The goal of this thesis is to use fringe-pattern phase analysis to calibrate the distortion of a camera lens. The benefit of using this method is that the distortion can be calculated using data from each individual pixel and the methodology does not need any model. The phase used to calibrate the images is calculated in two different ways, either utilizing the monogenic signal or through fringe-pattern phase analysis. The calibration approaches were also validated through different methods. Primarily by utilizing the Hough transform and calibrating simulated distortion. The thesis also introduces a validation approach utilizing the phase orientation calculated through the monogenic signal. The thesis also implements different approaches such as flat field correction to limit the impact of the image sensor noise to mitigate the phase noise. It is also investigated which fringe-pattern frequencies are best suited for calibration through comparative analysis. The comparative analysis identified problems with too high and low frequencies of the fringe-patterns when calibrating using fringe-pattern phase analysis.

No description available.

Objective: To describe clinical presentation/longterm outcomes of patients with ABCC8/KCNJ11 variants in a large cohort of patients with diabetes. Research Design and Methods: We analyzed patients in the Diabetes Prospective Follow-up (DPV) registry with diabetes and pathogenic variants in the ABCC8/ KCNJ11 genes. For patients with available data at three specific time-points— classification as K+-channel variant, 2-year follow-up and most recent visit—the longitudinal course was evaluated in addition to the cross-sectional examination. Results: We identified 93 cases with ABCC8 (n = 54)/KCNJ11 (n = 39) variants, 63 of them with neonatal diabetes. For 22 patients, follow-up data were available. Of these, 19 were treated with insulin at diagnosis, and the majority of patients was switched to sulfonylurea thereafter. However, insulin was still administered in six patients at the most recent visit. Patients were in good metabolic control with a median (IQR) A1c level of 6.0% (5.5–6.7), that is, 42.1 (36.6–49.7) mmol/mol after 2 years and 6.7% (6.0– 8.0), that is, 49.7 (42.1–63.9) mmol/mol at the most recent visit. Five patients were temporarily without medication for a median (IQR) time of 4.0 (3.5–4.4) years, while two other patients continue to be off medication at the last follow-up. Conclusions: ABCC8/KCNJ11 variants should be suspected in children diagnosed with diabetes below the age of 6 months, as a high percentage can be switched from insulin to oral antidiabetic drugs. Thirty patients with diabetes due to pathogenic variants of ABCC8 or KCNJ11 were diagnosed beyond the neonatal period. Patients maintain good metabolic control even after a diabetes duration of up to 11 years

In this thesis we prove the following: The semigroup which is a disjoint union of two or three copies of a group is a Clifford semigroup, Rees matrix semigroup or a combination between a Rees matrix semigroup and a group. Furthermore, the semigroup which is a disjoint union of finitely many copies of a finitely presented (residually finite) group is finitely presented (residually finite) semigroup. The constructions of the semigroup which is a disjoint union of two copies of the free monogenic semigroup are parallel to the constructions of the semigroup which is a disjoint union of two copies of a group, i.e. such a semigroup is Clifford (strong semilattice of groups) or Rees matrix semigroup. However, the semigroup which is a disjoint union of three copies of the free monogenic semigroup is not just a strong semillatice of semigroups, Rees matrix semigroup or combination between a Rees matrix semigroup and a semigroup, but there are two more semigroups which do not arise from the constructions of the semigroup which is a disjoint union of three copies of a group. We also classify semigroups which are disjoint unions of two or three copies of the free monogenic semigroup. There are three types of semigroups which are unions of two copies of the free monogenic semigroup and nine types of semigroups which are unions of three copies of the free monogenic semigroup. For each type of such semigroups we exhibit a presentation defining semigroups of this type. The semigroup which is a disjoint union of finitely many copies of the free monogenic semigroup is finitely presented, residually finite, hopfian, has soluble word problem and has soluble subsemigroup membership problem.

