NiAl ist eine intermetallische Verbindung mit kubischer B2-Struktur. Unterhalb der Spröd-duktil-Übergangstemperatur, die bei Normaldruck bei etwa 300°C liegt, können nach dem Von-Mises-Kriterium nicht ausreichend viele unabhängige Gleitsysteme zur homogenen plastischen Verformung aktiviert werden, da die Bruchspannung unterhalb der kritischen Schubspannung zur Aktivierung des sekundären Gleitsystems liegt. Um NiAl trotzdem massiv plastisch verformen zu können, muss die Verformung bei hohem Druck erfolgen. Dies ist beispielsweise möglich bei der Verformung mittels Gleichkanal- Winkelpressen (ECAP) oder Hochdrucktorsion (HPT). Hierbei werden sehr hohe Verformungsgrade erreicht. In dieser Arbeit wird nun die Gefüge- und Texturentwicklung bei Verformung mittels HPT bei Temperaturen zwischen Raumtemperatur und 500°C in Abhängigkeit von Temperatur und hydrostatischem Druck sowie Verformungsgrad untersucht und mit den entsprechenden Größen bei der Verformung mit ECAP verglichen. Es zeigt sich, dass bei der HPT-Verformung die für kubisch-raumzentrierte Metalle typische Schertextur auftritt; zudem findet sich ab einer Verformungstemperatur von 100°C eine geneigte Würfellage, die durch dynamische Rekristallisation entstanden ist und deren Intensität mit der Verformungstemperatur ansteigt. Auch bei den ECAP-Proben findet man die typische Schertextur, eine Würfeltextur tritt nicht auf. Bei beiden Prozessen kommt es zur Kornfeinung, die beeinflusst wird von Verformungstemperatur, Druck und Verformungsgrad. Eine verbesserte Duktilität kann im Zugversuch nicht festgestellt werden, während eine gesteigerte Festigkeit durch Mikro- härtemessungen bestätigt wird. Bei genügend hoher Verformung findet man auch nach der Verformung von Einkristallen eine typische Schertextur. / NiAl is an intermetallic compound with a cubic B2 structure. Below the brittle-to-ductile transition temperature at about 300°C under ambient pressure the number of independent slip systems that have to be activated for a homogeneous plastic deformation is not sufficiently high according to the von Mises criterion. This is because the fracture stress is smaller than the critical yield stress for the activation of the secondary slip system. Despite this, severe plastic deformation is possible under a high pressure. It can be realized by deforming by equal channel angular pressing (ECAP) or high pressure torsion (HPT). Thereby a very high degree of deformation is reached. In this work, texture and microstructure evolution after deformation by HPT at different tem- peratures between room temperature and 500°C and at different hydrostatic pressures and degrees of deformation are analysed and compared to texture and microstructure after ECAP. After deformation by HPT, a texture typical for sheared body-centred metals is found; besides, for a deformation temperature of 100°C and higher an oblique cube component appears. It develops by dynamic recrystallization and grows with increasing deformation temperature. The shear texture also arises in the ECAP deformed samples, but no oblique cube texture is found. Both processes lead to grain refinement, which is influenced by deformation temperature, pressure, and degree of deformation. Tensile testing doesn’t show an enhanced ductility, but an improved strength is confirmed by microhardness measurements. If the degree of deformation is high enough, a shear texture can even be found after deforming single crystals.

