To date, elastographic imaging techniques such as magnetic resonance elastography (MRE) have primarily been considered isotropic material properties, despite the fact that most biological tissues tend to have some anisotropic qualities. In this thesis, a finite-element based orthotropic, incompressible material model is used as the basis for the in vitro MRE gelatin phantom. This study includes the use of biologically based orthotropic gelatin phantoms, with MRI data acquisition and boundary conditions suitable to describe the orthotropic material behavior. Fabricating a biological gelatin phantom using pineapple for MRE in vitro testing is a novel technique which was developed specially for this study. Multiple motion measurements from the pineapple gelatin phantom were made by applying directionally independent boundary conditions within the 85-125 Hz frequency range. Such multiple, orthogonal excitation data is needed to provide a complete description of the mechanical properties of this anisotropic phantom, given the potential for non-uniqueness of the reconstructed property estimates. Orthotropic image reconstructions were then carried out to map orthotropic elasticity properties in 3-D based on MR detected motion datasets captured from the pineapple gelatin phantom. The subzone based orthotropic incompressible reconstruction algorithm was based on the Conjugate Gradient optimization method, to gain computational efficiency, and used total volitional (TV) regularization techniques to constraint the solution process. The adjoint-residual method was utilized to improve the efficiency of the gradient descent based algorithm. The elasticity image reconstruction results presented for the orthotropic incompressible phantom are also correlated with isotropic property reconstructions for the same phantom.

A robust, reliable method to non-invasively measure in-vivo mechanical properties of large tissue areas was unavailable until the advent of a new Magnetic Resonance Imaging (MRI) technique known as Magnetic Resonance Elastography (MRE). MRE is a phase-contrast imaging technique that enables quantification of tissue mechanical properties by capturing the motion of induced shear waves via a synchronised Motion Encoding Gradient (MEG). The complex shear modulus is determined via mathematical inversion and reported as the magnitude of the complex shear modulus, |G*|, and phase angle, φ. The work reported in this thesis focuses on the development of MRE data acquisition and analysis protocols optimised to study thigh muscle mechanical properties. The protocols are subsequently applied in healthy volunteers to study natural phenomena such as contraction and ageing and interventions such as an experimental protocol to produce Exercise Induced Muscle Damage (EIMD). Methodological advances made throughout this work include moving from 2D to 3D MRE data acquisition protocols and the application of advanced inversion software to extract muscle viscoelastic properties from the acquired MRE data. Results obtained include observation of reduced muscle stiffness in 6 elderly subjects (>80 years old) compared to 4 young subjects in the Vastus Lateralis (32%), quadriceps muscle group (22%) and entire thigh cross-section (19%), higher resting stiffness of agonist quadriceps compared to antagonist hamstrings (18%) and an increase in quadriceps stiffness (40%) during a leg raise task in 11 healthy subjects. Variability in muscle group recruitment patterns during the contraction were also observed, with the phase angle of the Vastus Intermedius (VI) increasing significantly during contraction. The final experiment involved the recruitment of 20 healthy male subjects to perform an eccentric exercise protocol designed to induce EIMD. Subjects who displayed a Maximum Voluntary Contraction (MVC) force deficit of >10% were considered to have experienced EIMD. A further severe EIMD group were defined based on the presence of hyper-intense signal on T2 weighted imaging following the protocol. The T2 hyper-intensity was found to occur exclusively in the Rectus Femoris (RF) and VI muscle groups. Increased muscle stiffness was observed in the RF muscle in subjects who experienced moderate EIMD (6%). A greater increase in RF stiffness (48%) was observed in the severe EIMD group. The severe EIMD group also displayed significantly increased VI stiffness (14%). The experiments carried out provide several novel findings which can support the development of beneficial strategies to promote both healthy ageing and rehabilitation in athletes, and potentially contribute to improving muscle performance evaluation tests which will expand the opportunities for clinical applications of muscle MRE.

