·lulars han estat acompanyats d'una resposta transcriptòmica amb una regulació diferencial de rellevants processos de senyalització relacionats amb creixement muscular, desenvolupament, contracció, metabolisme i angiogènesi. A més, la via de mTOR, característica en processos d'hipertròfia muscular en resposta a l'exercici, apareix activada conjuntament amb un augment de marcadors de proliferació cel·lular. És rellevant l'augment de l'activitat de AMPK, una quinasa reguladora de biogènesi mitocondrial, juntament amb l'augment de pgc1a. Conjuntament, aquests resultats suggereixen una adaptació del múscul a un estat més oxidatiu. S'ha observat una regulació dinàmica en el temps d'algunes "mioquines", factors descrits en mamífers de ser alliberats per les cèl·lules musculars que poden jugar un paper important en els efectes fisiològics de l'exercici. En mamífers les cel·lules musculars presenten una capacitat d'expressar factors del sistema immunitari sota determinats estímuls. Després d'una estimulació amb lipopolisacàrid, s'observa una expressió més notable de factors immunes i musculars en els músculs dels animals prèviament exercitats, però l'exercici no altera la supervivència després d'una infecció aguda amb P. aeruginosa. L'exercici en el peix zebra promou la proliferació dels cardiomiòcits i una tendència a creixement cardíac. El peix zebra té la capacitat de regenerar completament el cor. En un context de lesió cardíaca (simulant un infart de miocardi) l'exercici millora la recuperació de la funció cardíaca i indueix una resposta transcriptòmica que coincideix amb un augment de proliferació dels cardiomiòcits. En aquest estudi es conclou que l'exercici en el peix zebra promou adaptacions musculars i cardíaques a nivell cel·lular i molecular i el seu estudi pot contribuir en el coneixement de patologies musculars, metabòliques i cardiovasculars.
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Martinez, Cristobal Paula. "Role of DOR/TP53INP2 in the control of muscle protein degradation = Papel de DOR/TP53INP2 en el control de la degradación de proteínas en el músculo esquelético." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/402713.
Full textAbstract:
Protein homeostasis (proteostasis) results from the fine regulation of synthesis and degradation. The nuclear cofactor DOR/TP53INP2 was identified originally as a protein expressed in PML of nuclear bodies. However, in response to cellular stress, DOR/TP53INP2 exits the nucleus, localizes to early autophagosomes and regulates autophagy. Recent data from our laboratory has demonstrated that DOR promotes muscle wasting by the activation of basal autophagy in skeletal muscle.
Aim of this project is to analyze the role of DOR/TP53INP2 in combining the regulation of autophagy with other muscle homeostatic processes like the Ubiquitin- Proteasome System. Our results indicate that DOR is a negative regulator of the proteasome activity in C2C12 cells and skeletal muscle. Our data suggest that this upregulation of the proteasome activity in DOR-deficient cells is modulated by an induction of some subunits of the proteasome such as PSMD4 and PSMD11, subunits of the 19S regulatory particle involved in the recognition of Ub and proteasome assembly. Moreover, results suggest that DOR is also a negative regulator of protein synthesis. The comprehension of DOR function in regulating proteostasis will potentially identify new targets against muscle atrophy. Indeed, DOR expression is repressed in wasting conditions such as diabetes and cancer cachexia.La homeostasis de proteinas (proteostasis) resulta de una buena regulación de la síntesis y degradación proteica. El cofactor nuclear DOR/TP53INP2 fue identificado originariamente como una proteina expresada en PML de nuclear bodies. Sin embargo, en respuesta a estrés celular, DOR/TP53INP2 sale del núcleo, localiza con autofagosomas tempranos y regula la autofagia. Datos recientes de nuestro laboratorio han demostrado que DOR/TP53INP2 promueve la perdida de masa muscular por la activación de autofagia basal en el músculo esquelético. El objetivo de este proyecto es analizar el papel de DOR/TP53INP2 como regulador que interconecta la autofagia con otros procesos homeostáticos como el sistema de ubiquitina proteasoma (UPS) en el músculo esquelético. Nuestros resultados indican que DOR/TP53INP2 es un regulador negativo de la actividad de la acividad del proteasoma en celulas C2C12 y en el musculo esqueletico. Nuestros datos sugieren que ese incremento de la actividad del proteasoma en células deficientes para DOR/TP53INP2 está modulado por un aumento de algunas subunidades de la parte regulatoria 19S del proteasoma como PSMD4 y PSMD11, las cuales estan implicadas en el reconocimiento de proteinas ubiquitinadas y en el ensamblaje del proteasoma respectivamente. Además, los resultados sugieren que DOR/TP53INP2 es tambien un regulador negativo de la síntesis proteica. El conocimiento de la funcion de DOR/TP53INP2 en regular la prteostasis nos ha permitira identificar nuevas dianas contra la atrofia muscular. De hecho, la expresión de DOR/TP53INP2 está reprimida en condiciones de pérdida muscular así como en diabetes y caquexia cancerosa.
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Ruby, Christina L. "Ethanol Disruption of the Mammalian Circadian Timing System." Kent State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=kent1270053064.
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Rodríguez, García Mª Ángeles. "Papel del colágeno VI en la homeostasis del músculo esquelético y tejido adiposo: implicaciones en la patofisiología de las distrofias musculares." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/398992.
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El colágeno VI es una proteína de la matriz extracelular cuyos defectos conducen a una variedad de trastornos musculares en humanos caracterizados por una debilidad muscular entre otros múltiples síntomas. Tanto el colágeno VI, como su fragmento soluble carboxilo terminal llamado endotrofina se encuentran altamente expresados en los dos principales tejidos periféricos que regulan la glucemia, el músculo esquelético y tejido adiposo. Los niveles de ARNm de colágeno VI en el tejido adiposo se han asociado con la obesidad y la resistencia a la insulina y su expresión está regulada por los niveles de glucosa, agonistas PPAR-gamma y la leptina. Se ha demostrado como, en modelos de ratón expuestos a una dieta alta en grasas, la sobreexpresión de endotrofina en el tejido adiposo contribuye a la fibrosis e inflamación de este tejido así como al empeoramiento de un estado de resistencia a la insulina. En relación a lo anterior, la ausencia de colágeno VI en ratones obesos mejora su perfil metabólico incluyendo resistencia a la insulina. A pesar de estas evidencias no se han investigado un papel del colágeno VI en la homeostasis de la glucosa así como sus implicaciones en el contexto de la deficiencia de colágeno VI en los seres humanos.
En este trabajo se utilizó un modelo in vitro basado en el tratamiento de líneas celulares musculares y adiposas, humanas y murinas, con colágeno VI o endotrofina para investigar sus efectos en la captación y la utilización de glucosa, así como las vías de señalización y genes implicados. Se estudiaron dichas vías en biopsias musculares de pacientes con mutaciones en colágeno VI y se estudió mediante absorciometría de doble energía la cantidad y distribución del tejido magro y adiposo en estos pacientes y su correlación con la función motora de los mismos y los niveles de adipoquinas circulantes.
Se demostró que el colágeno VI y la endotrofina son capaces de producir, mediante la acción de la quinasa ligada a integrinas (ILK), un aumento significativo en la captación de glucosa de una manera independiente a la acción de la insulina en las células musculares y adiposas en el caso del colágeno VI y en células musculares en el caso de la ETP. Además, hallamos que el colágeno VI es capaz de producir cambios en los niveles de expresión de genes codificantes para proteínas mitocondriales, así como para la proteína GLUT1 en células musculares. Pudimos observar que los pacientes con mutaciones en colágeno VI manifiestan un aumento en los niveles de proteína GLUT1 en músculo esquelético así como un incremento de los niveles circulantes de adiponectina de alto peso molecular en suero. También evidenciamos como la cantidad de masa magra de estos pacientes se encuentra reducida, mientras que sufren un considerable incremento en la cantidad de masa grasa, la cual se correlaciona negativamente con su estado funcional y su calidad de vida.
En resumen, en este estudio se evidenció el papel del colágeno VI y la ETP en el control de la captación de glucosa de manera independiente a la insulina en miotubos y adipocitos in vitro. Además, el colágeno VI es capaz de producir cambios en relación a la expresión de numerosos genes. Y finalmente, se ha descrito una alteración en la cantidad y distribución de masa muscular y adiposa en pacientes con miopatías relacionadas con déficits el colágeno VI indicando que el aumento de masa grasa en estos pacientes contribuye a la fisiopatología de la enfermedad.Collagen VI is an extracellular matrix protein whose defects lead to a range of musculoskeletal conditions. Post-translational modification of collagen VI results in the cleavage and release of a carboxyterminal soluble fragment named endotrophin (ETP). Collagen VI is highly expressed in the two major tissues regulating glycemia, skeletal muscle and adipose tissue. COL6A3 mRNA levels in adipose tissue have been associated with obesity and insulin resistance and its expression is regulated by glucose levels, PPAR-γ agonists and leptin. In mice, ETP over-expression contributes to fibrosis, inflammation of adipose tissue and insulin resistance. In line with this, the lack of collagen VI in obese mice improves insulin resistance. Despite these evidences a signaling role for collagen VI in glucose homeostasis and its implications in the context of collagen VI deficiency in humans have not been investigated. Human and murine skeletal muscle and adipose cell lines treated with collagen VI or ETP were used to investigate the effect of collagen VI in glucose utilization and signaling pathways and genes involved. Same pathways were studied in muscle biopsies from patients with mutations in collagen VI. It was investigated, by Dual-energy X-ray absorptiometry, the amount and distribution of lean mass and adipose tissue in these patients and their correlation with motor function and levels of circulating adipokines. We demonstrated that collagen VI and endotrophin induce, through the action of integrin-linked kinase (ILK), a significant increase in glucose uptake independently of insulin action in muscle cells and adypocites. Furthermore, collagen VI is able of producing changes in expression levels of genes encoding for mitochondrial proteins as well as for GLUT1 in muscle cells. Patients with mutations in collagen VI showed an increase in GLUT1 protein level in skeletal muscle and an increase in circulating of HMW adiponectin level in serum. Finally, we see that the amount of lean mass of these patients is reduced, while suffering a considerable increase of fat mass, which is negatively correlated with functional status and quality of life. In summary, in this study we demonstrate a role for collagen VI and ETP in in vitro glucose uptake regulation and in the regulation of the expression of numerous genes. And finally, we described an alteration in the amount and distribution of adipose and muscle mass in patients with collagen VI related myopathies indicating that the increase in fat mass in these patients contributes to the pathophysiology of the disease.
