身体運動計測の重要性は増してきているが，作業で必須となる手指運動を精度良く計測することは困難である．本論文の目的は，手指運動計測システムを開発し，高精度な手指運動計測および解析手法を構築することである．そのため，手指運動計測用の慣性センサシステムを開発し，それに適した手指モデルの構築手法，計測誤差補正手法を提案，適用することで，より動作制約のない手指運動を精度良く計測，解析可能とする手法を構築した． / 博士(工学) / Doctor of Philosophy in Engineering / 同志社大学 / Doshisha University

Fingrar som verktyg är ett fenomen som individer både lärare, elever och vårdnadshavare runt om i världen har skilda åsikter om. Vissa ser fingrarna som ett positivt verktyg för elevers matematiska tänkande medan andra tvekar på fingrarnas tillgång. Syftet med studien är därför att ge bild av hur lärare uppfattar elevers användande av fingrar som verktyg i matematik. För att besvara syftet har studien tagit utgångspunkt i följande frågeställningar: på vilka skilda sätt uppfattar lärare i årskurs 1–6 elevers användande av fingrar som verktyg och vad karaktäriserar respektive uppfattning? Vilka kritiska aspekter kan identifieras relaterat till de skilda uppfattningarna? Studien tar sin utgångspunkt i den fenomenografiska ansatsen. I studien har fem lärare intervjuats för att få bild av hur de uppfattar användandet av fingrar som verktyg i matematik. Allt material har transkriberats och även analyserats för att kunna redogöra för ett tillförlitligt resultat. Resultatet presenteras genom ett utfallsrum som visar att samtliga lärare uppfattar fenomenet mestadels som något positivt, då en uppfattning är mer negativ. Dessa uppfattningar kan i sin tur delas in i fyra skilda uppfattningar: fingrar som ett hinder för elevers lärande, fingrar som ett konkret material, fingrar som ett stöd i matematik samt fingrar som en grund för aritmetisk förståelse. Av de fyra uppfattningarna gick det att urskilja tre kritiska aspekter, nämligen urskilja möjligheter, att fingrar är ett medierenade verktyg samt urskilja relationer/förståelse. / Fingers as a tool is a phenomenon that individuals such as teachers, pupils and caregivers around the world has different opinions about. Some consider that the fingers are a positive tool to pupils mathematical thinking, while others hesitate the fingers access. The purpose of this study is therefore to give a picture of how teacher perceive the use of fingers as a tool in mathematic. To answer the purpose, following questions have been used: In what ways perceive teacher in grade 1-6 pupils use of fingers as a tool and what characterizes each perception? Which critical aspects can be identified related to the different perceptions? The study is based on phenomenography. Five teachers have been interviewed to give a picture of how teacher perceive the use of fingers as a tool in mathematic. The material has been transcribed and analyzed to be able to account a reliable result. The result presented through an outcome space that shows each teacher perceives the phenomenon mostly as something positive, since one perception is more negative. These perceptions can be divided into four different perceptions: fingers as an obstacle for pupils learning, fingers as a concrete material, fingers as a support in mathematics and fingers as a foundation for arithmetic comprehension. Based on these four perceptions, it was possible to distinguish three critical aspects namely, distinguish possibility, that fingers are a mediating tool and distinguish relations/understanding.

Assessment of finger range of motion (ROM) is often required for monitoring the effectiveness of rehabilitative treatments and for evaluating patients' functional impairment. There are several devices which are used to measure this motion, such as wire tracing, tracing onto paper and mechanical and electronic goniometry. These devices are quite cheap, excluding electronic goniometry; however the drawbacks of these devices are their lack of accuracy and the time- consuming nature of the measurement process. The work described in this thesis considers the design, implementation and validation of a new medical measurement system utilized in the evaluation of the range of motion of the human finger joints instead of the current measurement tools. The proposed system is a non-contact measurement device based on computer vision technology and has many advantages over the existing measurement devices. In terms of accuracy, better results are achieved by this system, it can be operated by semi-skilled person, and is time saving for the evaluator. The computer vision system in this study consists of CCD cameras to capture the images, a frame-grabber to change the analogue signal from the cameras to digital signals which can be manipulated by a computer, Ultra Violet light (UV) to illuminate the measurement space, software to process the images and perform the required computation, a darkened enclosure to accommodate the cameras and UV light and to shield the working area from any undesirable ambient light. Two calibration techniques were used to calibrate the cameras, Direct Linear Transformation and Tsai. A calibration piece that suits this application was designed and manufactured. A steel hand model was used to measure the fingers joint angles. The average error from measuring the finger angles using this system was around 1 degree compared with 5 degrees for the existing used techniques.