Zu den wichtigsten Werkzeugen in der medizinischen Diagnostik gehören bildgebende Verfahren, wie die Magnetresonanztomographie. Ein weiteres diagnostisches Hilfsmittel ist die Palpation, die es erlaubt, Veränderungen oberflächennaher Organe qualitativ zu erfassen. Die Magnetresonanzelastographie (MRE) stellt eine Kombination dieser Techniken dar. Das Prinzip der MRE besteht darin Gewebedeformationen aufgrund extern induzierter Scherwellen mittels bewegungssensitiver MR-Bildgebung darzustellen und über die Art der Deformation auf die Elastizität des Gewebes zu schließen. Einen großen Anteil schwerwiegender Erkrankungen bilden Störungen des Herz-Kreislaufsystems. Das Ziel dieser Arbeit war es, eine Methode zu entwickeln, die in-vivo MRE am menschlichen Herzen ermöglicht. Die Weiterentwicklung der mechanischen Anregungseinheit ergab mit Einführung eines Audio-Lautsprechers das nötige Instrument, Vibrationen in innere Organe zu übertragen. Der entscheidende Faktor bei der Herz-MRE war die Geschwindigkeit der Aufnahme, die zur Entwicklung der ''fraktionierten MRE'' führte. Die Basis waren schnelle Herzbildgebungstechniken, wie die balancierte Steady-State- (bSSFP) und Spoiled Steady-State-Technik (SPGRE). Die Einführung eines unbalancierten Phasenpräparationsgradienten in der bSSFP-Aufnahmetechnik lieferte ein verbessertes SNR und zusammen mit der SPGRE-MRE-Aufnahmetechnik ließen sich damit MRE-Studien auch am menschlichen Herzen durchführen. Es gelang erstmals, extern induzierte mechanische Schwingungen in das Herz zu koppeln und mittels fraktionierter MRE mit hoher zeitlicher Auflösung zu detektieren. Die in 6 gesunden Probanden beobachtete Modulation der Scherwellenamplituden innerhalb des Myokards korrelierte sehr gut mit den Kontraktionszuständen des Herzens. Die entwickelten Techniken und Methoden sind ein Schritt hin zur routinemäßigen klinischen Anwendung der MRE am Herzen und deuten auf ein hohes Potential im Bereich der Diagnostik kardialer Erkrankungen hin. / Imaging techniques, including magnetic resonance imaging, belong to the most important tools in modern medical diagnostics. Another diagnostic aid is palpation, which is suitable for the qualitative characterization of pathological changes in organs near the surface. Magnetic resonance elastography (MRE) is a combination of these techniques. In principle, MRE uses motion-sensitive MR-imaging to depict tissue deformation caused by externally induced shear waves. The type of deformation supply useful information about the elasticity of the tissue. Cardiac disorders are among the most common diseases. The goal of this study was to develop a method of applying in-vivo MRE to the human heart. The development of the mechanical stimulus, ultimately resulting in the introduction of an audio speaker as the source of vibration, provided the necessary means to introduce vibrations into inner organs. A crucial factor in applying MRE to the heart is the speed of the recording, which led to the development of "fractional MRE". The currently conventional fast heart imaging techniques were used as a starting point. The use of an unbalanced phase preparation gradient in the balanced steady-state imaging technique resulted in an improved phase-to-noise ratio. Along with the spoiled steady-state MRE imaging technique, initial MRE-studies on the human heart were performed. For the first time, externally induced mechanical vibrations were successfully introduced into the heart and were detected using fractional MRE with a high temporal resolution. The modulation of the shear wave amplitudes observed in the myocard of 6 healthy subjects correlated with the phases of the cardiac cycle. The techniques and methods developed here are a step toward routine clinical application of MRE of the heart and indicate high potential in the area of early diagnosis of cardiac disease.