Ce travail de thèse présente le développement de phototransistors bipolaires à hétérojonction (HPT) SiGe/Si mis en œuvre dans une technologie de processus 80GHz SiGe bipolaire pour des applications de transmission Radio-sur-Fibre. Le cas particuliers d'un réseau domestique sans fil à infrastructure optique est considéré pour lequel le critère de coût est prépondérant. Le fonctionnement des ce HPT SiGe/Si est étudié sous une longueur d'onde optique de 850 nm en exploitant des fibres optique multimode (MMF) suffisantes pour les besoins de bande passante dans un environnement de réseau domestique. Le HPT SiGe/Si est également développé dans l'objectif de permettre une intégration combiné du photorécepteur et circuit intégré monolithiquement, conduisant à des structures de type Opto-electronic Microwave Monolithically Integrated Circuit (OE-MMIC), visant à poursuivre l'intégration et la réduction des cours. Deux topologies ont été explorées principalement: 1) une topologie avec élargissement de la base et du collecteur (xBC HPT) et 2) une topologie avec élargissement des trois régions de base, émetteur et collecteur simultanément (xEBC HPT). Des variations technologies ont été réalisées et analysées en détail, à la fois en terme de couches verticales que de dessin de masque (layout). Les mesures ont démontré la validité technologique de chacune de ces approches, et permis d'isoler l'impact sur les performances statiques et dynamiques de chacune de ces couches. Une solution de type xEBC se montre ainsi préférable pour le cas de composants de petites dimensions inférieure à 50x50µm², dans la bande du GHz. Les phototransistors sont développés dans une configuration à trois terminaux (3T-HPT). Le type de polarisation de la base du HPT influe également sur la responsivité du phototransistor. Une polarisation de courant constant (CC) démontre une plus grande responsivité par rapport au cas d'une polarisation en tension ( CV). Une analyse détaillée montre aussi les différences de responsivité mesurées en continue et celles mesurées en basse fréquence à 50MHz. La connexion de base permet également de varier l'impédance de charge présentée sur celle-ci. La théorie de l'adaptation des phototransistors est rappelée. L'effet de différentes impédances de base sont étudiées par la simulation et la mesure des circuits réalisés technologiquement. L'intégration du phototransistor au sein d'un circuit élémentaire est enfin explorée. Différentes configurations de paires HPT - HBT sont étudiées, formant des circuits élémentaires. Des caractérisations expérimentales permettent de vérifier l'amélioration apportées par ces topologies par rapport au phototransistor unique. Enfin, un phototransistor SiGe en configuraiton 2T-HPT est utilisé et intégré avec succès pour la première fois au sein d'un module de type Receiving Optical Sub Assembly (ROSA) pour la mise au point d'une transmission Radio-sur-Fibre multiGigabit par seconde pour un réseau domestique / This research is focused on the study of silicon germanium based heterojunction bipolar phototransistors (SiGe HPTs) implemented in an 80GHz SiGe Bipolar process technology. It's application in a radio over fiber system for home area networks are investigated. RoF for Home area networks are envisioned to implemented with a minimal system cost. Operation at 850nm is identified as a critical parameter to achieve this goal. Low cost off the shelf optical components are readily available at this wavelength. The use of multi mode fibers (MMF) as opposed to higher cost single mode fiber (SMF) is sufficient for the bandwidth requirements in a home network environment. A monolithically integrated OE receiver chip would help in the overall reduction of the system cost by having the optical detector in the same chip with the electronic circuits. We have designed and implemented three terminal HPT (3T-HPT) structures. The two main groups of the HPT structures are: 1) HPTs with extended Base and Collector regions (xBC HPT) and 2) HPTs with extended Emitter, Base and Collector regions (xEBC HPT). Variations to improve optical coupling the though optimizations in the vertical stack and lateral size of the HPT. The measurements and characterization showed that all the structures are compatible with the process technology. The type of biasing used in the base of the HPT also influences the HPT performance. A constant current (CC) bias has higher extracted DC responsivity as compared to a constant voltage (CV) bias. The effects of the different passive base loads on the HPT responsivity are studied through simulation and measurement of fabricated circuits. The impedance presented on the base has a great influence on the HPT responsivity. The performance of an HPT as circuit component is studied using different HPT-HBT pair configurations. Tests and measurements verify that improvement in the classical transistor pair configurations are also present in the opto microwave response of the HPT-HBT pair. Finally, SiGe hpt is used in the development of a ROSA module for a radio over fiber systems for home area network

Title: Complex investigation of fine-grained polycrystals of Cu and CuZr alloy processed by equal channel angular pressing and high pressure torsion Author: RNDr.Ondřej Srba Department: Department of Physics of Materials, Faculty of Mathematics and Physics, Charles University Prague Supervisor: Doc. RNDr. Miloš Janeček, CSc. Abstract: In the thesis the microstructure development, mechanical, elastic and corrosion properties of deformed specimens of pure Cu and binary alloy CuZr processed by equal channel angular pressing (ECAP) are investigated. Several properties of pure Cu processed by ECAP are compared with properties of the same material processed by high pressure torsion (HPT). The microstructure development is characterized in detail by several experimental techniques (light and electron microscopy, electron back scatter diffraction, positron annihilation spectroscopy, etc.). The microstructure development in specimens processed by ECAP is characterized by the continuous fragmentation of the initial coarse grain structure and the formation of new grains having the sizes in the submicrocrystalline range (of 460 nm and 260 nm in Cu and CuZr alloy, respectively). During the deformation by ECAP the fraction of high-angle grain boundaries, the dislocation density and the concentration of vacancies are...