A idade normal para início da puberdade em meninas varia bastante, de 8 a 13 anos, e os genes envolvidos nesse controle são parcialmente conhecidos. Fatores ambientais, como alimentação e exposição a disruptores endócrinos, contribuem para essa variabilidade, de modo que genes modulados epigeneticamente podem justificar parte da complexidade desse processo. O termo epigenética se refere às modificações na expressão gênica que não são causadas por alterações na sequência do DNA. A metilação do DNA é o mecanismo epigenético mais bem estudado. Na última década surgiram evidências demonstrando a relação entre metilação do DNA e desenvolvimento puberal. Em fêmeas de roedores, a hipermetilação do DNA levou à puberdade precoce. Em humanos, a puberdade precoce central (PPC) familial causada por mutações nos genes MKRN3 e DLK1 é considerada um defeito do imprinting, fenômeno epigenético no qual apenas um dos alelos parentais é expresso, estando o outro metilado e inativo. Além disso, um conceito atual propõe que o início da puberdade requer a repressão epigenética de fatores inibidores do eixo gonadotrófico. Recentemente, genes zinc finger (ZNF) foram relacionados ao processo puberal, e muitos deles codificam repressores transcricionais. Neste trabalho, estudamos a metilação do DNA do sangue periférico de 10 pacientes do sexo feminino com PPC familial (casos índices) e 33 meninas com desenvolvimento puberal normal (15 pré-púberes e 18 púberes), usando a plataforma Human Methylation 450 BeadChip. Duas pacientes tinham PPC de causa genética (uma com mutação no MKRN3 e outra com deleção no DLK1) e oito tinham PPC idiopática, sem mutações identificadas pelo sequenciamento exômico global. Cento e vinte regiões diferencialmente metiladas foram identificadas entre as meninas saudáveis pré-púberes e púberes, estando 74% delas no cromossomo X. Apenas uma região mostrou-se hipometilada no grupo púbere e, de maneira importante, contém a região promotora do ZFP57, fator necessário para manutenção do imprinting. Uma vez que a hipermetilação nas regiões promotoras dos genes é relacionada à inibição transcricional, o achado de hipermetilação global do DNA na puberdade sugere que haja inibição de fatores inibidores do eixo gonadotrófico, o que resultaria no início do processo puberal. O receptor estrogênico destacou-se como um fator transcricional que se liga a sete genes diferencialmente metilados entre os controles pré-púberes e púberes. As pacientes com PPC apresentaram mais sítios CpG hipermetilados tanto na comparação com as meninas pré-púberes (81%) quanto púberes (89%). Há doze genes ZNF contendo sítios CpG hipermetilados na PPC. Não foram encontradas anormalidades de metilação nos genes MKRN3 e DLK1 nem em suas regiões regulatórias. Em conclusão, este estudo evidenciou hipermetilação global do DNA em meninas com puberdade normal e precoce, sugerindo que esse padrão é uma marca epigenética da puberdade. Pela primeira vez, mudanças no metiloma de pacientes com PPC foram descritas. Modificações na metilação de vários genes ZNF parecem compor a complexa rede de mecanismos que leva ao início da puberdade humana / Normal puberty initiation varies greatly among girls, from 8 to 13 years, and the genetic basis for its control is partially known. Environmental factors, such as nutrition and exposure to endocrine disruptors, contribute to this variance, and epigenetically modulated genes may justify some of the complexity observed in this process. Epigenetics refers to alterations in gene expression that are not caused by changes in DNA sequence itself. DNA methylation is the best studied epigenetic mechanism. In the last decade, evidence has emerged showing the relationship between DNA methylation and pubertal development. In female mice, DNA hypermethylation led to precocious puberty. In humans, familial central precocious puberty (CPP) caused by mutations in the MKRN3 and DLK1 genes is considered a disorder of imprinting, an epigenetic phenomenon in which only one parental allele is expressed, and the other allele is methylated and inactive. In addition, animal studies indicated that pubertal timing requires epigenetic repression of inhibitory factors of the gonadotrophic axis. Recently, zinc finger genes (ZNF) were related to pubertal development, many of which encode transcriptional repressors. In the present study, we analyzed the DNA methylation of peripheral blood samples from 10 female patients with familial CPP (index cases) and 33 girls with normal pubertal development (15 pre-pubertal and 18 pubertal), using the Human Methylation 450 BeadChip assay. Genetic CPP was diagnosed in two patients (one with a MKRN3 mutation and the other with a DLK1 deletion). The remaining eight cases with idiopathic CPP were previously evaluated by whole exome sequencing and no causative