A three-dimensional, incompressible, Rayleigh damped magnetic resonance elastography (MRE) material property reconstruction algorithm capable of reconstructing the spatial distribution of both the real and imaginary parts of the shear modulus, density and bulk modulus from full-field MR-detected harmonic motion data was developed. The algorithm uses a subzone-based implementation of motion error minimization techniques, using 27 hexahedral finite elements, and is written in FORTRAN to run on high performance distributed computing systems. The theory behind the methods used is presented in a form that is directly applicable to the code's structure, to serve as a reference for future research building on this algorithm. Globally defined Rayleigh damping parameter reconstructions using simulated data showed that it is possible to reconstruct the correct combination of Rayleigh parameters under noise levels comparable to MR measurements. The elastic wave equation is used to demonstrate that use of a one parameter damping model to fit a Rayleigh damped material can lead to artefacts in the reconstructed damping parameter images, a prediction that is verified using simulated reconstructions. Initial results using MR-detected motion data from both gelatine phantoms and in-vivo cases produced good reconstructions of real shear modulus, as well as showing promise for successful imaging of damping properties. An initial investigation into an alternative elemental basis function approach to supporting the material property distribution produced some promising results, as well as highlighting some significant issues with large variations across the elements.

abstract: Hepatocellular carcinoma (HCC) is a malignant tumor and seventh most common cancer in human. Every year there is a significant rise in the number of patients suffering from HCC. Most clinical research has focused on HCC early detection so that there are high chances of patient's survival. Emerging advancements in functional and structural imaging techniques have provided the ability to detect microscopic changes in tumor micro environment and micro structure. The prime focus of this thesis is to validate the applicability of advanced imaging modality, Magnetic Resonance Elastography (MRE), for HCC diagnosis. The research was carried out on three HCC patient's data and three sets of experiments were conducted. The main focus was on quantitative aspect of MRE in conjunction with Texture Analysis, an advanced imaging processing pipeline and multi-variate analysis machine learning method for accurate HCC diagnosis. We analyzed the techniques to handle unbalanced data and evaluate the efficacy of sampling techniques. Along with this we studied different machine learning algorithms and developed models using them. Performance metrics such as Prediction Accuracy, Sensitivity and Specificity have been used for evaluation for the final developed model. We were able to identify the significant features in the dataset and also the selected classifier was robust in predicting the response class variable with high accuracy. / Dissertation/Thesis / M.S. Industrial Engineering 2013

Mechanical properties of muscle tissue are linked to its function. Magnetic Resonance Elastography (MRE) has the capability toquantitively measure these mechanical properties of soft tissue in-vivo. However, most MRE methods assume tissue isotropy during MRE reconstruction which is not an appropriate assumption for muscle tissue. To obtain tissue mechanical properties with higher accuracy, muscle anisotropy must be considered during MRE reconstruction. Therefore, the aim of this thesis was to implement an anisotropic MRE reconstruction. The anisotropic MRE reconstruction used solves three independent viscoelastic parameters (G||, G⊥, E||), that is based on a transverse isotropic (TI) inversion. The reconstruction was validated in a phantom study by comparison with an isotropic reconstruction, and in-vivo on gastrocnemius (ankle plantar flexor) and tibialis anterior (ankledorsi flexor) of one human subject. Also, a TI phantom was created to be included in the phantom study along with a commercial isotropic phantom. However, due to poor image quality, the TI phantom was excluded from further validation. Results from the isotropic phantom did not agree with the assumption of equal shear modulus in different planes of the isotropic medium. In-vivo study showed that the anisotropic reconstruction yielded mean moduli values in the range of what the literature suggests. The unequal shear modulus and young's modulus G||≠G⊥≠E|| of anisotropy in TI material was observed, indicating that the reconstruction method was able to identify the anisotropy ofmuscle tissue. However, further analysis including more human subjects are needed to conclude the reliability of the reconstruction method. / Muskelvävnadens mekaniska egenskaper är kopplade till dess funktion. Magnetresonans-Elastografi (MRE) har förmågan att kvantitativt mätadessa mekaniska egenskaper i mjukvävnad in-vivo. De flesta MRE metoder antar dock att vävnaden är isotropisk under MRE rekonstruktionen, vilket inte är ett lämpligt antagande för muskelvävnad. För att med högre noggrannhet estimera mekaniska egenskaper i vävnad måste muskel anisotropi tas i hänsyn under MRE rekonstruktionen. Därav var syftet i denna uppsats att implementera en anisotropisk MRE rekonstruktion. Den implementerade anisotropa MRE rekonstruktionenlöser tre oberoende viskoelastiska parametrar (G||, G⊥, E||), som ärbaserad på en transversell isotropisk (TI) inversion. Rekonstruktionen validerades i en fantomstudie genom jämförelse med en isotropisk rekonstruktion samt in-vivo på gastrocnemius (ankel plantarflexion) och tibialis anterior (ankel dorsalflexion) hos en människa. Dessutom skapades en TI-fantom för att inkluderas i fantomstudien tillsammansmed en kommersiell isotropisk fantom. På grund av dålig bildkvalitet uteslöts TI-fantomen från ytterligare validering. Resultat från den isotropa fantomen överensstämde inte med antagandet om lika skjuvmodul i olika plan av det isotropa mediet. In vivo-studien visade att den anisotropa rekonstruktionen gav medelvärden för modulerna inom intervallet av vad litteraturen antyder. Olikheten av skjuvmodulen och elasticitetsmodulen för anisotropi i TI-material G||≠G⊥≠E|| observerades vilket är en indikation att rekonstruktionsmetoden kunde identifiera muskelvävnadens anisotropi. Det krävs dock ytterligare analys inklusive fler mänskliga försökspersoner för att dra slutsatsen ifall rekonstruktionsmetoden är tillförlitlig