Cette thèse vise à analyser en détails la possibilité d'améliorer les futurs systèmes Radio-sur-Fibre (RoF) dans différents scénarios de télécommunication, tels que les réseaux cellulaires actuels et de la prochaine génération, ainsi que dans d'autres applications telles que la radioastronomie. Le système RoF étudié est donc composé d’un laser à cavité verticale (VCSEL) fonctionnant à 850 nm, d'une fibre standard monomode (SSMF) et d'un phototransistor à hétérojonction SiGe (HPT), adoptant la technique appelée détection directe par modulation d'intensité qui est aujourd'hui l'architecture à moindre coût et la plus simple pour RoF. Cette thèse décrit en détail la propagation non naturelle dans le SSMF (conçue pour fonctionner uniquement à 1310 nm et 1550 nm) à 850 nm. A travers un modèle mathématique développé, la propagation à deux modes est décrite et les principaux phénomènes impliqués sont analysés. En particulier, le modèle se concentre sur la dispersion intermodale et le bruit modal, considérés comme les deux principales contributions de performance nuisible. Le modèle mis au point permet d'identifier les principaux paramètres qui contribuent à renforcer les effets néfastes de la dispersion intermodale et du bruit modal, à la fois en fréquence et dans le temps. A partir du modèle, des techniques possibles pour améliorer les performances sont alors proposées. En fait, une technique de pré-filtrage est réalisée afin d'éviter l'excitation du mode du second ordre, permettant une propagation quasi-monomode au sein du SSMF. La technique est validée théoriquement et expérimentalement soit pour une transmission sinusoïdale à radiofréquence unique, soit pour une transmission de signal passe-bande centrée sur une bande de radiofréquence. Il est démontré expérimentalement que possibilité d'augmenter la bande passante de modulation du système RoF, tout en réduisant les fluctuations de puissance et de gain. De plus, la technique est validée dans un véritable système de transmission LTE, ce qui permet à la technologie RoF de transmettre un signal LTE 256-QAM de 20 MHz, confirmant la possibilité d'utiliser cette technologie pour réduire le coût global et la consommation du réseau. Des travaux supplémentaires ont été réalisés sur le modèle mathématique. En fait, la propagation des deux modes est exploitée en sens inverse pour caractériser le chirp du VCSEL utilisé. Enfin, le problème du couplage entre les fibres et les dispositifs optoélectroniques est discuté et étudié afin d’améliorer les performances tout en gardant un faible coût. La possibilité d'utiliser une structure collective et passive pour coupler la fibre optique avec des photodétecteurs à petite surface et VCSEL est présentée, montrant des améliorations importantes sur l'efficacité du couplage et la tolérance au désalignement / This dissertation aims to analyze the possibility of improving in terms of cost and consumption the future Radio-over-Fiber (RoF) systems in different telecommunication scenarios, such as current and next generation of cellular networks and in other applications such as Radio Astronomy. The RoF system studied is hence composed of a Vertical Cavity Surface Emitting Laser (VCSEL) operating at 850 nm, standard single mode fiber (SSMF) and SiGe Heterojunction Phototransistor (HPT), adopting the technique called Intensity Modulation{Direct Detection which is nowadays the cheapest and simplest architecture for RoF. This dissertation describes in detail the multimode propagation within the SSMF (designed to operate only at 1310 nm and 1550 nm) which is present at 850 nm. Through a developed mathematical model, the two-modes propagation is described and the main phenomena involved are analyzed. In particular, the model focus on intermodal dispersion and modal noise which are considered the two main contributions of performance detrimental. The model developed is able to identify the main parameters which contribute to enhance the detrimental effects produced by intermodal dispersion and modal noise both in frequency and time domain. Starting from the model, possible techniques to improve the performances are then proposed. In particular, a pre-filtering technique is realized in order to avoid the excitation of the second order mode, allowing a quasi-single-modepropagation within the SSMF. The technique is theoretically and experimentally validated either for single radio frequency sinusoidal transmission either for bandpass signal transmission centered in radio frequency