Monogenic disorders, i.e., disorders caused by mutations in a single gene, are rare and clinically heterogeneous conditions. Identification of the genetic cause of monogenic traits can bring new insights into molecular pathways and disease mechanisms. The aims of the present study were to identify the mutant genes in two autosomal recessive skin disorders and to characterize the functions of the mutated genes.  In order to identify candidate genes for the two disorders whole-genome SNP analysis, homozygosity mapping and gene sequencing were used. Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by extensive scaling and redness of the skin.  A subgroup of ARCI patients (n=27) was selected based on specific ultrastructural aberrations in their skin, revealed by electron microscopy. Mutations were identified in the Ichthyin gene in 93% of the selected patients, indicating a strong association between mutant Ichthyin and the specific morphological abnormalities. Ichthyin mRNA levels were shown to increase during keratinocyte differentiation in cells from healthy and affected individuals. Electron microscopy revealed a localization of ichthyin protein to keratins and desmosomes in epidermis. Staining of epidermal lipids identified aberrant lipid aggregates in skin sections of patients with Ichthyin mutations, indicating a role for Ichthyin in epidermal lipid metabolism. In twelve KLICK syndrome patients with ichthyosis, palmoplantar keratoderma and keratotic striae on joints, a single-nucleotide deletion was identified in the 5’ region of the proteasome maturation protein (POMP) gene.  The deletion caused an increase in the proportion of POMP transcripts with long 5’ UTR’s in patient keratinocytes.  Immunohistochemical analysis of differentiated skin cell layers revealed aberrant expression of POMP, proteasome subunits and the skin protein filaggrin in patients. CHOP expression, associated with endoplasmic reticulum stress, was increased in the same layers. siRNA silencing of POMP in cell cultures reduced proteasome subunit levels and induced expression of CHOP.  The results indicate that the mutation in KLICK patients causes POMP and proteasome insufficiency with subsequent cellular stress. This study conclusively contributes to the understanding of epidermal physiology and the pathogenesis of two inherited skin diseases.

Submitted by Socorro Pontes (socorrop@ufersa.edu.br) on 2016-11-25T14:08:49Z No. of bitstreams: 1 AnânkiaOR_DISSERT.pdf: 597580 bytes, checksum: a044a0afd2f68a5d8f127a9167ef8a63 (MD5) / Approved for entry into archive by Vanessa Christiane (referencia@ufersa.edu.br) on 2017-03-21T14:38:31Z (GMT) No. of bitstreams: 1 AnânkiaOR_DISSERT.pdf: 597580 bytes, checksum: a044a0afd2f68a5d8f127a9167ef8a63 (MD5) / Approved for entry into archive by Vanessa Christiane (referencia@ufersa.edu.br) on 2017-03-21T15:05:15Z (GMT) No. of bitstreams: 1 AnânkiaOR_DISSERT.pdf: 597580 bytes, checksum: a044a0afd2f68a5d8f127a9167ef8a63 (MD5) / Made available in DSpace on 2017-03-21T15:05:24Z (GMT). No. of bitstreams: 1 AnânkiaOR_DISSERT.pdf: 597580 bytes, checksum: a044a0afd2f68a5d8f127a9167ef8a63 (MD5) Previous issue date: 2016-02-29 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Powdery mildew is a disease that causes substantial losses in melon production around the world. Obtaining resistant cultivars is possible through introgression of alleles in the breeding program. In this study, it was investigated the inheritance of resistance of AC-02 accession to races 1 and 5 of Podosphaera xanthii in cross with susceptible cultivar ‘Védrantais’, under greenhouses conditions. The segregations ratios for resistance/susceptibility observed in the different populations (F1, F2, RC1 and RC2) indicated a monogenic and dominant inheritance