mutations were identified so far. We evidenced 120 differentially methylated regions between pre-pubertal and pubertal healthy girls, and 74% of them were located at the X chromosome. Only one genomic region was hypomethylated in the pubertal group. Of note, it contains the promoter region of ZFP57, an important factor for imprinting maintenance. As DNA hypermethylation in gene promoters is related to gene silencing, the finding of global DNA hypermethylation in puberty suggests inhibition of inhibitory factors of the hypothalamic-pituitary-gonadal axis that results in puberty onset. Importantly, the estrogen receptor was identified as a transcriptional factor that binds to seven differentially methylated genes associated with pubertal process. Patients with CPP exhibited more hypermethylated CpG sites compared to both pre-pubertal (81%) and pubertal (89%) controls. Twelve ZNF genes were recognized as having hypermethylated CpG sites in CPP. The methylation analyses of MKRN3 and DLK1 genes showed no abnormalities. In conclusion, this study revealed a widespread DNA hypermethylation in girls with normal and precocious puberty, suggesting that this pattern can be an epigenetic signature of puberty. For the first time, changes in the methylome of patients with CPP were described. We highlight that alterations in methylation levels of several ZNF genes may impact the onset of human puberty

By means of reverse-transcription polymerase chain reaction, overexpression of ZNF146 was detected in two human HCC cell lines HepG2 and Hep3B and a clear relationship between HCC and overexpression of ZNF146 has been established. Subcellular localization of ZNF146 protein in liver cells was studied by generation and expression of a green fluorescent protein (GFP) fusion protein. The nuclear localization and the reported DNA binding ability of ZNF146 protein provided a hint that ZNF146 may carry out its function in the cell system by interacting with specific genomic DNA sequences. Recombinant ZNF146 protein was expressed using bacterial and yeast system for the genomic DNA pull down assay in the identification of potential interacting genomic DNA sequences. Several potential genomic DNA sequences that interact with ZNF146 were identified and the gene MDM2 is the one of the candidates that is directly related to human carcinogenesis. MDM2 is a negative regulator of the tumor suppresser protein p53. Deregulation of MDM2 will impair the cell's ability in cell cycle arrest, DNA repair and apoptosis upon induced DNA damage. / Hepatocellular carcinoma (HCC) is a type of primary malignant liver tumor. And is one of the most frequent malignancies worldwide. The focus of this research project is the characterization of a Kruppel zinc finger protein, zinc Finger Protein 146 (ZNF146) using HCC as a disease model. The aim of this project is to understand the functional role ZNF146 and try to explore the mechanism of how ZNF146 might be involved in the carcinogenesis of HCC. / In order to have a better understanding with the protein ZNF146, SUMOylation properties of this protein has been studied. SUMO1 modification on ZNF146 has already been reported. And in our study, experimental result demonstrated that ZNF146 is also modified by SUMO2 and SUMO3 in liver cells. Other than the SUMOylation sites for SUMO1 protein which has been reported, modification sites for SUMO2 at the K247 and K275 positions were mapped, while K191R, K219R, K247R, K256R and K275R, five positions were mapped for SUMO3 modification. A more complete picture of the SUMOylation properties of ZNF146 has been revealed. Since we hypothesized that ZNF146 is related to the p53 tumor suppressor, cell cycle control and DNA repair pathway, a cell cycle study using flow cytometry was performed for the investigation of the effect on cell cycle regulation by ZNF146 overexpression. In our study, ZNF146 overexpression promoted the G1/S transition in the cell division cycle, which indicated that liver cells were more active for the progression of cell cycle. / On the other hand, using cDNA microarray technology expression profiles of ZNF146 overexpressing and non-overexpressing liver cell lines were compared and with real-time polymerase chain reaction, six candidate genes CRLF1, IFI44, ST6GAL1, LOC441601, IL18 and RAD17 were confirmed with their deregulation induced by the overexpression of ZNF146. Four of the candidates, IFI44, LOC441601, IL18 and RAD17 were found to be related to the p53 tumor suppressor activity or DNA damage, repair response and control. This observation, together with the result of genomic DNA pull down assay, gives us a hint that ZNF146 is possibly involved in liver carcinogenesis by affecting DNA repair and cell cycle control upon induced DNA damage. / The gene ZNF146 codes for a member of the