Attenuation and damping in elastography are naturally of great interest as the presence of these effects in biological tissue goes without question and therefore must be addressed if quantitative assessment of tissue elastic properties is to be achieved. Additionally, given the change in the tissue structure present in the diseases that elastographic imaging seeks to detect and diagnose, there is every reason to expect that the resulting lesions will also exhibit a change in their attenuation behaviour, indicating diagnostic value to any description of the damping property distribution elastographic methods are able to provide. This thesis will present the unique contribution of the development of several Elastographic models for MR based reconstructions of soft tissue. A method for the reconstruction of both Viscoelastic and Rayleigh damping based damped elastic properties has been developed for use with MR detected time-harmonic motion data and has been shown to lead to reasonable results in both homogeneous and heterogeneous phantoms of varying material types. A poro-elastic modelling is thought to provide a more accurate description of tissue structure by accounting for, in part, the complex interactions between the solid and fluid phases present in vivo. The foundation for a poro-elastic material behaviour will be explored and presented to support the premise. A meaningful mapping of the orthotropic shear moduli distributions in three directions has demonstrated enough evidence that the orthotropic MRE can be a feasible technique to determine orthotropic elasticity parameters of a biological tissue, noninvasively. The orthotropic achievements throughout this project can be useful for future clinical cancer diagnostics by augmenting the information obtained from the orthotropic MRE reconstructions between normal tissue and tumours.

Meiosis is a highly regulated process, partly due to the need to break and then repair DNA as part of the meiotic program. In this thesis, mechanisms of meiotic regulation are investigated, including the post-translational modification termed SUMOylation, and a potential novel negative regulator of error-prone DNA repair pathways. Post-translational modifications are widely used during meiotic events to regulate steps such as protein complex formation, checkpoint activation, and protein attenuation. In this thesis, we investigate how proteins that are obligatory components of the SUMO pathway, one such post-translational modification, affect the C. elegans germline. We show that UBC-9, the E2 conjugation enzyme, and the C. elegans homolog of SUMO, SMO-1, localized to germline nuclei throughout prophase I. Mutant analysis of smo-1 and ubc-9 revealed increased recombination intermediates throughout the germline, originating during the mitotic divisions. SUMOylation mutants also showed late meiotic defects including defects in the restructuring of oocyte bivalents and endomitotic oocytes (EMO). Increased rates of non-interfering crossovers (COs) were observed in ubc-9 heterozygotes, even though interfering COs were unaffected. We have also identified a physical interaction between UBC-9 and DNA repair protein MRE-11. ubc-9 and mre-11 null mutants exhibited similar phenotypes at germline mitotic nuclei and were synthetically sick. These phenotypes and genetic interactions were specific to MRE-11 null mutants as opposed to RAD-50 or resection-defective MRE-11. We propose that the SUMOylation pathway acts redundantly with MRE-11, and in this process MRE-11 likely plays a structural role. We also found a candidate negative regulator of non-homologous end joining through an RNAi screen using the mre-11(iow1) resection-defective mutant. Mutant analysis did not rescue the resection-defective phenotype when multiple CRISPR-generated nhr-2 deletion alleles were generated. Therefore, nhr-2 does not appear to be directly involved in DNA repair.