in AC-02 to races 1 and 5. The distance between the gene controlling resistance to race 1 (px1-ac02) and the gene which confers resistance race 5 (px5-ac02) is 28.5 cM. / oídio é uma doença que causa perdas significativas na produção de melão em todo o mundo. A obtenção de cultivares resistentes é feita mediante introgressão de alelos de resistência. Neste estudo, investigou-se a herança da resistência do acesso AC-02 às raças 1 e 5 de Podosphaera xanthii por meio de cruzamento com a cultivar suscetível ‘Védrantais’, sob condições de casa de vegetação. As razões de segregações de resistência/suscetibilidade observadas nas diferentes populações (F1, F2, RC1 e RC2) indicaram que a herança da resistência do AC-02 às raças 1 e 5 é controlada, cada uma por um gene composto por dois alelos, de modo que o alelo que confere resistência domina o alelo para suscetibilidade. A distância entre o gene que controla a resistência à raça 1 (px1-ac02) e o gene que confere resistência à raça 5 (px5-ac02) é 28,5 cM. / 2016-11-23

De nombreux algorithmes de traitement d'image numérique (compression, restauration, analyse) sont basés sur une représentation en ondelettes. Les outils mathématiques disponibles étant souvent pensés pour des signaux 1D à valeurs scalaires (comme le son), ils sont mal adaptés aux signaux 2D vectoriels comme les images couleur. Les méthodes les plus répandues utilisent ces outils indépendamment sur chaque ligne et chaque colonne (méthodes « séparables »), de chaque plan couleur (méthode « marginale ») de l'image. Ces techniques trop simples ne donnent pas accès aux informations visuelles élémentaires, aboutissant à des traitements qui risquent d'introduire des artefacts rectangulaires et de fausses couleurs. Notre axe de recherche se situe autour des représentations analytiques qui utilisent un modèle oscillatoire des signaux. Ces outils de traitement du signal sont connus pour être bien adaptés à la perception humaine (auditive et visuelle), et leur extension à des dimensions supérieures est un sujet encore très actif, qui révèle des propriétés intéressantes pour l'analyse de la géométrie locale. Dans cettethèse, nous faisons une revue des ondelettes analytiques existantes pour l'image en niveaux de gris (dites complexes, quaternioniques et monogènes), et nous proposons des expérimentations qui valident leur intérêt pratique. Nous définissons ensuite une extension vectorielle qui permet de manipuler facilement le contenu géométrique d'une image couleur, ce que nous validons à travers des expérimentations en codage et analyse d'image. / Many digital image processing algorithms (compression, restoration, analysis) are based on a wavelet representation. Available mathematical tools are often designed for 1D and scalar-valued signals (e.g. sound) so ill-adapted for 2D vector signals such as images. Most methods use those tools independently on every row and column (“separable methods”) of each color channel (“marginal methods”) of the image. These too simple techniques cannot give access to elementary visual information, sometimesresulting in rectangular artifacts or false colors. Our topic is about analytic representations using an oscillatory model for signals. These signal processing tools are known to fit well the human perception (auditory and visual), and their extension to higher dimensions is still an active topic revealing interesting properties for local geometry analysis. In this thesis we review existing analytic wavelets for grayscale images (complex, quaternionic and monogenic) and we propose experiments that validate their practical interest. We then define a vector extension that handles well the geometric content of a color image, whatwe further validate through experiments of image coding and analysis.