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Núñez, Álvarez Yaiza. "Role of HDAC11 in muscle cell differentiation and regeneration = Paper de HDAC11 en la diferenciació i regeneració musculars." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/457955.
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HDAC11 is the newest member of the histone deacetylase (HDAC) family and one of the less studied. Its expression was described to be enriched in skeletal muscle tissues from the first moment of its discovery, yet now after 15 years, its roles in myogenesis remain unknown. We started this thesis by analyzing the expression changes of all HDAC’s’ members between proliferation and early differentiation conditions, which constitutes a crucial cell fate point in which cells have to decide whether to continue proliferating or enter to irreversible G0 arrest state to differentiate. With this analysis, we found HDAC11 as the HDAC family member the most upregulated in the skeletal muscle differentiation process. By CRISPR/Cas9 knock-in tagging of endogenous HDAC11, we show that HDAC11 protein levels are absent in proliferating cells and increased through differentiation. The silencing of HDAC11 in proliferation conditions is mediated, at least in part, by class I HDAC’s deacetylation of MYOD. In differentiation conditions, acetylated MYOD and myogenin, the two master regulators of muscle differentiation, bind to HDAC11 promoter regions and trigger its expression.
HDAC11 deficient myoblasts did not present major alterations in cell proliferation or differentiation capacities but show reduced fusion ability. Genome-wide transcriptomic analysis of differentiating HDAC11 deficient myoblasts revealed an upregulation of genes involved in proliferation and a decreased expression of genes involved in muscle contraction, suggesting a delayed entry in G0 irreversible arrest state. Our ChIP results suggest that HDAC11 would mediate repression of proliferation related genes by deacetylation of H3 in their promoter regions. Moreover, HDAC11 expression is also highly expressed in additional G0 states, like in reversible arrested quiescent satellite cells.
In skeletal muscle tissues, HDAC11 is higher expressed in fast muscles than slow ones, especially in males. The analysis of HDAC11 deficient mice concludes that HDAC11 absence do not cause major alterations in muscle development, adult myofiber growth or fiber type composition in basal conditions. In regeneration conditions, HDAC11 deficient mice show advanced regeneration capacity at 7 days post injury, probably mediated at least in part, by an increased expression of Il-10 by HDAC11 deficient macrophages.
Finally, we show that HDAC11 upregulation through differentiation is conserved in human myoblast and its expression is reduced in rhabdomyosarcoma cells, which present impaired differentiation capabilities.
Altogether, our results place HDAC11 as a new epigenetic regulator in in vitro an in vivo myogenesis.HDAC11 és el membre més recentment descobert de la família de deacetilases d'histones (HDAC) i un dels menys estudiats. En el moment del seu descobriment es va veure que estava altament expressada en teixits de múscul esquelètic encara que després de 15 anys, les seves funcions en la miogènesi resten encara desconegudes. Vam començar aquesta tesi analitzant els canvis d'expressió de tots els membres de la família HDAC entre les condicions de proliferació i diferenciació primerenca, un moment crucial on les cèl·lules han de decidir si continuen dividint-se o entren en l'estat d'aturada irreversible G0 per diferenciar-se. Amb aquesta anàlisi vam trobar HDAC11 com el membre de la família HDAC que augmentava més la seva expressió en aquest procés. Amb la tècnica d'enginyeria genètica CRISPR/Cas9 vam aconseguir inserir un epítop en el locus genòmic de HDAC11, que ens permeté demostrar que la proteïna HDAC11 està absent en condicions de proliferació i augmenta amb la diferenciació. El silenciament de l'expressió de HDAC11 durant la proliferació està mitjançada, almenys en part, per la deacetilació de MYOD per part de la classe I de HDACs. Durant la diferenciació, MYOD acetilat i miogenina, els dos reguladors responsables d’iniciar la diferenciació muscular, s'uneixen al promotor de HDAC11 i activen la seva expressió. Els mioblasts deficients en HDAC11 no presenten greus alteracions en la proliferació cel·lular o en la seva capacitat de diferenciar-se però mostren una reduïda capacitat de fusió. L'estudi transcriptòmic a escala global de mioblasts deficients en HDAC11 va revelar una sobreexpressió de gens involucrats en la proliferació cel·lular i una reducció en l'expressió de gens amb funcions en la contracció muscular, suggerint una entrada més tardana en la fase G0 d'aturada irreversible. Els nostres resultats de ChIP suggereixen que HDAC11 podria intervindre en la repressió dels gens involucrats en la proliferació cel·lular mitjançant la deacetilació de les histones H3 dels seus promotors. A més, l'expressió d'HDAC11 també és alta en estats addicionals de G0 com l'arrest reversible de les cèl·lules satèl·lit quiescents. En teixits de múscul esquelètic, HDAC11 està més expressada en músculs ràpids que lents, especialment en mascles. L'anàlisi de ratolins deficients en HDAC11 conclogué que l'absència de HDAC11 no causa greus alteracions en el desenvolupament muscular, el creixement de miofibres adultes o en la composició en tipus de fibres en condicions basals. Durant la regeneració muscular, els ratolins deficients en HDAC11 mostren un avanç en la seva capacitat de regeneració 7 dies després de la lesió, probablement mitjançat en part per un increment en l’expressió de Il-10 per part dels macròfags deficients en HDAC11. Finalment, mostrem que l’augment d’expressió de HDAC11 està conservat en la diferenciació de mioblasts humans i que la seva expressió està reduïda en rabdomiosarcoma, patologia tumoral que presenta un impediment en la diferenciació muscular. En conjunt, els nostres resultats situen HDAC11 com un nou regulador epigenètic en la miogènesi in vitro i in vivo.
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Tristán, Noguero Alba. "Tyrosine Hydroxylase Deficiency: Studies in patient samples and in a cellular model." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668313.
Full textAbstract:
Monoamine Neurotransmitter diseases are a rare group of inherited disorders of metabolism that encompass 12 different genetic defects leading to abnormal dopamine and/or serotonin brain homeostasis. They correspond to enzymatic deficiencies involved in the biosynthesis, catabolism and transport of dopamine and serotonine. From a clinical point of view, they can appear at any age and manifest diverse clinical features. However, movement disorders ranging from dopa-responsive dystonia to severe parkinsonism, associated to variable degrees of cognitive impairment is the most common form of presentation.
The pathophysiology underlying the wide spectrum of clinical phenotypes (from mild to severe) and response to neurotransmitter precursors (L-Dopa+carbidopa, BH4 and other dopaminergic enhancers) has not been studied in detail. Here we aim to address this important issue through different approaches: i) the study of a particular disease of neurotransmitters, Tyrosine Hydroxylase deficiency (THD), as a model of dopaminergic deficiency. Tyrosine hydroxylase (TH) enzyme catalyses the rate-limiting step in the biosynthesis of dopamine (DA). THD exhibits a wide spectrum of clinical manifestations that have been grouped according to the severity in two clinical phenotypes: “Type A” tends to present as L-Dopa responsive parkinsonism-dystonia whereas “Type B” produces a severe encephalopathy of early-onset with sub-optimal L-Dopa response. ii) The study of a large cohort of patients with neurotransmitter defects thanks to an international collaboration (I-NTD group). We have used both patients’ samples and an iPSc model to address these questions.
A) Patients’ samples:
A.1) We studied one THD B phenotype postmortem brain and we observed that the expression of key synaptic proteins and neurodevelopmental markers were altered: TH, VMAT 1 and 2 and dopamine receptors, especially D2DR were decreased. GABAergic and glutamatergic proteins such as GABAVT, NMDAR1 and calbindin were also altered. Finally, developmental markers for synapses, axons and dendrites were decreased, whereas markers of neuronal volume were preserved.
A.2) 94 CSF samples of patients with neurotransmitter defects from 9 centres belonging to different countries/continents were collected in an international collaboration through the I-NTD working group. The proteomic study showed that the main category of overrepresented proteins was related to nervous system development. Moreover, different proteins were detected that could be useful biomarkers for severity prognosis and response to treatment that are specific of disorders. Four of them were correctly validated with an ELISA analysis: APOD, COL6A3, APOH and OMGP. These proteins are involved in diverse important biological functions such as myelination, phospholipid and other lipid related processes.
B) iPSC model of THD:
iPSC lines from Type A and B patients, controls and an isogenic corrected iPSC line were generated. Upon Dopaminergic differentiation, THD A and B neurons reproduced the disease-associated phenotype: decreased TH Protein, reduced enzyme activity and alteration on DA genes expression. A new neuronal phenotype was also described: less TH-immunoreactive cells and fiber density in both mutant TH+ neurons, Type A and B DAn presented altered morphology (reduced neuronal arborisation only in THD-Type B) and a reduced axonal TH localization was observed in THD-Type A. We were also able to test therapeutic approaches such as L-Dopa + carbidopa.