band. In particular it is demonstrated experimentally the possibility of increasing the modulationbandwidth of the RoF system, reducing at the same time the fluctuations of power and gain. Furthermore, the technique is validated in a real LTE transmission system, making the RoF technology proposed able to transmit 256-QAM LTE signal of 20 MHz bandwidth, confirming the possibility of using this technology to decrease the overall cost and consumption of the network. Further work hasbeen done on the mathematical model. In particular the two modes propagation is exploited reversely in order to characterize the chirp parameter of the VCSEL employed. Finally, the problem of coupling between fiber and opto-electronic devices is also discussed and investigated, in order to enhance theperformances while keeping low the cost. The possibility of utilizing a collective and passive ploymerbased structure for coupling the optical fiber with small area photodetectors and VCSEL is presented, showing important improvements on coupling efficiency and tolerance to misalignment

NiAl ist eine intermetallische Verbindung mit kubischer B2-Struktur. Unterhalb der Spröd-duktil-Übergangstemperatur, die bei Normaldruck bei etwa 300°C liegt, können nach dem Von-Mises-Kriterium nicht ausreichend viele unabhängige Gleitsysteme zur homogenen plastischen Verformung aktiviert werden, da die Bruchspannung unterhalb der kritischen Schubspannung zur Aktivierung des sekundären Gleitsystems liegt. Um NiAl trotzdem massiv plastisch verformen zu können, muss die Verformung bei hohem Druck erfolgen. Dies ist beispielsweise möglich bei der Verformung mittels Gleichkanal- Winkelpressen (ECAP) oder Hochdrucktorsion (HPT). Hierbei werden sehr hohe Verformungsgrade erreicht. In dieser Arbeit wird nun die Gefüge- und Texturentwicklung bei Verformung mittels HPT bei Temperaturen zwischen Raumtemperatur und 500°C in Abhängigkeit von Temperatur und hydrostatischem Druck sowie Verformungsgrad untersucht und mit den entsprechenden Größen bei der Verformung mit ECAP verglichen. Es zeigt sich, dass bei der HPT-Verformung die für kubisch-raumzentrierte Metalle typische Schertextur auftritt; zudem findet sich ab einer Verformungstemperatur von 100°C eine geneigte Würfellage, die durch dynamische Rekristallisation entstanden ist und deren Intensität mit der Verformungstemperatur ansteigt. Auch bei den ECAP-Proben findet man die typische Schertextur, eine Würfeltextur tritt nicht auf. Bei beiden Prozessen kommt es zur Kornfeinung, die beeinflusst wird von Verformungstemperatur, Druck und Verformungsgrad. Eine verbesserte Duktilität kann im Zugversuch nicht festgestellt werden, während eine gesteigerte Festigkeit durch Mikro- härtemessungen bestätigt wird. Bei genügend hoher Verformung findet man auch nach der Verformung von Einkristallen eine typische Schertextur. / NiAl is an intermetallic compound with a cubic B2 structure. Below the brittle-to-ductile transition temperature at about 300°C under ambient pressure the number of independent slip systems that have to be activated for a homogeneous plastic deformation is not sufficiently high according to the von Mises criterion. This is because the fracture stress is smaller than the critical yield stress for the activation of the secondary slip system. Despite this, severe plastic deformation is possible under a high pressure. It can be realized by deforming by equal channel angular pressing (ECAP) or high pressure torsion (HPT). Thereby a very high degree of deformation is reached. In this work, texture and microstructure evolution after deformation by HPT at different tem- peratures between room temperature and 500°C and at different hydrostatic pressures and degrees of deformation are analysed and compared to texture and microstructure after ECAP. After deformation by HPT, a texture typical for sheared body-centred metals is found; besides, for a deformation temperature of 100°C and higher an oblique cube component appears. It develops by dynamic recrystallization and grows with increasing deformation temperature. The shear texture also arises in the ECAP deformed samples, but no oblique cube texture is found. Both processes lead to grain refinement, which is influenced by deformation temperature, pressure, and degree of deformation. Tensile testing doesn’t show an enhanced ductility, but an improved strength is confirmed by microhardness measurements. If the degree of deformation is high enough, a shear texture can even be found after deforming single crystals.