Endometriosis is an oestrogen-dependent gynaecological condition defined as the presence of endometrial tissue outside the uterus cavity. The condition is predominantly found in women in their reproductive years, and associated with significant pelvic and abdominal chronic pain and infertility. The disease is believed to affect approximately 33% of women by a recent study. Currently, surgical intervention, often laparoscopic surgery, is the gold standard for diagnosing the disease and it remains an effective and common treatment method for all stages of endometriosis. Magnetic resonance imaging (MRI) of the patient is performed before surgery in order to locate any endometriosis lesions and to determine whether a multidisciplinary surgical team meeting is required. In this dissertation, our goal is to use image processing techniques to aid surgical planning. Specifically, we aim to improve quality of the existing images, and to automatically detect bladder endometriosis lesion in MR images as a form of bladder wall thickening. One of the main problems posed by abdominal MRI is the sparse anisotropic frequency sampling process. As a consequence, the resulting images consist of thick slices and have gaps between those slices. We have devised a method to fuse multi-view MRI consisting of axial/transverse, sagittal and coronal scans, in an attempt to restore an isotropic densely sampled frequency plane of the fused image. In addition, the proposed fusion method is steerable and is able to fuse component images in any orientation. To achieve this, we apply the Riesz transform for image decomposition and reconstruction in the frequency domain, and we propose an adaptive fusion rule to fuse multiple Riesz-components of images in different orientations. The adaptive fusion is parameterised and switches between combining frequency components via the mean and maximum rule, which is effectively a trade-off between smoothing the intrinsically noisy images while retaining the sharp delineation of features. We first validate the method using simulated images, and compare it with another fusion scheme using the discrete wavelet transform. The results show that the proposed method is better in both accuracy and computational time. Improvements of fused clinical images against unfused raw images are also illustrated. For the segmentation of the bladder wall, we investigate the level set approach. While the traditional gradient based feature detection is prone to intensity non-uniformity, we present a novel way to compute phase congruency as a reliable feature representation. In order to avoid the phase wrapping problem with inverse trigonometric functions, we devise a mathematically elegant and efficient way to combine multi-scale image features via geometric algebra. As opposed to the original phase congruency, the proposed method is more robust against noise and hence more suitable for clinical data. To address the practical issues in segmenting the bladder wall, we suggest two coupled level set frameworks to utilise information in two different MRI sequences of the same patients - the T2- and T1-weighted image. The results demonstrate a dramatic decrease in the number of failed segmentations done using a single kind of image. The resulting automated segmentations are finally validated by comparing to manual segmentations done in 2D.

The rising prevalence of type 2 diabetes (T2D) is a global problem, and suggests that we need better therapeutic strategies against this disease. The glycolytic enzyme glucokinase (GCK) catalyses the phosphorylation of glucose, and is a well-established T2D drug target. Rare GCK mutations cause monogenic beta-cell dysfunction, whilst common genetic variants within GCK are associated with fasting plasma glucose (FPG) levels and T2D risk. Since GCK is expressed in both the pancreas and liver, pharmacological GCK activation provides the promise of a two-pronged attack on hyperglycaemia. In vivo, GCK activity is modulated by the hepatic inhibitor glucokinase regulatory protein (GKRP, gene GCKR). GKRP negatively regulates GCK activity competitively with respect to glucose, and is controlled by fructose 6- and fructose 1-phosphate (F6P and F1P), which compete with each other for binding and enhance or diminish GCK inhibition respectively. GKRP also sequesters GCK in the nucleus and paradoxically stabilises the enzyme. As GCK and its regulatory protein are fundamental to glucose homeostasis, we aimed to investigate the role of genetic variation in both GCK and GCKR to further our understanding of these important T2D drug targets in a system that would be relevant to man. I demonstrated that two novel GCK mutations (T103S and V389L) identified in patients with hyperinsulinaemic hypoglycaemia were kinetically activating and through structural modelling identified a novel regulatory site for GCK activation by small molecular activators. Genome-wide association studies (GWAS) identified GCKR as a regulator of FPG and triglyceride levels, and showed a role for GKRP in T2D risk. Unlike most GWAS hits, this signal included a non-synonymous variant within GCKR (P446L), thus facilitating functional studies. P446L-GKRP was characterised kinetically and at the cellular sequestration-level. This variant showed diminished F6P-mediated modulation, which was proposed to reduce hepatic GCK inhibition, increase glycolytic flux (decreasing FPG), and feed metabolites into liver pathways (elevating triglycerides). As GCKR was not expressed at functional levels within human islets, this phenotype was thought to be driven by the liver. Preliminary analysis at the cellular level was inconclusive, with optimisation required to study human P446L-GKRP in this cellular system. Finally, I showed that mutations within GCKR are not a common cause of “GCK-Like” phenotypes in man, despite the regulatory protein directly modulating GCK activity. These data provide further insight as to the pathogenic consequences of perturbing GCK activity. This must be considered if this enzyme is to be the subject of therapeutic intervention in T2D.