To conclude, we have performed extensive and novel studies using different approaches and techniques to better characterize the pathophysiology underlying the spectrum of severity and response to the current pharmacological treatments of neurotransmitter defects. We have provided new information pointing towards a dysregulation of multiple neurodevelopmental functions in these diseases, and biomarkers of clinical severity that could be explored in the future as therapeutic targets. Additionally, an iPSC model for THD has been developed for the first time that introduces mechanistic and therapeutic insights in this early-parkinsonism model.Los errores congénitos de las monoaminas (ECMM) son defectos en la síntesis, degradación o transporte de catecolaminas y serotonina. Las manifestaciones neurológicas incluyen trastornos del movimiento, retraso mental y encefalopatías. La Deficiencia de la TIrosina Hidroxilasa (THD) es un ECMM causado por un defecto en el enzima TH que cataliza el paso limitante en la biosíntesis de Dopamina (DA). Dos fenotipos clínicos se han descrito: el “A” que tiende a responder a la L-Dopa y el “B” que produce una encefalopatía grave de inicio temprano con mala respuesta a la L-Dopa. Para elucidar la gran variabilidad en cuanto a fenotipo y respuesta al tratamiento de estas enfermedades hemos realizado diferentes aproximaciones en muestras de pacientes y en un modelo celular. A) Pacientes: A.1) Estudiamos un cerebro postmortem THD de fenotipo B y observamos que la expresión de proteínas sinápticas clave y marcadores de neurodesarrollo estaban alteradas: reducción en la expresión de TH, VMAT 1 y 2 y los receptores de dopamina, especialmente D2DR. También se detectaron proteínas GABAérgicas y glutamatérgicas (GABAVT, NMDAR1 y calbindina) alteradas. Finalmente, los marcadores de desarrollo para sinapsis, axones y dendritas estaban disminuidos, mientras que los marcadores de volumen neuronal estaban preservados. A.2) 94 muestras de LCR de pacientes con ECMM fueron recogidas. El estudio de proteómica mostró que la categoría principal de proteínas sobrerrepresentada estaba relacionada con el desarrollo del sistema nervioso. Además, se detectaron diferentes proteínas que podrían ser biomarcadores útiles para el pronóstico de severidad y respuesta al tratamiento. Cuatro se validaron mediante un análisis ELISA: APOD, COL6A3, APOH y OMGP. B) Modelo celular Generamos líneas iPSC a partir de pacientes A y B, controles y una línea iPSC corregida. Tras la diferenciación DAn, las neuronas THD A y B reproducen el fenotipo de la enfermedad: proteína TH y actividad enzimática disminuidas y alteración en la expresión de genes DA. También se describió un nuevo fenotipo neuronal: menos células TH-inmunorreactivas, menor densidad fibrilar y alteraciones morfológicas en las nDA de ambos. Una reducción de la arborización neuronal en el B y la reducción de la localización axonal de TH en el A. Pudimos probar diferentes aproximaciones terapéuticas.
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Stolz, Thomas [Verfasser], Joachim [Gutachter] Schmidt, and Peter [Gutachter] Kloppenburg. "Descending Octopaminergic Neurons in the Stick Insect: Their Inputs and their Output Effects on the Locomotor System / Thomas Stolz ; Gutachter: Joachim Schmidt, Peter Kloppenburg." Köln : Universitäts- und Stadtbibliothek Köln, 2018. http://d-nb.info/1182533221/34.
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Toledo, Soler Miriam. "Teràpia multimodal per al tractament de la caquèxia cancerosa." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/296794.
Full textAbstract:
La caquèxia és una síndrome clínicament evident en la seva fase avançada ja que es manifesta amb pèrdua substancial de greix i múscul esquelètic. Pels malalts els representa, en aquesta última etapa, una reduïda probabilitat d'èxit de rehabilitació. Aquesta síndrome en pacients amb càncer s'associa amb una reduïda supervivència, i això es deu en part a una disminució de la tolerància als tractaments contra el càncer, a una major susceptibilitat a les infeccions i altres complicacions. La manca de consciència dels problemes de nutrició i l'estat dels pacients amb càncer, juntament amb la manca d'evidències d'una teràpia adequada, fa de la caquèxia una gestió rarament activa, que freqüentment resulta en una progressiva pèrdua de pes que va avançant sense diagnosticar fins que es torna greu.
Tenint en compte que la caquèxia és una síndrome multifactorial, és poc probable que un sol medicament sigui efectiu per contrarestar-la. Per tant, la línia de recerca futura és el disseny d'un enfocament multimodal, és a dir, una combinació de fàrmacs que actuen sobre diferents vies fisiopatològiques, per prevenir o retardar l'aparició de la caquèxia en malalts de càncer. En primer lloc, l'estratègia terapèutica ideal hauria de contemplar el suport nutricional, ja sigui mitjançant suplements nutricionals, incorporant nutracèutics o fàrmacs. En segon lloc, la teràpia multimodal hauria d'incorporar una doble estratègia, tant anticatabòlica com anabòlica. De fet, el bloqueig de l'estat catabòlic vinculat a la caquèxia que pateixen el pacients amb càncer és absolutament essencial. Tal enfocament pot millorar la tolerància als tractaments contra el càncer agressiu i la capacitat funcional i la qualitat de vida, fins i tot en etapes avançades de la malaltia. A més, els tractaments futurs s'haurien d'iniciar en el moment del diagnòstic del càncer i s'haurien d'adaptar a l'estadi de caquèxia del pacient.
L'objectiu principal d'aquesta tesi doctoral ha estat demostrar la necessitat d'establir una teràpia multimodal per al tractament de la caquèxia cancerosa que englobi agents anabòlics i anticatabòlics amb base nutricional o farmacològica en models experimentals de caquèxia.
Normalment, la majoria d’estudis preclínics estan basats només amb l'efecte caquèctic induït en un curt interval de temps de creixement tumoral o amb fàrmacs antineoplàstics individuals, no amb una teràpia combinada. Aquests paràmetres experimentals, però, estan lluny de la pràctica clínica, on s’adopta una intervenció antitumoral tan aviat com es diagnostica el càncer, però no es té en compte la caquèxia fins que aquesta ja està avançada. Per altra banda, l'estudi de la toxicitat del fàrmac i la farmacocinètica en absència de tumor podria ocultar aspectes importants. Com a conseqüència, l'ús de models preclínics inapropiats complica i limita la transferència dels descobriments bàsics.
Per això, els experiments realitzats durant aquesta tesi incorporen, juntament amb tractaments anticaquèctics, un tractament antitumoral. L’administració d’un agent quimioterapèutic redueix eficaçment la càrrega tumoral al mateix temps que allarga la supervivència a expenses d'un estat caquèctic dramàtic, reflectint les condicions clíniques dels pacients amb càncer. A més a més, els tractaments anticaquèctics testats (formoterol i acetat de megestrol, entre d’altres) resulten en una millora remarcable pel que fa a l’estat caquèctic dels models experimentals utilitzats que reben a la seva vegada aquest tractament antitumoral. Testar l'eficàcia dels fàrmacs candidats en aquestes condicions experimentals ofereix un enfocament vàlid i fiable per a la investigació translacional en el camp de la caquèxia associada al càncer. En conclusió, els resultats presentats reforcen la idea que un tractament anticaquèctic exitós ha de ser multifactorial.The presence of a tumour is very often associated with wasting in the host. The percentage of cachexia in cancer patients is quite high: 50 to 80%, and is a useful tool for survival prediction, being held responsible for more than 20% of the deaths of cancer patients. Patient’s ability to tolerate anticancer therapy will, in turn, be affected by their nutritional status preceding treatment, and it will determine the success of the therapy. So, nutritional support has to be considered rather as part of the oncological treatment than as a separated action. In spite of this, several studies demonstrated that nutritional strategies are not sufficient to reverse the cachectic syndrome. This points out the need that, any therapeutic approach has to be multifactorial to counteract metabolic changes. The aim of the present thesis has been to assess the efficacy of a multifactorial treatment in cachectic tumour-bearing animals. The effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in preclinical rodent models where only the tumour-induced alterations are taken into account, excluding the co-presence of anti-tumour molecules that could worsen the scenario and/or interfere with the treatment. As a consequence, the use of inappropriate preclinical models complicates and limits the transfer of basic discoveries from the bench to the bedside. These results incorporates antitumour (sorafenib) together with anticachectic treatments (formoterol and megestrol acetate) this being proved to be a promising strategy for treating cancer cachexia in a preclinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients. In conclusion, the present results reinforce the idea that a successful cachexia treatment has to be multifactorial.
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Martínez, Vergara Hernando [Verfasser], and Detlev [Akademischer Betreuer] Arendt. "Descriptive and functional approaches for a system-level understanding of Platynereis dumerilii and the evolution of locomotor circuits in Bilateria / Hernando Martinez Vergara ; Betreuer: Detlev Arendt." Heidelberg : Universitätsbibliothek Heidelberg, 2017. http://d-nb.info/1177688360/34.
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Contreras, Muñoz Paola. "Nuevas aproximaciones terapéuticas para la regeneración muscular basadas en el ejercicio físico, plasma rico en plaquetas (PRP) y glicosaminoglicanos en modelo de rata." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/404884.
Full textAbstract:
Las lesiones del músculo esquelético son las lesiones más comunes en el ámbito deportivo (su frecuencia puede variar del 10-55%), siendo una preocupación importante en la medicina deportiva. Más del 90% de todas las lesiones deportivas son debidas traumas mecánicos, tales como contusiones musculares o lesiones por distensión, que a menudo conllevan la incapacidad del atleta para entrenar o competir durante varias semanas. Estas lesiones se caracterizan por sufrir rotura de sus fibras musculares, lámina basal y capilares cercanos; y se encuentran frecuentemente localizadas cerca de las uniones miotendinosas.