The purpose of this study is to investigate the phases of change process of integrating a quality development model into an information technology company in Turkey. While the transformation phases were being examined by a qualitative study, the factors that affect the change process also were investigated. This study explores the process of traveling through the way to CMMI (Capability Maturity Model Integration) level 3 certification by a company that gives information technologies service to banking sector. Since circulation of staff prevents us from obtaining what an exact number of workers, the company has about 450 employees. At the beginning, the company had no quality standards and most of the work processes were not documented, even documented processes were not consistent. After the commencement of the quality development project, work flows of processes were defined and documented. The company changed its organization according to the new process improvement model, called CMMI. In this case study, interviews performed with ten experts from inside of the company and three experts from outside of the company, observation diaries and assets of the company were data sources. Participant observation, questionnaire and document analysis were used as data gathering methods. Collected data were interpreted by descriptive analysis. As a result of the research, while resistance to change came out naturally, it is determined that transformation has four stages such as: &ldquo / motivation and adoption&rdquo / , &ldquo / adaptation&rdquo / , &ldquo / acceptance and implementation&rdquo / and finally &ldquo / use and improvement&rdquo / .

Les relais de phosphorylation de type histidine/aspartate constituent des voies de signalisation impliquées dans la perception et la transduction des signaux jusqu’à la mise en place de réponses spécifiques. Ils mettent en jeu un récepteur ou Histidine aspartate Kinase (HK), des protéines navettes en charge de la transmission du phosphate (HPt) et des Régulateurs de Réponse (RR). L’implication d’un tel système dans la transduction du signal de la contrainte osmotique est avérée chez la levure et fortement suspectée chez Arabidopsis. Ce travail de thèse visait d’une part à caractériser l’implication de cette voie de transduction de la contrainte osmotique chez le peuplier, avec l’identification de partenaires HPt et RR en aval du récepteur HK1 et d’autre part à caractériser le mode de fonctionnement d’un RR de type-B. HK1, un osmosenseur membranaire détecterait le signal et le transmettrait à trois HPt préférentielles. De plus, un partenariat d’interaction se dégagerait entre ces trois HPt et certains RR-B. La régulation transcriptionnelle observée lors d’une contrainte osmotique pour deux des représentants des RR-B témoigne d’une possible implication de ces RR dans cette voie. Ces protéines sont des facteurs de transcription dont la fonction a été confirmée in planta pour l’un d’entre eux. La dimérisation du domaine receveur du RR et son interaction avec le domaine de fixation à l’ADN ou domaine GARP apparaissent comme des points de contrôle clés dans la régulation de l’activité effectrice des RR-B. De plus, la capacité d’un RR-B à se fixer sur ses motifs de reconnaissance (boîtes AGAT) a pu être vérifiée in vitro et la présence de ces séquences a d’ailleurs été retrouvée dans des gènes régulés par la contrainte osmotique. Ce travail prospectif ouvre des perspectives concernant l’implication des RR-B dans la voie de transduction du signal de la contrainte osmotique, et propose notamment des mécanismes fins pour l’élaboration d’une réponse hautement spécifique. / Multistep His-to-Asp phosphorelay systems are signaling pathways devoted to signal perception and transduction for establishment of specific responses. These systems are composed of three successive partners: Histidine-aspartate Kinases (HKs), Histidine-containing Phosphotransfer proteins (HPts), and Response Regulators (RRs). One of the best characterized corresponding systems is the osmo-responsive pathway in yeast. Such systems are also suspected in Arabidopsis. This work aimed to characterize the involvement of an osmosensing pathway in Populus by identifying HPt and RR elements downstream of HK1 and to reveal the underlying mechanisms for the activity of a RR-B. HK1, membrane osmosensor, is expected to be responsible for signal detection and propagation by triggering the activation of three preferential HPt. Furthermore, an