O diabetes mellitus tipo MODY (maturity-onset diabetes of the young) é caracterizado por defeito na secreção de insulina, herança autossômica dominante, hiperglicemia de início precoce e anticorpos anti-células beta negativos. Até o momento, já foram descritas mutações em 14 genes diferentes. A confirmação do diagnóstico de MODY é feita por estudo genético-molecular, tradicionalmente pelo método de Sanger. Diante da grande heterogeneidade genética de MODY, acrescida da dificuldade de estudo de alguns genes por seu grande tamanho e ausência de hotspots, o sequenciamento em larga escala (SLE) mostra-se promissor para uma análise genética custo-efetiva na suspeita de MODY. No Brasil, existem poucos estudos genéticos de rastreamento de MODY e uma alta prevalência de casos sem mutações identificadas nos genes testados (MODY X). Os objetivos deste estudo foram: 1) analisar simultaneamente todos os genes associados a MODY em uma coorte de pacientes com suspeita clínica, utilizando um painel de SLE; 2) avaliar a patogenicidade das variantes alélicas identificadas de acordo com os critérios da Sociedade Americana de Genética Médica (ACMG). Foram selecionados 80 casos com fenótipo de MODY e análise prévia negativa dos 2 genes mais prevalentes, GCK e HNF1A, pelo método de sequenciamento de Sanger. Estes casos foram analisados pelo método de SLE, direcionado para regiões gênicas alvo, por meio de um painel customizado, com sequenciamento simultâneo de 51 genes nucleares e do genoma mitocondrial. As mutações identificadas foram correlacionadas com o fenótipo e foi realizada a segregação familiar. Uma cobertura de no mínimo 20x foi obtida em 98% das regiões alvo. Dos 80 pacientes avaliados, foram detectadas variantes patogênicas/potencialmente patogênicas em 16 casos (20%), confirmando o diagnóstico genético de MODY. Em 15 dos 80 pacientes foram identificadas 16 variantes de significado incerto, restando ainda 42 casos com diagnóstico molecular não esclarecido. Dos 16 casos confirmados geneticamente: 6 foram no gene GCK, 1 no HNF1A, 1 no HNF4A, 1 no HNF1B, 6 em genes raros associados a MODY (1 no ABCC8, 1 no KCNJ11, 1 no PDX1, 2 no PAX4, 1 no NEUROD1), e 1 no NEUROG3, gene associado a diabetes neonatal. Dentre estas 16 variantes, 2 não haviam sido descritas previamente. As 6 mutações no GCK não tinham sido detectadas na análise prévia por: a) 4 casos falso negativos no sequenciamento por Sanger (3 devido ao fenômeno genético de allelic dropout e 1 por erro na leitura do eletroferograma); b) 2 erros na hipótese clínica inicial do subtipo de MODY (baseada no padrão glicêmico e na resposta terapêutica dos pacientes), levando ao sequenciamento prévio de outro gene. A variante no HNF1A não foi detectada previamente por erro na leitura do eletroferograma (caso falso negativo no Sanger). Uma variante foi identificada no gene HNF4A, que não tinha sido sequenciado anteriormente e apresenta fenótipo semelhante ao do HNF1A. O paciente com variante no HNF1B não apresentava relato prévio de cistos renais ou malformações genito-urinárias e por isso não tinha sido considerada a hipótese clínica de MODY5. Além disso, o SLE confirmou o diagnóstico genético de 6 pacientes com variantes em genes de MODY considerados raros, que habitualmente não são sequenciados na rotina de Sanger e ainda detectou uma variante em um gene de diabetes neonatal (sendo necessário maiores estudos para estabelecer uma relação causal com MODY). Em 13 dos 16 casos índices diagnosticados, os familiares encontravam-se disponíveis para exame genético e a co-segregação foi concordante em 8 famílias. Todos os probandos avaliados apresentavam características clínico-laboratoriais típicas de MODY. Os achados deste estudo mostraram que o SLE foi capaz de aumentar a acurácia no diagnóstico de MODY, permitindo a confirmação molecular de 20% dos casos antes negativos e reduzindo, assim, o número de casos MODY X no Brasil. A abordagem genética por painel de SLE para