Submitted by Paula Quirino (paula.quirino@ufpe.br) on 2015-03-11T19:31:50Z No. of bitstreams: 1 DISSERTAÇÃO Maria Eduarda Paiva de Oliveira.PDF: 974514 bytes, checksum: 96fd057834c1e4b2a6db1d57cb8b6284 (MD5) / Made available in DSpace on 2015-03-11T19:31:50Z (GMT). No. of bitstreams: 1 DISSERTAÇÃO Maria Eduarda Paiva de Oliveira.PDF: 974514 bytes, checksum: 96fd057834c1e4b2a6db1d57cb8b6284 (MD5) Previous issue date: 2014 / CNPq / Após o período de ditadura militar, o Estado democrático brasileiro favoreceu a convergência política com a Argentina na busca de superar animosidades históricas mútuas. Na fase de negociação dos tratados de cooperação que culminaram na criação do Mercado Comum do Sul (Mercosul), dois atores emergem como figuras principais. O primeiro deles é o corpo burocrático especializado, o Ministério das Relações Exteriores (MRE) ou Itamaraty, agente tradicionalmente principal na concepção da inserção internacional do país. O segundo ator importante a intervir é o Presidente da República, assumindo um papel cada vez maior na solução de problemas, e, em certas situações, participando de negociações. A literatura sobre processo decisório, em geral, enfatiza um Itamaraty que perde seu monopólio na tomada de decisão, em favor de um Presidente da República forte e de ministérios especializados em determinados temas da agenda externa. No entanto, essas novas interpretações foram raramente testadas frente a um caso concreto. Além disso, visto que o Presidente da República responde pela política interna nacional, ele somente interfere em demandas específicas- o que certamente afeta a abrangência de sua diplomacia presidencial. O presente trabalho busca esclarecer, no âmbito da crise e reconstrução do Mercosul, entre 2001 e 2006, se é possível encontrar embasamento empírico para as assertivas estabelecidas pela literatura. Para tanto, discute-se, a partir da metodologia de estudo de caso, o papel do Presidente da República, do MRE e de outros ministérios relacionados ao tema (1) na crise dos bens de informática; (2) na manutenção de uma Tarifa Externa Comum do Mercosul e (3) na criação do Mecanismo de Adaptação Competitiva (MAC). O estudo conclui que o Presidente da República concentra a tomada de decisão quando há um conflito interministerial em questões estratégicas.

<p>This thesis is composed of six chapters. First MRE is briefly introduced together with some relevant literature in Chapter one. The second chapter is about the principles and theory of magnetic resonance imaging, with the MRE theory, software and hardware addressed in Chapter 3. Chapters 4 and 5 describe the hardware design, software programming, experimental setup and elasticity reconstruction. Chapter 6 is a general discussion, introducing challenges and future directions.</p> <p>A vibration actuator and coil was designed and constructed, then combined with the necessary hardware required to induce the motion in the actuator. A Gradient Echo pulse sequence was modified using the Siemens IDEA environment for MRE application. A phantom was made with concentrations of 1%, 2%, and 3% agar gel.</p> <p>The phantom was scanned using the MRE sequence while inducing the propagating waves. Waves were selected to have frequencies of 125 Hz and 250 Hz. Magnitude and phase images acquired at these frequencies were used to construct the elasticity map using the MRE/Wave reconstruction software. Mean Shear Modulus measured in 1% gel cylinder is 10 kPa and standard deviation (SD) is 6 kPa. Mean elasticity value measured in 3% gel is 49 kPa and SD is 9 kPa. Mean value measured in the background which is 2% gel is 28 kPa and SD is 6 kPa. The results obtained are comparable to the values calculated in literature.</p> / Master of Applied Science (MASc)