interacting partnership between those HPts and particular B-type RRs was observed. Two of them appear to be regulated by an osmotic stress, suggesting their possible involvement in this pathway. The B-type RR members, the final output elements of the pathway, act as transcription factors, as shown for at least for one of them in planta. Taken together, the dimerization of the RR receiver domain and its interaction with its DNA binding domain (GARP), are likely key checkpoints in the regulation of RR-B activity. Besides, the ability of one RR-B to bind its cognate specific DNA sequences (AGAT boxes) was confirmed in vitro and those were found in promoters of osmotic response genes. This work opens up prospects for the involvement of RR-B in the osmotic stress signaling pathway and suggests mechanisms tuning induction of specific responses.

Sunflower (Helianthus annuus) consists of high levels of polyunsaturated fatty acids, making its oil susceptible to oxidation. Tocopherols can retard or prevented oxidation. The aim of this study is to determine the phenotypic tocopherol (vitamin E) composition and genetic diversity of the biosynthetic pathway genes. Seeds were characterized for fatty acid and tocopherol content. A positive correlation was found between oleic acid, γ (r =0.17) and δ (r =0.23) tocopherol but none between linoleic acid and all four tocopherol derivatives. Vitamin E gene homologues were identified and a concomitant pathway constructed, with genes of interest sequenced to determine their genetic variation. A sunflower gene database was developed for these genes and used to obtain 489 SNPs and 145 indels from the accessions evaluated. Only 139 of these SNPs were located in the exon regions of the gene candidates. These exon-based SNPs may influence tocopherol flow through possible enzyme structural modifications / School of Agriculture and Life Sciences / M. Sc. (Life Sciences)

Live simulations play an important role in allowing users to practice and develop skills they learn in training. Although live simulations are playing an increasingly important role in training, ways to improve them are not well understood or documented. In order to improve the efficacy of live simulation and maximize results from funds spent on training; this research examines the relationship between the affective variables of the participants and their performance in the live simulation. Prior to participating in the instructor development live simulation used in this study two training preference scales were administered to a group of trainees. These scales measured the trainees’ locus of control and immersion tendencies. During the live simulation the trainees’ performance was evaluated by a panel of expert observers. The trainees also self-reported their performance through the use of a self-rating instrument. Analysis of the data revealed significant positive correlations between the trainees’ internal locus of control and their performance in the simulation, both self-reported (p=0.026) and as reported by the expert observers (p=0.033). The correlation between immersion tendency scores and performance in the live simulation were mixed; while not always statistically significant they did reveal some slight positive correlation. This research did provide a number of lessons learned and implications for instructional and simulation developers wishing to employ live simulation in a training environment. These include performance of sub-populations within the greater population of subjects, consideration of roles assigned to participants, and the need to increase presence within the live simulation. Application of these lessons learned can reduce training costs and/or improve the effectiveness of live simulation in a training environment, this in turn can be of significant benefit to instructional and simulation designers. Additionally, understanding these relationships can lead iv to better assignments of roles or activities within live simulation and improve the transfer of experience from live simulation training to on the job performance. However, additional research needs to be conducted in order to make more conclusive statements regarding the most appropriate affective variable that would allow for predicting transfer of the simulated experience to the ‘real’ world, the individuals who would benefit most from live simulation, and to develop additional prescriptive methods for improving live simulation utilized in training environments.