Kruppel zinc finger proteins, however ZNF146 protein is different from most members of the Kruppel zinc finger proteins subfamily. It encodes a 33 kDa protein solely composed of 10 zinc finger motifs and is devoid of any non-zinc finger regulatory domain for interactions with other proteins. ZNF146 overexpression has been reported in a number of cancers including colon cancer and pancreatic carcinoma. However, the functional role of ZNF146 overexpression in tumorigenesis is yet to be solved and not much research on how ZNF146 might be invovled in the establishment of HCC was published. / To conclude, the experimental results of this study support the hypothesis that ZNF146 overexpression may deregulating the cell division cycle and some genes differentially regulated upon over-expression of ZNF146 are related to the regulations of DNA damage response. Future research on ZNF146 can be focused on the detail regulatory pathway of ZNF146 overexpression and its interaction between the p53 tumor suppressor, DNA damage response and cell cycle regulation, and a fuller picture of how ZNF146 overexpression might induce hepatocarcinogenesis can be revealed. / Yeung, Tsz Lun. / Adviser: Miu Yee (Mary) Waye. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3329. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 287-304). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Os projetos genoma têm fornecido uma grande quantidade de informação sobre a arquitetura gênica e sobre a configuração física de suas respectivas regiões flanqueadoras (RF). Estas RF contêm informações com o potencial de auxiliar na elucidação de vários processos biológicos, como os mecanismos de expressão gênica e de sua regulação. Estes mecanismos são de extrema importância para a compreensão do correto funcionamento dos organismos e das patologias que os afetam. Uma parte significativa dos mecanismos de controle de expressão gênica atuam na fase transcricional. Na base destes mecanismos está o recrutamento de proteínas que se ligam às regiões promotoras da transcrição, as quais são segmentos específicos de DNA que podem estar localizados tanto próximos à região de início da transcrição (TSS) quanto a centenas ou até a milhares de pares de bases dela. Essas proteínas compõem a maquinaria transcricional e podem ativar ou inibir o processo de transcrição. Experimentalmente, os segmentos regulatórios podem ser identificadas utilizando métodos complexos de biologia molecular, tais como SELEX, ChiP-ChiP, ChIP-Seq, dentre outros. Uma estratégia alternativa aos métodos experimentais é a utilização de metodologias computacionais. Análises computacionais tendem a ser mais rápidas, baratas e flexíveis do que protocolos experimentais, além de poderem ser utilizadas em larga escala. Atualmente, os métodos computacionais disponíveis necessitam de informações experimentais para a definição de padrões globais de preferências de sequências de DNA para a ligação de fatores de transcrição (TFBS, em inglês transcription factor binding sites). Entretanto, esses métodos apresentam uma elevada taxa de falso positivos e, por vezes, apresentam também taxas significativas de falso negativos, além de serem limitados ao estudo de fatores de transcrição de espécies bem conhecidas, o que diminui a área de aplicação dos mesmos. Diante deste cenário, o uso de métodos computacionais que não necessitem da informação referente aos sítios de ligação, bem como os que utilizem parâmetros mais robustos de detecção dos resultados, em detrimento dos escores de pontuação provindos de alinhamentos, podem acrescentar uma sensível melhoria ao processos de predição de regiões regulatórias. Neste projeto, foi desenvolvido um novo modelo computacional (TFBSAnalyzer) para análise e identificação de TFBS em elementos regulatórios, que utiliza técnicas de modelagem molecular para a construção de complexos entre um fator de transcrição ancorado a estruturas de DNA com sequências variáveis de bases e, através de cálculos termodinâmicos de entalpia de ligação, determina uma função de pontuação baseada na energia de ligação e realiza a predição de sítios de ligação ao DNA para o fator de transcrição em análise. Esta abordagem foi testada com três fatores de transcrição como sistemas-modelo, pertencentes à família dos receptores nucleares, a saber: o receptor de estrógeno ER-alfa (Estrogen Receptor Alpha), o receptor de ácido retinoico RAR-beta (Retinoid Acid Receptor Beta) e o receptor X retinóico RXR (Retinoid X Receptor). Os modelos previstos computacionalmente foram comparados aos dados experimentais disponíveis para estes receptores nucleares, os quais apresentaram as seguintes taxas de FP/FN: 10%/0 para RAR-beta e RXR, 21%/6% para ER-alfa. Também simulamos um experimento de ChIP-seq do ER-alfa no genoma humano, cujos genes selecionados