El músculo esquelético tiene capacidad regenerativa en respuesta a una lesión, desencadenando un proceso de reparación altamente sincronizado que implica la activación de diversas respuestas celulares. Sin embargo, en lesiones severas, la fase de remodelación puede incluir un proceso de cicatrización (fibrosis) que perjudica la recuperación funcional del músculo y representa un importante riesgo de recurrencia. A pesar de que en los últimos años se han ampliado nuestros conocimientos sobre el proceso de regeneración del músculo esquelético, sus complejas vías de regulación todavía siguen siendo poco conocidas. Por todo ello, se plantea como necesario el desarrollo de nuevas aproximaciones terapéuticas para mejorar la regeneración muscular y evitar los problemas asociados a lesiones músculo-tendinosas; lo que podría generar un fuerte impacto social y económico en el campo de las patologías musculo-esqueléticas y lesiones musculares en el ámbito deportivo.
En el presente proyecto se estableció con éxito un nuevo modelo de lesión quirúrgica muscular inducida en ratas, fácil de generar, altamente reproducible y capaz de imitar las lesiones más frecuentes del músculo esquelético observadas en la clínica deportiva humana. Así mismo, se demostró el efecto terapéutico de la administración de una dosis única de PRP mediante inyección intramuscular y, especialmente de la rehabilitación activa temprana (basada en el ejercicio), en la recuperación muscular, tanto a nivel histológico como en la recuperación de la fuerza del músculo esquelético lesionado mediante el uso del nuevo modelo experimental en ratas. No se observó un efecto sinérgico en la combinación de ambos tratamientos, lo que sugiere que el PRP no añade ningún efecto beneficioso al tratamiento basado en el ejercicio en el músculo esquelético lesionado. Estos resultados corroboran la falta de sinergia del PRP con respecto a la rehabilitación por actividad física demostrada en los últimos ECA realizados en clínica humana, donde los atletas fueron sometidos a protocolos de rehabilitación basados en el principio de movilización activa temprana tras la administración de una dosis única de PRP intramuscular. Por otro lado, se evaluaron también los efectos del tratamiento combinado de Condroitín Sulfato y Glucosamina, los cuales demostraron tener un efecto beneficioso en la regeneración del músculo esquelético lesionado en el modelo de lesión muscular en rata, tanto a nivel histológico como en la recuperación de la fuerza muscular, corroborando el papel clave de los componentes de la ECM durante el desarrollo muscular y la regeneración.
A pesar de que se requieren más investigaciones, estos enfoques terapéuticos podrían abrir nuevas vías en el tratamiento de las lesiones del músculo esquelético humano y especialmente en el campo de la medicina deportiva.Skeletal muscle injuries are the most common sports-related injuries in sports medicine. In this work, we have generated a new surgically-induced skeletal muscle injury in rats, by using a biopsy needle, which could be easily reproduced and highly mimics skeletal muscle lesions detected in human athletes. . By means of histology, immunofluorescence and MRI imaging, we corroborated that our model reproduced the necrosis, inflammation and regeneration processes observed in dystrophic mdx-mice, a model of spontaneous muscle injury, and realistically mimicked the muscle lesions observed in professional athletes. MRI imaging analysis demonstrated that our muscle injury model reproduces the grade I-II type lesions detected in professional soccer players, including edema around the central tendon and the typically high signal feather shape along muscle fibers. A significant reduction of 30 % in maximum tetanus force was also registered after 2 weeks of muscle injury. This new model represents an excellent approach to the study of the mechanisms of muscle injury and repair, and could open new avenues for developing innovative therapeutic approaches to skeletal muscle regeneration in sports medicine. We also evaluated the effects of an ultrasound-guided intramuscular PRP injection, administered 24 hours after injury, and/or post traumatic daily exercise training for 2 weeks on skeletal muscle healing in a recently established rat model of skeletal muscle injury. Intramuscular PRP injection and, especially, treadmill exercise improve histological outcome and force recovery of the injured skeletal muscle in a rat injury model that imitates sports-related muscle injuries in athletes. However, there was not a synergistic effect when both treatments were combined, suggesting that PRP does not add any beneficial effect to exercise-based therapy in the treatment of injured skeletal muscle. This could explain why PRP therapies have failed in randomized clinical trials where the athletes have adhered to post-injection rehabilitation protocols based on the principle of early, active mobilization. Moreover, we evaluated the beneficial effects of the combination of chondroitin sulfate (CS) and glucosamine (GLU) hydrochloride administration (both compounds used for the symptomatic osteoarthritis (OA) treatment) on muscle healing. The combined CS+GLU treatment improved muscle healing and force recovery of the injured skeletal muscle in rats, thus suggesting an important role of these products as potential new therapies for the treatment of muscle injuries in sports medicine.
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Moras, Feliu Gerard. "Amplitud de moviment articular i la seva valoració: el test flexomètric." Doctoral thesis, Universitat de Barcelona, 2003. http://hdl.handle.net/10803/672208.
Full textAbstract:
La preocupació per la flexibilitat i el seu entrenament no ha estat sempre la mateixa. No fa pas gaires anys que en alguns esports els entrenadors no volien ni sentir parlar d'estirar la musculatura, ja que creien que era contraproduent. Actualment ja ningú dubta deis beneficis d'un bon programa d'exercicis de mobilitat articular, pero en realitat mai o gairebé mai té el mateix tractament que les altres qualitats físiques, probablement perqué tampoc no ha estat estudiada amb la mateixa profunditat
La flexibilitat ocupa un lloc privilegiat en els programes de condicionament físic i en el camp esportiu en general i els entrenadors volen coneixer els avantatges i inconvenients de l'aplicació deis exercicis de flexibilitat, tot reclamant tests que els permetin treballar i dissenyar els seus programes amb rigor. Tot i que la bibliografia especialitzada dóna suport a l'entrenament de la flexibilitat per la seva influencia positiva, cal anar amb cura a l'hora de fer-ho extensible a totes les activitats (Shellock i Prentice , 1985).
Tot i l'inteèes que té la flexibilitat en el món de l'activitat física i l'esport, peques investigacions permeten extrapolar els resultats a altres poblacions i, fins i tot, els metodes utilitzats moltes vegades no permeten cap tipus de comparació entre subjectes. L'origen d'aquesta situacíó està en la manca de tests senzills i de facil aplicació que permetin valorar !'amplitud de moviment articulard'una manera valida i fiable .
Aquesta tesí doctoral pretén donar resposta a aquestes deficiencies, i proposar correccions als tests més utilitzats que permetin quantificar amb rigor el grau de mobilitat articular de la major part d'articulacions del cos humà.
L'estructura de la tesi consta de quatre parts clarament diferenciades. D'una banda, una primera part en la qual es tracta deis factors relacionats amb la mobilitat articular. Una segona part, també teòrica, en que es fa una analisi deis principals tests de flexibilitat. En la tercera part es proposa, en primer lloc, un métode corrector per aplicar als principals tests de flexibilitat i, en segon lloc, una part empírica que consta de tres estudis; en el primer es determina la validesa i fiabilitat de l'índex corrector proposat. En un segon estudi es comparen els diferents valors d'amplitud de moviment obtinguts al passar diversos tests a esportistes de diferents modalitats. L'estudi ha tingut dos vessants; d'una banda, posar en practica l'índex corrector i, de l'altra, fer una analisi comparativa entre díferents esports. Fínalment, en el tercer estudi, es determina la importancia relativa de la influencia genética i ambiental de la flexibilitat utilitzant l'índex d'heretabilitat, estudi realitzat amb germans bessons que no presentaven diferencies perinatals ni ambientals significatives.
Com a fonament d'aquests estudis s'inclouen en la part teòrica estudis experimentals propis que pretenen aprofundir en l'estat de la qüestió. En aquest sentit, val a destacar l'estudi realitzat en la segona part d'aquesta tesi, en el qual es comprova la influència de les mesures antropomètriques en alguns tests de camp indirectes. L'estudi pretén comprovar la hipótesi de l'existència d'una estreta relació entre els resultats dels tests de flexibllitat indirectes i les mesures antropomètriques dels segments corporals implicats en el moviment.
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El, Hakam Carole. "Modèles animaux et pathologies humaines : caractérisation de 3 lignées murines ENU présentant des anomalies du système vestibulaire ou locomoteur." Thesis, Limoges, 2016. http://www.theses.fr/2016LIMO0004/document.