diagnosticar casos com suspeita clínica de MODY mostrou-se promissora para elucidar as bases genéticas desse tipo de diabetes monogênico / Diabetes mellitus type MODY (maturity-onset diabetes of the young) is characterized by defects in insulin secretion, autosomal dominant inheritance, early onset of hyperglycemia, and negative anti-beta cell antibodies. To date, mutations in 14 genes are associated with MODY. The definitive diagnosis relies on genetic tests, traditionally by Sanger sequencing. However, given the genetic heterogeneity of this condition, added to the difficulty of studying some genes due to their large size and lack of hotspots, large-scale sequencing (LSS) seems promising for cost-effective genetic analysis on suspicion of MODY. In Brazil, there are few cohorts screened for MODY and a high prevalence of MODY X (unclear genetic diagnosis). This study aimed to analyze simultaneously all MODY genes in a cohort of clinically suspected patients using a LSS panel; and to evaluate the pathogenicity of identified allelic variants according to the criteria of the American College of Medical Genetics and Genomics (ACMG). We selected 80 subjects with MODY phenotype and negative previous analysis of the 2 most prevalent genes, GCK and HNF1A, by Sanger sequencing method. These cases were analyzed by LSS method, with simultaneous sequencing of target genes. We designed a customized panel, including 51 nuclear genes and the mitochondrial genome. The identified mutations were correlated to the phenotype and family segregation was evaluated. At least 20x coverage was obtained in 98% of the targeted regions. Of 80 evaluated subjects, pathogenic/probably pathogenic variants were detected in 16 cases (20%), confirming the genetic diagnosis of MODY. In 15 of 80 patients, 16 variants of uncertain significance were identified, remaining 42 cases with unexplained molecular diagnosis. Of the 16 genetically confirmed cases: 6 were in the GCK gene, 1 in HNF1A, 1 in HNF4A, 1 in HNF1B, and 6 in rare genes associated with MODY (1 in ABCC8, 1 in KCNJ11, 1 in PDX1, 2 in PAX4 and 1 in NEUROD1), and 1 in NEUROG3, a gene associated with neonatal diabetes. Of these 16 variants, 2 had not been previously described. Those 6 variants in GCK were not detected in the prior analysis because of: a) 4 false negative cases in Sanger sequencing (allelic dropout had occurred in 3 cases and one variant was overlooked, due to electropherogram interpretation failure); b) 2 errors in the initial clinical hypothesis of the MODY subtype (based on the glycemic pattern and therapeutic response), leading to the prior sequencing of another gene. The variant in HNF1A was not previously identified due to misinterpretation in electropherogram (Sanger false negative case). One variant were detected in the HNF4A gene, not formerly sequenced, and had a similar phenotype to that of HNF1A. The patient with HNF1B variant did not have a previous report of renal cysts or genito-urinary malformations and therefore the clinical hypothesis of MODY5 was not considered. In addition, LSS confirmed the genetic diagnosis of 6 patients harboring variants in MODY genes considered to be rare, which are not usually sequenced in the Sanger routine, and also detected one variant in a neonatal diabetes gene (further studies are necessary to establish a causal relationship with MODY). Relatives were available for genetic testing in 13 of these 16 index cases diagnosed and co-segregation was concordant in 8 families. All probands evaluated showed typical clinical and laboratory characteristics of MODY. These study findings showed that targeted-LSS could increase accuracy in MODY diagnosis, enabling molecular confirmation of 20% of previous negative cases and thus reducing the number of MODY X cases in Brazil. The genetic approach of LSS panel to diagnose cases with clinical suspicion of MODY has shown promise for elucidating the genetic basis of this type of monogenic diabetes