foram submetidos a uma análise de enriquecimento de fatores de transcrição curados experimentalmente, que fazem sua regulação, revelando que o receptor de estrógeno está realmente envolvido no processo. Para mostrar a aplicabilidade geral de nosso método, nós modelamos a distribuição de energia de ligação para o receptor NHR-28 isoforma a de Caenorhabditis elegans com DNA . Obtivemos distribuições de energia semelhantes àquelas encontradas para os NRs modelos, portanto seria possível aplicar o método para buscar possíveis TFBSs para este receptor no genoma de C. elegans. Os dados gerados e as metodologias desenvolvidas neste projeto devem acrescentar uma sensível melhoria aos processos de predição de regiões regulatórias e consequentemente auxiliar no entendimento dos mecanismos envolvidos no processo de expressão gênica e de sua regulação. / The genome projects have provided a lot of information about the genetic architecture, as well as on the physical configuration of their flanking regions (FR). These FR have the potential to aid in the elucidation of many biological processes, such as the mechanisms involved in gene expression and its regulation. These mechanisms are extremely important for undeerstanfind the correct functioning of organisms as well as the pathologies that affect them. A significant part of the control mechanisms of gene expression act during transcription. On the basis of this mechanisms is the recruitment of proteins that bind to promoter regions of transcription, which are specific segments of DNA that can be located either near the transcription start site or at hundreds or even thousands of base pairs away. These proteins form the transcription machinery, which can activate or inhibit the transcription process. The regulatory segments can be identified experimentally using complex methods of molecular biology, such as SELEX, ChIP-chip, ChIP-seq, among others. An alternative strategy to these experimental methods is the use of computational methodologies for predicting regulatory regions. Computational analysis tend to be faster, cheaper and more flexible than the experimental protocols, and can be used on a larger scale. Currently, the available computational methods require information previously obtained from experiments in order to define global standards of preference of DNA-Binding sequences for transcription factors (TFBS - Transcription Factor Binding Sites). However, these methods have a high rate of false positives and sometimes also have significant rates of false negatives, besides being limited to the study of transcription factors of well-known species, which decreases their application area. In this scenario, the use of computational methods that do not require previous information concerning the binding sites and use more robust parameters of results detection, instead of alignment scores, may add significant improvement to the processes of predicting regulatory regions. In this project, we developed a new computational model TFBSAnalyzer) for analysis and identification of regulatory elements using molecular modeling techniques for the construction of complexes between a transcription factor bound to specific DNA structures with variable sequences of bases and, by means of thermodynamic calculations of bond enthalpy, provides a scoring function based on the binding energy and predicts the DNA binding sites for the transcription factor in analysis. This approach was tested initially with three transcription factors as models, belonging to the nuclear receptor family, namely estrogen receptor ER-alpha (Estrogen Receptor Alpha), the retinoic acid receptor RAR-beta (Retinoid Acid Receptor Beta) and the retinoic X receptor RXR (Retinoid X Receptor). The computationally predicted models were compared to experimental data available for these nuclear receptors, and presented the following rates of FP/FN: 10%/0 for RAR-beta and RXR, 21%/6% for ER-alpha. We also simulated an experiment of ChIP-seq with ER-alpha with the human genome, where the selected genes were subjected to a transcription factor enrichment analysis, with curated information, revealing that the estrogen receptor is indeed involved in their regulation. To show that our method has a general applicability, we modeled the binding energy distribution for the NHR-28 receptor, isoform a, from Caenorhabditis elegans. The energy distributions obtained were similar to the ones obtained for the model NR, so it would be possible to use the method and search for possible TFBS in the C. elegans genome. The data generated and the methodologies developed in this project should add a significant improvement to the prediction processes of regulatory regions and, consequently, help to understand the mechanisms involved in the gene expression process and its regulation.