Full textAbstract:
La mutagenèse chimique aléatoire par l’Ethyl-Nitroso-Urée (ENU), dont la puissance a été largement démontrée au cours de ces dernières décennies dans la création de modèles murins constitue un outil remarquable et essentiel en génomique fonctionnelle. Cette approche est en effet d’un apport considérable pour la compréhension de la fonction des gènes et de leur régulation et constitue un accélérateur pour identifier des éléments clés dans une voie de signalisation. Cette approche systématique, basée sur le criblage simultané d’un grand nombre de souris ne nécessite aucune connaissance préalable sur l’identité et la fonction des gènes étudiés. Les mutants sont identifiés au travers de cribles phénotypiques spécifiques, hiérarchisés et non-invasifs. L’identification du gène et de la mutation causale responsable du phénotype sont réalisés par un travail de cartographie génique en utilisant une série de marqueurs polymorphes ou par séquençage nouvelle génération. L’objectif de ma thèse a été de caractériser au niveau phénotypique et moléculaire, 3 lignées murines indépendantes issues de deux cribles ENU, un crible récessif et un crible dominant sensibilisé. Le premier crible visait à développer des modèles de pathologies humaines, à partir duquel a été isolée la lignée vdb, qui présente des défauts du système vestibulaire dus à une mutation dans le gène otog codant pour l’otogeline, et constitue un modèle de surdité chez l’homme. Le deuxième crible avait été mis en place dans le but d’approfondir nos connaissances fondamentales sur le développement du système squeletto-musculaire chez les mammifères, plus particulièrement chez l’homme et le bovin. Les analyses de deux lignées issues de ce crible, GMA24 et GMA06, ont permis d’identifier la mutation dans le gène Phex pour les souris GMA24 qui présentent un retard de croissance et constituent un modèle pour la maladie XLH (X-Linked Hypophosphatemic Rickets) chez l’homme. Pour les souris GMA06 présentant une hypermusculature, la mutation a été localisée sur le chromosome 2 et son identification est en cours. Ces trois modèles murins constituent des outils intéressants qui peuvent s’ajouter aux modèles déjà existants pour la surdité, la maladie XLH et les maladies type myopathies pour mieux appréhender les mécanismes moléculaires impliqués dans ces pathologies et les interactions génétiques mises en jeu dans l’objectif de tester de nouvelles thérapiesThe random chemical mutagenesis with the Ethyl-Nitroso-Urea (ENU), whose power has been widely demonstrated during these last decades in the murine models creation, is a remarkable and essential tool in functional genomics. This approach is indeed a significant contribution to the understanding of the genes’ function and regulation; it also establishes an accelerator to identify the key elements in a signaling pathway. This systematic approach, based on the simultaneous screening of a large number of mice, requires no prior knowledge on the identity and the function of the studied genes. The mutants are identified through specific, hierarchical and non-invasive phenotypic screens. The identification of the gene and the causal mutation responsible for the mutant phenotype are achieved by gene mapping by using a series of polymorphic markers or by new generation sequencing. The objective of my thesis has been to characterize at the phenotypic and molecular level 3 independent murine lines from two ENU screens, a recessive and a sensitized dominant one. The first screen aimed to develop models for human diseases, from which has been isolated the vbd murine line, presenting vestibular system defects due to a mutation in the Otog gene coding for the otogelin. This mouse line presents a model for human deafness. The second screen had been established in order to deepen our fundamental knowledge on the skeletto-muscular system development in mammals, more particularly in humans and cattle. Analyzes of two lines from this screen, GMA24 and GMA06, have allowed to identify the mutation in Phex gene for GMA24 mice showing a growth retardation and modeling XLH (X-linked Hypophosphatemic rickets) disease in humans. For the GMA06 mice presenting an increase muscle mass, the mutation has been localized on chromosome 2 and its identification is in progress. These three murine models are interesting added tools to the existing models for deafness, XLH and myopathies diseases for a better understanding of the molecular mechanisms and genetic interactions involved in these pathologies and so testing new therapies
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Bello, Hellegouarch Gaëlle. "Adaptaciones anatómicas de la escápula y del manguito rotador a las diferentes formas de locomoción en el orden de los primates." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/145326.
Full textAbstract:
La evolución de los primates se caracteriza por cambios significativos en la función de las extremidades anteriores, que se fueron volviendo menos relevantes para soportar el peso corporal y más importantes a la hora de proporcionar estabilidad, agarre y manipulación en un medio arbóreo discontinuo, aumentando su movilidad y precisión. En este contexto, la función principal del hombro ha sido proporcionar la movilidad necesaria para alcanzar los soportes irregulares, manteniendo al mismo tiempo una estabilización adecuada de la articulación glenohumeral.
La morfología de la escápula está determinada en gran medida por la función, durante la locomoción, de la musculatura que se inserta en ella, especialmente del manguito rotador (músculos subescapular, supraespinoso, infraespinoso y redondo menor). Por ello, en esta Tesis Doctoral se integran diferentes enfoques metodológicos con el fin de caracterizar las adaptaciones anatómicas y funcionales de la escápula y de los músculos del manguito rotador a los tipos de locomoción presentes en el orden de los Primates.
Los resultados obtenidos tanto con metodologías cualitativas (morfometría geométrica) como cuantitativas (índices de proporciones entre fosas) apuntan a una influencia clara de la locomoción de los primates y la función de los diferentes miembros del manguito rotador en la morfología de la escápula. Las principales diferencias en la morfología de la escápula están relacionadas con la proporción entre las fosas supraespinosa e infraespinosa y con la longitud e inclinación de la espina de la escápula. Además, las diferencias funcionales de los músculos según el tipo de locomoción también se reflejan en los patrones de expresión de las isoformas de la cadena pesada de las miosinas (MHC).Primate locomotor evolution is characterized by significant changes in the functional role of the forelimbs, which became less relevant in weight-bearing, while increasing their mobility and ability to provide stability, grasping and manipulation in a discontinuous arboreal environment. In this context, the main role of the shoulder girdle is to provide the mobility required to reach the irregular supports within the discontinuous arboreal substrate, while keeping the glenohumeral joint adequately stabilized. The morfology of the scapula is largely determined by the function of the glenohumeral joint muscles during locomotion, particularly the rotator cuff muscles (subscapularis, supraspinatus, infraspinatus and teres minor). For that reason, in this Thesis we employed different methodological approaches in order to characterize the anatomical and functional adaptations of the scapula and the rotator cuff muscles to the types of locomotion observed in the order Primates. The results obtained with the different methodologies (both geometric morphometrics and the ratio between fossae size) show a clear influence of primate locomotion and the role of the rotator cuff muscles in the morphology of the scapula. The main differences in its morphology are related to the ratio between the supraspinous and infraspinous fossae, and to the length and the inclination of the spine of the scapula. Moreover, the functional differences of the muscles related to the modes of primate locomotion are also reflected in the differential expression patterns of the isoforms of the myosin heavy chain (MHC).
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Sala, Cano David. "Caracterització funcional de la proteïna DOR en el múscul esquelètic." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/109310.
Full textAbstract:
DOR (Diabetes and Obesity Regulated) es va identificar com un factor de risc potencial associat a la diabetis mellitus de tipus 2. Concretament, s’observà com presentava una reducció de l’expressió del 77% en el múscul esquelètic de rates Zucker diabètiques i obeses. Aquesta observació es va estendre a subjectes obesos i diabètics de tipus 2. Estudis realitzats en models cel•lulars van permetre demostrar que DOR té almenys dues funcions diferenciades: d’una banda, és un coactivador de diferents receptors nuclears i, de l’altra, és un regulador de l’autofàgia. De fet, quan DOR es troba en el citoplasma es localitza parcialment en els autofagosomes i interacciona directament amb proteïnes associades a la membrana d’aquests orgànuls com són LC3 i GATE16. D’aquesta manera promou la formació dels autofagosomes.
Tot i això, hi havia la necessitat de traslladar aquesta recerca a models animals que permetessin una visió més fisiològica de la funció de DOR. Considerant els antecedents descrits juntament amb el fet que el múscul és un dels teixits on l’expressió de DOR és més alta, ens portaren a plantejar com a objectius principals d’aquesta tesi doctoral trobar la funció de DOR en el múscul esquelètic i determinar la seva relació amb altres patologies que afecten aquest teixit (especialment la diabetis mellitus de tipus 2).
Per portar-ho a terme s’utilitzaren models de ratolí de sobreexpressió i ablació de DOR específica en el múscul esquelètic. Això va permetre definir DOR com un nou regulador negatiu de la massa muscular. Així doncs, el guany de funció de DOR causà una reducció de la massa muscular, mentre que l’ablació de DOR va resultar en hipertròfia muscular. Aquests efectes foren primaris a alteracions en el funcionament de la fibra muscular adulta i no foren efectes indirectes deguts a canvis d’altres paràmetres que poden afectar la massa muscular com serien el tipus de fibra, el nivell d’apoptosi present en els músculs o defectes en el procés de formació de les fibres musculars (en aquest cas avaluat a través de la inducció del procés de regeneració).
Els efectes de DOR sobre la massa muscular es podien explicar pel seu paper com a activador de l’autofàgia en el múscul esquelètic. El guany de funció de funció de DOR en aquest teixit va augmentar la taxa de degradació de proteïnes i el flux d’autofàgia, mentre que la seva ablació va reduir aquest flux. DOR incrementà la formació d’autofagosomes i colocalitzà amb LC3 en les fibres musculars, cosa que suggerí l’existència de mecanismes d’acció conservats entre el múscul esquelètic i cèl•lules en cultiu. A més, DOR també va augmentar l’expressió de gens relacionats amb la degradació de proteïnes en el múscul esquelètic de ratolins mascles dejunats. Aquest efecte s’explicà per l’augment de l’activitat FoxO i l’increment de l’activitat AMPK. Estudis en cèl•lules musculars en cultiu demostraren que l’activació d’AMPK per efecte del dejuni depenia dels nivells d’expressió de DOR. Concretament, la sobreexpressió de DOR va accelerar la fosforilació d’AMPK induïda pel dejuni mentre que la seva repressió va comprometre aquest procés. La inhibició de l’autofàgia bloquejà la fosforilació d’AMPK induïda pel dejuni, cosa que suggerí que l’efecte de DOR sobre AMPK està mediat a través dels seus efectes sobre l’autofàgia.