As Neoplasias endócrinas múltiplas (NEMs) são síndromes herdadas de modo dominante e causadas por mutações germinativas em genes específicos. Caracterizam-se pela presença de tumores em um conjunto de glândulas endócrinas, conjunto este típico de cada tipo-específico de NEM. Dentre os diferentes tipos de NEMs, há a neoplasia endócrina múltipla tipo 2 (NEM2) que envolve os fenótipos, carcinoma medular de tireóide (CMT), hiperparatiroidismo primário (HPT), feocromocitoma (FEO) e megacólon congênito (doença de Hirschsprung, HSCR). Apesar da prevalência da NEM2 na população em geral ser baixa (~ 1:30.000), o número de casos afetados por família pode ser expressivo, uma vez que sua penetrância é praticamente completa (~100%). A doença de HSCR ou aganglionose intestinal congênita quando ocorre está geralmente associada à mutações RET nos códons 609, 618 e 620; apresenta ampla variação fenotípica, padrão de herança complexa e baixa penetrancia. Poucos casos de HSCR podem apresentar mutações em outros genes. Mutações no gene RET são responsáveis por aproximadamente metade (~50%) dos casos familiares de HSCR e alguns casos esporádicos (~10-20%), sugerindo fortemente que a HSCR seja doença poligenica. Tem-se também sugerido que polimorfismos genéticos no RET podem influenciar o fenotipo da NEM2/HSCR. No presente estudo, analisamos o gene RET no sentido de investigar se o desenvolvimento de megacólon em pacientes com a mutação germinativa RET p.C620R estaria associado à presença de ou a) a uma segunda mutação germinativa ou b) a um SNP, ou c) a um haplótipo informativo, que possivelmente poderia estar potencialmente interagindo genicamente com a mutação RET principal e eventualmente modulando o fenótipo HSCR / The multiple endocrine neoplasias (MENs) are inherited multi-tumoral conditions caused by germline mutations in specific genes. Specifically, the multiple endocrine neoplasia type 2 (NEM2) is a hereditary endocrine disorder transmitted dominantly and involving three main tumors, medullary thyroid carcinoma (CMT), primary hyperparathyroidism (HPT) and pheochromocytoma (PHEO). Despite the low prevalence of MEN2 in general population, the number of affected individuals per family can be significant as the penetrance of MEN2 is almost complete (~100%). In addition to CMT, PHEO and HPT, other conditions as congenital megacólon (Hirschsprung disease, HSCR or congenital intestinal aganglionosis) may occur in MEN2 (HSCR/MEN2). HSCR/MEN2 usually is due to RET mutations in codons 609, 618 and 620. HSCR has a wide phenotypic variation; is a complex multigenic disease; and has a low penetrance. Mutations in the RET gene are responsible for approximately 50% of the familial HSCR cases and ~10% of the sporadic HSCR cases, supporting that HSCR is a polygenic disease and this is confirmed by a few HSCR cases associated with mutations in the EDNRB and EDN3 genes. In the present study, we focused in the analysis of the RET gene in order to investigate whether the development of congenital megacólon in patients with RET mutation p.C620R is associated with the presence of, a) a second RET germline mutation, b) a SNP, or with a haplotype that co-segregate with the disease