Although upper limb motor impairments are common, the primary tools for assessing and tracking these impairments in a clinical setting are subjective, qualitative rating scales that lack resolution and repeatability. Markerless motion capture technology has the potential to greatly improve clinical assessment by providing quick, low-cost, and accurate tools to objectively quantify motor deficits. Here we lay some of the groundwork necessary to enable markerless motion capture systems to be used in clinical settings. First, we adapted five motor tests common in clinical assessments so they can be administered via markerless motion capture. We implemented these modified tests using a particular motion capture sensor (Leap MotionTM Controller, hereafter referred to as the Leap Motion sensor) and administered the tests to 100 healthy subjects to evaluate the feasibility of administrating these tests via markerless motion capture. Second, to determine the ability of the Leap Motion sensor to accurately measure tremor, we characterized the frequency response of the Leap Motion sensor. During the administration of the five modified motor tests on 100 healthy subjects, the subjects had little trouble interfacing with the Leap Motion sensor and graphical user interface, performing the tasks with ease. The Leap Motion sensor maintained an average sampling rate above 106 Hz across all subjects during each of the five tests. The rate of adverse events caused by the Leap Motion sensor (mainly jumps in time or space) was generally below 1%. In characterizing the frequency response of the Leap Motion sensor, we found its bandwidth to vary between 1.7 and 5.5 Hz for actual tremor amplitudes above 1.5 mm, with larger bandwidth for larger amplitudes. To improve the accuracy of tremor measurements, we provide the magnitude ratios that can be used to estimate the actual amplitude of the oscillations from the measurements by the Leap Motion sensor. These results suggest that markerless motion capture systems are on the verge of becoming suitable for routine clinical use, but more work is necessary to further improve the motor tests before they can be administered via markerless motion capture with sufficient robustness for clinical settings.

The observations made in brain-lesioned patients and the result of functional brain imaging studies converge to the hypothesis that the posterior parietal cortex (PPC) is involved in calculation and number processing. However, if numerical disorders generally result from a left parietal lesion, the results of some brain imaging studies suggest that the right PPC could also play a role in number magnitude processing. In order to clarify this question, we used transcranial magnetic stimulation to induce a virtual lesion of the left or right PPC in healthy subjects while they performed number comparison. Our results show that the integrity of the left PPC is a necessary condition for the precise discrimination required during close number comparison; whereas the comparison of far numbers can be performed by either hemisphere as suggested by the fact that this task is affected only by the simultaneous virtual lesion of both hemispheres. In order to better identify which processes underlie the numerical competence of the PPC, we then studied the possible interactions between number processing and visuo-motor functions. Indeed, a meta-analysis performed on functional imaging data revealed that number processing depends on parietal regions, but also on certain premotor areas, which are very close to those involved in the control of finger movements. In a first series of experiments, we thus observed an excitability increase in motor circuits during the enumeration of dots presented on a computer screen. Given that the counting task was performed with both hands at rest, this increase was interpreted as reflecting the mental simulation of pointing movements or sequential finger rising as counting goes on. In a second series of experiments, we showed that information related to number magnitude could interfere with the aperture of the finger grip required to grasp an object. These results suggest that the conformation of the hand to object size shares, with the representation of numbers, common processes for magnitude estimate. In conclusion, our thesis supports the hypothesis that our numerical capacities rely, at least partially, on visuo-motor functions involving the PPC; this could explain why the numerical capacities of the left hemisphere, which is dominant for motor activities, are more precise. / Les observations réalisées chez les patients cérébrolésés ainsi que le résultat des études d'imagerie cérébrale fonctionnelle convergent vers l'hypothèse selon laquelle le cortex pariétal postérieur (CPP) est impliqué dans le traitement des