Respecte la relació de DOR amb la diabetis, s’observà com el guany de funció de DOR afavoria la pèrdua de massa muscular en la diabetis induïda per estreptozocina. A més, resultats preliminars indicaren que l’ablació de DOR permetia mitigar aquests efectes. Sobre la base d’aquestes dades, proposem que la repressió de DOR en situacions de resistència a la insulina forma part d’un mecanisme adaptatiu per tal de preservar la massa muscular.DOR (Diabetes and Obesity Regulated) gene was identified as a potential risk factor that could trigger type 2 diabetes. This gene showed a reduction of 77% in its expression in the skeletal muscle of diabetic and obese Zucker rats, as well as in obese or type 2 diabetic patients. DOR was found to have two different functions in cellular models: 1) as a coactivator of different nuclear receptors and 2) as an autophagy regulator. Actually, DOR localizes in autophagosomes and is able to interact with proteins found in the membrane of these organelles (such as LC3 and GATE 16) to promote autophagosome formation. However, there was the necessity to study DOR function in a more physiologic way. Thus, considering the way that DOR was discovered and that skeletal muscle is one of the tissues with the highest expression of DOR, the main objectives of this PhD were to unravel DOR function in skeletal muscle and its putative relationship with different pathologies (specially with type 2 diabetes). To do so, we used transgenic mouse models and two different approaches: specific DOR overexpression and ablation in skeletal muscle. This allowed us to define DOR as a new negative regulator of skeletal muscle mass. Thus, DOR gain-of-function caused a reduction in muscle mass whereas DOR loss-of-function resulted in muscle hypertrophy. These effects were due to alterations in adult fiber function and were not secondary to changes in fiber type, apoptosis or myofiber formation (assessed by evaluating regeneration). DOR effects in muscle mass could be explained through its role as an activator of autophagy in skeletal muscle. Thus, DOR gain-of-function increased protein degradation and autophagy flux, whereas DOR ablation reduced that flux. Specifically, DOR increased autophagosome formation and colocalized with LC3 in myofibers, suggesting that DOR mechanism of action was conserved between muscle and cellular models. Moreover, DOR enhanced the expression of genes involved in protein degradation in the muscle of fasted male mice. This could be explained by an increased activity of FoxO and AMPK in these muscles. Based on muscle cell culture studies, DOR expression levels were found to affect AMPK activation by fasting. Thus, DOR overexpression accelerated AMPK phosphorylation whereas DOR repression abolished this phosphorylation. Given that inhibition of autophagy blocked AMPK phosphorylation by fasting, we propose that DOR effects on AMPK are mediated through its effects on autophagy. Regarding the relationship between DOR and diabetes, we observed that DOR gain- of-function enhanced muscle wasting in streptozotocin-induced diabetes. Moreover, preliminary results showed that DOR ablation mitigated muscle loss under these conditions. Thus, we propose that DOR repression in insulin resistant conditions is part of a mechanism aimed to preserve muscle mass.
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San, Millán Alonso Marta. "Estudio de la variabilidad morfológica del acetábulo y los caracteres de senescencia de la región acetabular y otros marcadores de edad del hueso coxal mediante series osteológicas. Aplicaciones en antropología y medicina forense." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/350564.
Full textAbstract:
Conocer en detalle la morfología del acetábulo de los primates en general, y de los humanos en particular, tiene implicaciones importantes tanto en Antropología como en Medicina Clínica y Forense. Con este objetivo, se ha analizado la morfología del acetábulo y de su fosa mediante Morfometría Geométrica. Esta metodología, que ha experimentado un notable avance en los últimos años, cuantifica y analiza las estructuras morfológicas mediante coordenadas cartesianas de puntos anatómicos homólogos (landmarks). El acetábulo, por pertenecer a la articulación coxofemoral, que conecta el esqueleto axial con las extremidades inferiores, tiene implicaciones biomecánicas directas. Los resultados de la presente Tesis Doctoral, basados en el estudio de 303 primates actuales de 40 especies distintas, incluyendo humanos, han demostrado la relación significativa entre la locomoción de los primates y su morfología acetabular. Se abren así nuevas vías de investigación sobre las condiciones de vida de los primates fósiles y la evolución de los distintos tipos de locomoción. Siguiendo el mismo protocolo, se ha evaluado la morfología acetabular de 682 humanos documentados de la Península Ibérica, resultando que la morfología del acetábulo es distinta entre hombres y mujeres menores de 65 años y cambia de manera significativa a lo largo de la vida de los individuos de ambos sexos. Los varones tienen escotaduras y fosas acetabulares más pequeñas que las mujeres de la misma edad, así como un borde acetabular más extendido en dirección posterior. Siguiendo un patrón similar, el acetábulo sufre tres cambios principales con la edad: reducción de la escotadura acetabular, disminución de la fosa acetabular y modificación del borde acetabular, proyectándose éste último en dirección superior y posterior y reduciéndose en dirección inferior. Los tres cambios se deben a la proliferación de hueso a lo largo de todo el borde de la facies lunata. Por otro lado, el conocimiento en profundidad de los marcadores de edad del hueso coxal es importante para mejorar las técnicas existentes de estimación de la edad adulta y desarrollar nuevas metodologías. Los métodos utilizados hasta ahora, basados en la sínfisis púbica y la superficie auricular, han demostrado ser fiables pero poco precisos en nuestra muestra ibérica de 139 individuos, sobre todo en los adultos de edad más avanzada. Teniendo en cuenta tanto la fiabilidad como la precisión, el método de Buckberry-Chamberlain, basado en la superficie auricular, proporciona mejores resultados globales que el método de Suchey-Brooks con la sínfisis púbica. Sin embargo, esta aparente mayor eficacia del primer método se debe fundamentalmente a la comparativamente mayor amplitud de los rangos de edad que utiliza, combinado con la baja proporción de individuos menores de 60 años de la muestra analizada, donde el método Suchey-Brooks parece ofrecer resultados más precisos. Por otra parte, los perfiles de mortalidad resultantes de ambas metodologías son sustancialmente diferentes, lo que puede inducir a distintas conclusiones dependiendo de la técnica elegida de diagnóstico de la edad. Con el objetivo de paliar algunas de las limitaciones de las metodologías anteriores, se ha revisado el método de Rissech et al. (2006) basado en los cambios morfológicos que experimenta el acetábulo con la edad y se ha ampliado su aplicabilidad a mujeres, estudiando las diferencias en el proceso de maduración del acetábulo entre ambos sexos. Así, esta nueva aproximación, evaluada en 611 individuos de la Península Ibérica, ha confirmado la utilidad de la combinación del acetábulo y del cálculo de probabilidades (estadística bayesiana) en la estimación de la edad de los individuos adultos de ambos sexos, resultando en una precisión superior a los métodos tradicionales basados en el coxal, incluso en los adultos de mayor edad. Asimismo, aunque ambos sexos siguen un patrón similar de maduración acetabular, se ha observado que la tasa de envejecimiento del acetábulo es diferente entre hombres y mujeres, lo que nos lleva a sugerir la aplicación del método a ambos sexos por separado.The acetabulum is located where the femoral head attaches to the os coxa, to create the hip joint. Knowledge of the precise morphology of the acetabulum has important implications for biology, biological anthropology, forensic medicine and clinical anatomy studies. The acetabular shape has been quantified and analyzed in primates, and particularly in humans, by geometric morphometrics, a powerful tool to analyze morphological variation in anatomical structures. This recent approach has found a significant association between shape and locomotion in primates, potentially leading to a better comprehension of the poorly understood gaits of fossil primate species. Furthermore, human data show that acetabular shape varies significantly between males and females younger than 65 years old. The shape of human acetabulum also changes progressively along the adult life span, due to bone proliferation throughout the entire edge of the facies lunata. These results improve the understanding of the native acetabular shape, assist in refining age-estimation methods, and enhance surgical and prosthetic procedures. Age estimation is essential in the identification process, both in forensic and archaeological contexts. The classical aging methods based on pubic symphysis (Suchey-Brooks´s method) and auricular surface (Buckberry-Chamberlain´s method) provided low levels of accuracy in the Iberian population analyzed, especially in older individuals. Furthermore, the classic methods resulted in different mortality profiles, consequently affecting the reconstruction of life conditions of the past populations. These results highlight the necessity of new age markers and methodologies for age diagnosis. At this respect, the results from the current revision of the acetabular method demonstrate the suitability of combining the acetabulum traits and the Bayesian approach to make age estimations in adults of both sexes. The mean absolute error for the age estimation of the Iberian sample was 7.28 years for males and 7.09 years for females; these values are significantly lower than the classical methods based on os coxae in Iberian and other populations. Interestingly, the acetabular aging process follows similar trends in both sexes. However, the aging rate seems to be different between males and females, especially in middle-aged individuals, showing that females have a relatively slower aging rate in the acetabular region.
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Pérez, Rius Carla. "Model animal de malalties associades a canals de clorur en peix zebra." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/482037.