nombres et le calcul. Cependant, si les troubles du calcul résultent le plus souvent d'une lésion pariétale gauche, les résultats de certaines études d'imagerie fonctionnelle suggèrent que le CPP droit pourrait également jouer un rôle dans le traitement de la magnitude des nombres. Afin de clarifier cette question, nous avons utilisé la stimulation magnétique transcrânienne pour induire une lésion virtuelle du CPP gauche ou droit chez des sujets sains réalisant une tâche de comparaison de nombres. Nos résultats montrent que l'intégrité du CPP gauche est une condition nécessaire à la discrimination précise requise lors de la comparaison de nombres proches; la comparaison de nombres éloignés peut, quant à elle, être réalisée par l'un ou l'autre hémisphère comme le suggère le fait que cette tâche n'est affectée que par lésion virtuelle simultanée des deux hémisphères. Afin de mieux appréhender les processus sur lesquels s'appuient les compétences numériques du CPP, nous avons ensuite étudié les interactions possibles entre le traitement des nombres et les fonctions visuo-motrices. En effet, une méta-analyse réalisée sur des données d'imagerie fonctionelle a révélé que le traitement des nombres dépend de régions pariétales, mais également de certaines aires prémotrices, proches de celles impliquées dans le contrôle des mouvements des doigts. Dans une première série d'expériences, nous avons ainsi observé une augmentation de l'excitabilité des circuits moteurs lors du comptage de points présentés sur l'écran d'un ordinateur. Etant donné que la tâche de comptage était réalisée avec les mains au repos, cette augmentation a été interprétée comme le reflet d'une simulation mentale de mouvements de pointage ou d'extension séquentielle des doigts pendant le comptage. Dans une deuxième série d'expériences, nous avons montré que l'information relative à la magnitude des nombres pouvait interférer avec l'ouverture de la pince bidigitale requise pour saisir un objet. Ces résultats suggèrent que la conformation de la main adaptée à la taille des objets partage, avec la représentation des nombres, des processus communs d'estimation de la magnitude. En conclusion, notre travail supporte l'hypothèse selon laquelle nos capacités numériques pourraient, en partie du moins, reposer sur des fonctions visuo-motrices impliquant le CPP ; ceci pourrait expliquer pourquoi les capacités numériques de l'hémisphère gauche, dominant pour les activités motrices, sont plus précises.

The observations made in brain-lesioned patients and the result of functional brain imaging studies converge to the hypothesis that the posterior parietal cortex (PPC) is involved in calculation and number processing. However, if numerical disorders generally result from a left parietal lesion, the results of some brain imaging studies suggest that the right PPC could also play a role in number magnitude processing. In order to clarify this question, we used transcranial magnetic stimulation to induce a virtual lesion of the left or right PPC in healthy subjects while they performed number comparison. Our results show that the integrity of the left PPC is a necessary condition for the precise discrimination required during close number comparison; whereas the comparison of far numbers can be performed by either hemisphere as suggested by the fact that this task is affected only by the simultaneous virtual lesion of both hemispheres. In order to better identify which processes underlie the numerical competence of the PPC, we then studied the possible interactions between number processing and visuo-motor functions. Indeed, a meta-analysis performed on functional imaging data revealed that number processing depends on parietal regions, but also on certain premotor areas, which are very close to those involved in the control of finger movements. In a first series of experiments, we thus observed an excitability increase in motor circuits during the enumeration of dots presented on a computer screen. Given that the counting task was performed with both hands at rest, this increase was interpreted as reflecting the mental simulation of pointing movements or sequential finger rising as counting goes on. In a second series of experiments, we showed that information related to number magnitude could interfere with the aperture of the finger grip required to grasp an object. These results suggest that the conformation of the hand to object size shares, with the representation of numbers, common processes for magnitude estimate. In conclusion, our thesis supports the hypothesis that our numerical capacities rely, at least partially, on visuo-motor functions involving the PPC; this could explain why the numerical capacities of the left hemisphere, which is dominant for motor activities, are more precise. / Les observations