Full textAbstract:
El clorur compleix un conjunt de funcions essencials perquè la cèl·lula pugui realitzar correctament diferents processos fisiològics, com la regulació de l’excitabilitat en les cèl·lules musculars, participa en el transport transepitelial d’aigua i sals, en la regulació del pH en l’interior dels lisosomes i en la regulació del volum cel·lular, entre d’altres. La família de proteïnes ClC es divideix en dos grups: en canals iònics presents en la membrana plasmàtica i en transportadors Cl-/H+ presents en compartiments intracel·lulars. Fins ara s’ha descrit que ClC-2, els dos canals ClC-K i ClC-7 presenten les subunitats accessòries anomenades GlialCAM, Barttin i Ostm1, respectivament. En aquesta tesi s’han estudiat els canals iònics de membrana plasmàtica ClC-1, ClC-2 i els canals ClC-K. Mutacions en els gens que codifiquen aquestes proteïnes donen lloc a malalties rares en humans i altres espècies animals, com la Miotonia congènita (degut a la pèrdua d’activitat ClC-1, es caracteritza per un retard en la repolarització muscular), un tipus rar de leucodistròfia vacuolitzant (degut a la pèrdua de ClC-2) i síndrome de Bartter tipus III (degut a la pèrdua de ClC-Kb). En aquesta tesi hem identificat i iniciat la caracterització dels gens ClC ortòlegs en el peix zebra. Hem estudiat el patró d’expressió tant en adults com en embrions. En adults, hem descrit que els canals clcn1a i clcn1b són específics de múscul esquelètic, el canal clcn2a és el més abundant en teixits excitables com el cervell, ull i cor; el canal clcn2b és ubic, el canals clcn2c s’expressa en teixits on es dóna intercanvi iònic amb el medi extern com les brànquies i el ronyó i el canals clcnk s’expressa en el ronyó. En embrions, només hem pogut estudiar la localització de clcn2b, el qual s’expressa en el túbul contornejat proximal del pronefros, i de clcn2c, el qual s’expressa en la regió dels arcs branquials. Hem detectat expressió dels gens clcn1a i clcn1b a partir de 1dpf i 2dpf, respectivament. Part important de la tesi ha estat la generació i validació d’anticossos policlonals tant pels canals clc-1a, clc-1b, clc-2a, clc-2b, clc-k com per les subunitats glialcama i barttin. També hem demostrat in vitro que es conserva la interacció dels canals clc-2 amb GlialCAM, modificant el seu tràfic a les unions cel·lulars i les corrents. De la mateixa manera, el paper estabilitzador de Barttin sobre els canals ClC-K també es troba conservat en el peix zebra. Estudis d’immunofluorescència en larves de peix zebra a 3dpf mostren una localització cel·lular diferent en el múscul esquelètic, mentre que clc-1a es localitza al sarcolema, clc-1b es troba envoltant els túbuls T. A més, hem desenvolupat eines de transgènesi amb promotors específics de teixit per tal de realitzar experiments d’expressió en múscul esquelètic (503unc) de proteïnes de fusió fluorescents (tant humanes com de peix zebra). Una part important d’aquest treball ha estat la generació de models de pèrdua de funció en peix zebra mitjançant la tecnologia CRISPR/Cas9. Hem aconseguit generar animals knock out dels gens clcn1a i clcn1b (el doble knock out encara està en procés), els quals han estat validats com a tal gràcies als anticossos generats durant aquesta tesi. Finalment, hem realitzat uns estudis locomotors preliminars i aquests mostren com les línies mutants per clcn1a i per clcn1b no presenten cap alteració en el moviment espontani ni en la resposta a estímuls de vibració. És probable que la manca d’un dels dos canals clc-1 sigui compensada pel seu paràleg, per aquesta raó estem generant una línia nul·la pel canal clc-1. En aquesta línia deficient per clc-1 esperem detectar alteracions motores reminiscents a les observades en pacients de Miotonia congènita.Chloride is the most abundant anion in body fluids. Chloride transport is involved in many different cellular processes, such as regulating the excitability of muscle cells, transepithelial transport and regulation of pH in lysosomes, among others. The ClC protein family comprises a group of proteins allowing this exchange between the intracellular and extracellular space. They are divided into two subgroups: the plasma membrane chloride channels and the Cl-/H+ co-transporters located in intracellular compartments. The plasma membrane chloride channels are ClC-1 (muscle-specific, is in charge of keeping the resting membrane potential in muscle cells), ClC-2 (ubiquitously expressed) and ClC-Ka and ClC-Kb (located in the distal renal tubule and inner ear, involved in renal salt reabsorption and sound transduction in the ear). Mutations in the genes encoding for these channels lead to human rare diseases. Loss of ClC-1 leads to Myotonia congenital resulting in hyperexcitable muscles, lack of ClC-2 leads to a rare type of vacuolating leukodystrophy and the loss of ClC-Kb leads to Bartter syndrome type III, which is characterized by renal salt loss. In this thesis, we have identified and characterized the zebrafish (Danio rerio) ClC orthologs. To accomplish that, we have generated and validated antibodies against the zebrafish proteins. Furthermore, we have developed transgenesis tools for native and mutant proteins expression experiments and generated clcn1a and clcn1b (human CLCN1 orthologs) loss-of-function alleles in zebrafish with CRISPR/Cas9 technology (the clcn1 null-mutant is in progress). We have validated these lines as knock out and a preliminary locomotor characterization shows these animals display normal spontaneous movement and no difference has been observed between wild-type and knock out animals when applying vibrational stimulus. We hope for the clcn1a-/- clcn1b-/- to show locomotor deficiencies reminiscent to those observed in Myotonia congenita patients.
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Siles, Mena Laura. "Role of ZEB1 in skeletal muscle: Regulation of cell differentiation, response to tissue damage and regeneration." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/587110.
Full textAbstract:
ZEB1 is a transcription factor best known for its role in cancer progression and metastasis. It is also expressed during embryonic development of different tissues although its function and mechanism of action have not always been elucidated. In this dissertation I show that ZEB1 is involved in muscle differentiation during embryonic development and it is also required for muscle response after injury and regeneration.
We found that, in the nucleus of myoblasts, ZEB1 represses muscle differentiation genes through direct binding to G/C-centered E-boxes present in the regulatory regions of muscle differentiation genes. Albeit to different degrees depending on the target gene, transcriptional repression of these genes by ZEB1 is mediated by its recruitment of the corepressor CtBP. Binding of ZEB1 to E-boxes in differentiation genes displaces MyoD and prevents their transcriptional activation during the myoblast stage. As myoblasts fuse, MyoD displaces ZEB1 from its DNA binding sites and differentiation proceeds. Knockdown of Zeb1 induces muscle differentiation genes, thus accelerating the formation of myotubes.
Muscle regeneration after damage depends on a timely regulated transition from pro- to anti-inflammatory signals. Injury of Zeb1-deficient mice results in increased recruitment of inflammatory macrophages and expression of pro-inflammatory cytokines, which delays the regenerative process. Adult muscle regeneration relies on a pool of functional SCs and we show that Zeb1-deficient SCs undergo premature activation after isolation and culture by downregulating Pax7 and quiescence-associated genes (Foxo3, Hes genes) and upregulating Myod1. Moreover, its regenerative potential when transplanted into mdx hosts is reduced compared to wild-type SCs and exhibit increased senescence in culture.
These results establish ZEB1 as an important potential regulator of muscle differentiation and regeneration by modulating inflammatory response and SC myogenic progression in response to injury. They also set ZEB1 as a potential therapeutic target in muscle dystrophies or following muscle insult.ZEB1 és un factor de transcripció conegut pel seu paper en progressió tumoral i metàstasi. També s’expressa durant el desenvolupament embrionari de diferents teixits tot i que la seva funció i mecanisme d’acció encara no han estat establerts. En aquesta tesi mostro que ZEB1 està implicat en la diferenciació muscular durant el desenvolupament embrionari i que es necessari en la resposta al dany i regeneració muscular. Hem trobat que, en els nuclis dels mioblasts, ZEB1 reprimeix gens de diferenciació muscular per unió directa a seqüències “E-box” amb nucleòtids G/C en posició central en les seves regions reguladores. Encara que en diferents graus, depenent del gen diana, la repressió exercida per ZEB1 es fa mitjançant el reclutament del seu corepressor CtBP. La unió de ZEB1 a aquestes “E-boxes” desplaça MyoD evitant la seva activació transcripcional. Un cop els mioblasts es fusionen, MyoD desplaça ZEB1 de la seva unió a l’ADN donant lloc al procés de diferenciació. D’aquesta manera, la inhibició de Zeb1 indueix els gens de diferenciació muscular accelerant la formació de miotubs. La regeneració desprès del dany muscular depèn de la transició de senyals proinflamatoris a antiinflamatoris. La lesió muscular de ratolins deficients per Zeb1 produeix un elevat nombre de macròfags inflamatoris i l’expressió de citocines pro-inflamatories que retarden el procés regeneratiu. La regeneració del teixit muscular adult requereix la participació d’una població de cèl·lules satèl·lit funcionals. Els nostres resultats demostren que les cèl·lules satèl·lit deficients per Zeb1 s’activen precoçment un cop aïllades i posades en cultiu. Aquesta activació succeeix per la inhibició de Pax7 i de gens associats a la quiescència d’aquestes cèl·lules (Foxo3, Hes) i la activació de Myod1. A més a més, presenten una més alta senescència i la seva capacitat regenerativa és reduïda quan es trasplanten en ratolins mdx en comparació a les wild-type. Aquests resultats situen ZEB1 com un important regulador de la diferenciació i la regeneració muscular per modulació de la resposta inflamatòria i de la progressió de les cèl·lules satèl·lit en la resposta al dany muscular. També suggereixen ZEB1 com una potencial diana terapèutica en distròfies musculars o en resposta a la lesió del múscul esquelètic.
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Marmeleira, José Francisco Filipe. "Lesões músculo-esqueléticas em praticantes de corrida de médias e longas distâncias." Master's thesis, Instituições portuguesas -- UTL-Universidade Técnica de Lisboa -- -Faculdade de Motricidade Humana, 2003. http://dited.bn.pt:80/30005.
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Karlsson, Rasmus, and Alvar Sveninge. "Virtual Reality Locomotion : Four Evaluated Locomotion Methods." Thesis, Högskolan Väst, Avd för informatik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:hv:diva-11651.
Full textAbstract:
Virtual Reality consumer hardware is now available for the masses through the HTC Vive, Oculus Rift and PlayStation VR. Locomotion or virtual travel inside immersive experiences is an area which is yet to be fully solved due to space constraints, problems with retaining immersion and potential sickness. This thesis had the goal of evaluating user preferences for four locomotion methods in Virtual Reality with a first generation HTC Vive through the gaming platform Steam. The theoretical framework provides an elementary understanding of the field of Virtual Reality and how humans interact and get affected by locomotion in that context. To contextualize the experience of evaluating the locomotion systems the Hedonic-Motivation System Adoption Model is used as it covers intrinsic motivation which is common in video games, social networking and virtual worlds. An extensive process for games selection has been performed which has resulted in four locomotion methods with four games per method. Sixteen participants got to test one locomotion method each where their gameplay got recorded for later observation. After each game session answers were provided by the participants based on surveys and after completion of all games a questionnaire gauged their sickness level. The conclusion proved inconclusive. While the results without interpretation showed the locomotion method Artificial as the overall winner a range of potential problems were found with the study in general. Some problems included observations which did not provide the expected results, introducing doubt into either how the study was conducted or the reliability of certain users. A larger sampler size along with a better study procedure could possibly have provided a more conclusive answer.