réalisées chez les patients cérébrolésés ainsi que le résultat des études d'imagerie cérébrale fonctionnelle convergent vers l'hypothèse selon laquelle le cortex pariétal postérieur (CPP) est impliqué dans le traitement des nombres et le calcul. Cependant, si les troubles du calcul résultent le plus souvent d'une lésion pariétale gauche, les résultats de certaines études d'imagerie fonctionnelle suggèrent que le CPP droit pourrait également jouer un rôle dans le traitement de la magnitude des nombres. Afin de clarifier cette question, nous avons utilisé la stimulation magnétique transcrânienne pour induire une lésion virtuelle du CPP gauche ou droit chez des sujets sains réalisant une tâche de comparaison de nombres. Nos résultats montrent que l'intégrité du CPP gauche est une condition nécessaire à la discrimination précise requise lors de la comparaison de nombres proches; la comparaison de nombres éloignés peut, quant à elle, être réalisée par l'un ou l'autre hémisphère comme le suggère le fait que cette tâche n'est affectée que par lésion virtuelle simultanée des deux hémisphères. Afin de mieux appréhender les processus sur lesquels s'appuient les compétences numériques du CPP, nous avons ensuite étudié les interactions possibles entre le traitement des nombres et les fonctions visuo-motrices. En effet, une méta-analyse réalisée sur des données d'imagerie fonctionelle a révélé que le traitement des nombres dépend de régions pariétales, mais également de certaines aires prémotrices, proches de celles impliquées dans le contrôle des mouvements des doigts. Dans une première série d'expériences, nous avons ainsi observé une augmentation de l'excitabilité des circuits moteurs lors du comptage de points présentés sur l'écran d'un ordinateur. Etant donné que la tâche de comptage était réalisée avec les mains au repos, cette augmentation a été interprétée comme le reflet d'une simulation mentale de mouvements de pointage ou d'extension séquentielle des doigts pendant le comptage. Dans une deuxième série d'expériences, nous avons montré que l'information relative à la magnitude des nombres pouvait interférer avec l'ouverture de la pince bidigitale requise pour saisir un objet. Ces résultats suggèrent que la conformation de la main adaptée à la taille des objets partage, avec la représentation des nombres, des processus communs d'estimation de la magnitude. En conclusion, notre travail supporte l'hypothèse selon laquelle nos capacités numériques pourraient, en partie du moins, reposer sur des fonctions visuo-motrices impliquant le CPP ; ceci pourrait expliquer pourquoi les capacités numériques de l'hémisphère gauche, dominant pour les activités motrices, sont plus précises.

Saccharomyces cerevisiae HOP1, which encodes a component of the synaptonemal complex, plays an important role in both gene conversion and crossing over between homologs, as well as enforces the meiotic recombination checkpoint control over the progression of recombination intermediates. The zinc-finger motif (Znf) 348CX2CX19CX2C374) of Hop1 is crucial for its function in meiosis, since mutation of conserved Cys371 to Ser in this motif results in a temperature-sensitive phenotype, which is defective in sporulation and meiosis. The direct role for Hop1 or its ZnF in the formation of joint molecules and checkpoint control over the progression of meiotic recombination intermediates is unknown. To understand the underlying biochemical mechanism, we constructed a series of recombination intermediates. Hop1 or its ZnF were able to bind different recombination intermediates. Interestingly, the binding affinity of Hop1 and its ZnF was much higher for the Holliday junction as compared to other recombination intermediates. The complexes of Hop1 or its ZnF with the Holliday junction were stable and specific as shown by NaCl titration and competition experiment. Hop1 and its ZnF blocked BLM helicase-induced unwinding of the Holliday junction, indicating that the interaction between Hop1 and its ZnF with the Holliday junction is specific. DNase I footprinting experiment showed that Hop1 or its ZnF bind to the center of the Holliday junction. 2-aminopurine fluorescence and KMnO4 experiments showed that Hop1 or its ZnF can distort the Holliday junction in a 2-fold symmetrical manner. The molecular modeling study showed that Hop1 ZnF folded into unique helix-loop-helix motif and bound to center of the Holliday junction. In summary, this study shows that Hop1 protein or its ZnF interact specifically with the Holliday junction and distort its structure. Taken together, these results implicate that Hop1 protein might coordinate the physical monitoring of meiotic recombination intermediates during the process of branch migration and that Hop1 ZnF acts as a structural determinant of Hop1 protein functions.