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Blyth, William Alexander. "Robotic pipe inspection : system design, locomotion and control." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/62665.
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The structural integrity of an industrial plant is a key safety and economic consideration for operators in many sectors including: power generation, oil and gas and petrochemical. To ensure safe operation, the plant often undergoes scheduled inspection using Non-Destructive Testing (NDT) methods to detect, size and locate defects such as cracks in welds or corrosion, with the accuracy and repeatability of inspections being critical to monitoring defect growth. Considering the significant cost of plant downtime for inspection, there is an economic benefit to be gained by increasing the speed of inspections, alongside reducing access requirements. Robotic NDT aims to address some of these issues, with an increase in inspection speed, repeatability and accuracy, and the added potential to remove human operators from hazardous environments. Conventional mobile climbing robots are limited by their manoeuvrability, with lateral drift, gravitational effects and continuous motion being particular issues that remain challenging in the context of complex geometries. This thesis aims to investigate the potential for enhanced mobility in mobile climbing robots to precisely follow inspection paths on cylindrical surfaces in various orientations, without drift. This has been done through the development of a reduced actuation mecanum wheel platform, using magnetic adhesion and external position encoding, allowing full translational motion whilst using kinematic and geometric constraints to prevent rotation. Through dynamic modelling of the platform, a model based control structure has been synthesised, allowing for improved consistency of performance in all orientations. The platform has been applied to representative inspection paths and used to conduct ultrasonic inspection of test samples, with the capability to correct for lateral drift and cover large inspection areas, improving the inspection accuracy and area coverage over conventional systems, without requiring operator intervention.
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Yang, Chuan Hao. "Development of a locomotion interface for portable virtual environment systems using an inertial/magnetic sensor-based system and a ranging measurement system." Thesis, Monterey, California: Naval Postgraduate School, 2014. http://hdl.handle.net/10945/41459.
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Approved for public release; distribution is unlimited.This dissertation describes the development of an integrated locomotion interface for building self-contained, portable, and immersive virtual environment (VE) systems. Such VE systems do not rely on any infrastructure support and can be used in indoor/outdoor open spaces. The natural walking motions of the user are utilized as a means of signal generation to drive the locomotion interface, which provides the user with a higher sense of presence. This work investigates the use of two types of measurement systems, the inertial/magnetic measurement units and the ranging measurement systems, to develop a locomotion interface for portable VE systems. Algorithms were developed for each of the two systems to provide the necessary functionalities of the desired locomotion interface. Fusing measurements from a head-mounted and a foot-mounted inertial/magnetic sensor, a locomotion interface was developed for allowing the use of natural walking motions to navigate through virtual environments. To prevent collisions with physical environment boundaries such as walls, a ranging measurement system was used to detect the presence of obstacles. An improved Iterative Closest Point (ICP) algorithm was developed for map-building of the physical environment and for estimating the user's orientation and position within the map. A redirected-walking mechanism was utilized for redirecting the user's walking direction away from boundaries in the physical environment. The two types of measurement systems were integrated to constitute a novel locomotion interface for portable VE systems, and its effectiveness was experimentally tested and demonstrated.
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Reeder, Janina. "Locomotif a graphical programming system for RNA motif search /." [S.l.] : [s.n.], 2007. http://deposit.ddb.de/cgi-bin/dokserv?idn=983651701.
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Melo, Janaina Aparecida Carneiro de. "A ancoragem funcional através do manejo de cão em tarefas de equilíbrio /." Rio Claro : [s.n.], 2011. http://hdl.handle.net/11449/87434.
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Orientador: Eliane Mauerberg de CastroBanca: Cynthia Yukiko Hiraga
Banca: Renato de Moraes
Resumo: O objetivo deste trabalho é avaliar, ao longo de uma caminhada, a contribuição do sistema háptico durante a condução de um cão em condições de desafios ao sistema postural. Os desafios nas tarefas deste estudo incluem restrição da base de suporte para a marcha e privação visual. Esperamos que a sincronização entre condutor e cão se reflita em melhores níveis de desempenho no controle da marcha, especialmente na condição onde a visão é obstruída. Para este estudo foram recrutados 10 adultos jovens, com idade de média de 23,7 ± 4,32 anos e um cão treinado em obediência básica e na tarefa de condução em superfície restrita de apoio (traves de equilíbrio). As condições de tarefas foram: com e sem restrição da visão (CVSC e SVSC, respectivamente), e com e sem condução do cão (CVCC e SVCC, respectivamente). A primeira condição foi sempre a condição controle (olhos abertos sem condução do cão). Cada tentativa foi repetida três vezes. As tarefas foram filmadas por duas câmeras com o objetivo de avaliar a duração de cada ciclo do andar. Uma ANOVA three-way com medidas repetidas em todos os fatores (visão, tarefa e repetições) foi realizada para as variáveis: duração do ciclo de cada passada, média da fase relativa e o desvio da fase relativa, com medidas também repetitivas em todos os fatores para: visão, tarefa, pernas, e repetições. Testes a posteriori de Bonferroni foram calculados para comparações aos pares. Em relação à média da fase relativa as tarefas executadas com o cão foi significativamente superior àquelas sem o uso do cão. O pior relacionamento temporal foi mantido nas médias... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The purpose of this study was to assess the contribution of the haptic system during walking with a dog on challenging tasks to the postural system. The challenges included restriction to the base support (walking on a balance beam for both, the human and the dog), and visual occlusion (for the human only). We expected that the synchronization between the walking individual and the dog reflected in improved levels of performance in motion control, especially in conditions where vision is occluded. We recruited 10 young adults with average age of 23.7 ± 4.32 years and a dog with obedience training and conditioned to walk on a restricted area of support (balance beam). The task conditions were: with and without vision (CVSC and SVSC, respectively), and with and without conducting the dog (CVCC and SVCC, respectively). The first condition was always the control condition (eyes open without conducting the dog). Each trial was repeated three times. The tasks were videotaped with two cameras in order to process the duration of each stepping cycle. A three-way ANOVA with repeated measures on all factors (vision, and task repetitions) was performed for the variables: duration of each stepping cycle, relative phase and standard deviation of the relative phase, also with repeated measures on all of the factors: vision, task conditions, legs, and trials. The mean relative phase of the tasks performed with the dog was significantly closer to symmetry than those without the use of the dog. The worst temporal relationship was maintained during the condition SVSC (right leg = 0,477 ± 0,030, left leg = 0,544 ± 0,035). However... (Complete abstract click electronic access below)
Mestre
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Zhang, Tingnan. "Modeling and control of locomotion in complex environments." Diss., Georgia Institute of Technology, 2016. http://hdl.handle.net/1853/54984.
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In this dissertation, we developed predictive models for legged and limbless locomotion on dry, homogeneous granular media. The vertical plane Resistive Force Theory (RFT) for frictional granular fluids accurately predicted the reaction forces on intruders (with complex geometries) translating and rotating at low speeds ( < 0.5 m/s). Using RFT and multibody simulation, we predicted the forward moving speed of legged robots. During the locomotion of lightweight robots and animals where instantaneous limb penetration speed can reach values greater than ~0.5 m/s, a Discrete Element Method (DEM) simulation was developed to capture the limb-ground interaction. We demonstrated that hydrodynamic-like forces generated by accelerated particles can balance the robot weight and inertia, and promote the rapid movement on granular media. Forces from the environment can not only determine locomotion dynamics, but also affect the locomotion strategy. We studied and simulated the limbless locomotion of snakes in a heterogeneous environment and demonstrated how touch sensing was used to adjust the movement pattern. In heterogeneous environments, the long-term locomotion dynamics is also poorly understood. We presented a theory for transport and diffusion in such settings.
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Flores, Álvarez Pedro Alonso. "Modelling, simulation and experimental verification of a wheeled-locomotion system based on omnidirectional wheels." Master's thesis, Pontificia Universidad Católica del Perú, 2016. http://tesis.pucp.edu.pe/repositorio/handle/123456789/7554.
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The following work focuses on the kinematic and dynamic study of a four-wheeled robot,
which is equipped with omnidirectional Mecanum wheels. The main objective of the
thesis is to obtain a mathematical model from which both the kinematics and kinetics of
the robot can be analyzed. Furthermore, the study presents a methodology to optimize
the torques (and subsequent associated voltages) provided by each of the motors on the
robot for a given trajectory.
A system in which a non-powered trailer pulled by the robot is also analyzed at a
kinematic level. In this stage, four different cases are considered. The construction of the
trailer is also described on this work.
In the first chapter, the global state of the art on analysis and control of omnidirectional
robots (with focus on robots with Mecanum wheels) is presented. In the second chapter,
the physical considerations for the general movement of the robot are analyzed, in order
to derive the kinematic constrain equations of the locomotion system. The differential
equation of motion is then derived using Lagrange-equations with multipliers. This
chapter presents as well the kinematic analysis for a robot-trailer system. The third
chapter describes the general process on the design of the trailer, including the rejected
ideas for its construction. The fourth chapter focuses on verifying the final results of the
design process, as well as tests to check the mobility of the system. Conclusions and
future work are analyzed on the final part of the document, as well as the references and
the acknowledgments to all the people involved in the project.Tesis
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Meister, Eugen [Verfasser]. "Adaptive Locomotion of Modular Reconfigurable Robotic Systems / Eugen Meister." Aachen : Shaker, 2013. http://d-nb.info/1050344782/34.
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Vijaykumar, R. "Motion planning for legged locomotion systems on uneven terrain /." The Ohio State University, 1988. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487335992904418.
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