Mutations in cardiac T-Box Factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy

The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.

Proteases and proteomics : cutting to the core of human skin pathologies

Preserving the integrity of the skin's outermost layer (the epidermis) is vital for humans to thrive in hostile surroundings. Covering the entire body, the epidermis forms a thin but impenetrable cellular cordon that repels external assaults and blocks escape of water and electrolytes from within. This structure exists in a perpetual state of regeneration where the production of new cellular subunits at the base of the epidermis is offset by the release of terminally differentiated corneocytes from the surface. It is becoming increasingly clear that proteases hold vital roles in assembling and maintaining the epidermal barrier. More than 30 proteases are expressed by keratinocytes or infiltrating immune cells and the activity of each must be maintained within narrow limits and confined to the correct time and place. Accordingly, over- or under-exertion of proteolytic activity is a common factor in a multitude of skin disorders that range in severity from relatively mild to life-threatening. This review explores the current state of knowledge on the involvement of proteases in skin diseases and the latest findings from proteomic and transcriptomic studies focused on uncovering novel (patho)physiological roles for these enzymes.

Varied Immune Response to FVIII: Presence of Proteolytic Antibodies Directed to Factor VIII in Different Human Pathologies

The versatility of antibodies is demonstrated by the various functions that they mediate such as neutralization, agglutination, fixation of the complement and its activation, and activation of effector cells. In addition to this plethora of functions, antibodies are capable of expressing enzymatic activity. Antibodies with catalytic function are a result of the productive interplay between the highly evolved machinery of the immune system and the chemical framework used to induce them (antigens). Catalytic antibodies are immunoglobulins with an ability to catalyze the reactions involving the antigen for which they are specific. Catalytic immunoglobulins of the IgM and IgG isotypes have been detected in the serum of healthy donors. In addition, catalytic immunoglobulins of the IgA isotype have been detected in the milk of healthy mothers. Conversely, antigen-specific hydrolytic antibodies have been reported in a number of inflammatory, autoimmune, and neoplastic disorders. The pathophysiological occurrence and relevance of catalytic antibodies remains a debated issue. Through the description of the hydrolysis of coagulation factor VIII as model target antigen, we propose that catalytic antibodies directed to the coagulation factor VIII may play a beneficial or a deleterious role depending on the immuno-inflammatory condition under which they occur.

Heat-stress and light-stress induce different cellular pathologies in the symbiotic dinoflagellate during coral bleaching

Coral bleaching is a significant contributor to the worldwide degradation of coral reefs and is indicative of the termination of symbiosis between the coral host and its symbiotic algae (dinoflagellate; Symbiodinium sp. complex), usually by expulsion or xenophagy (symbiophagy) of its dinoflagellates. Herein, we provide evidence that during the earliest stages of environmentally induced bleaching, heat stress and light stress generate distinctly different pathomorphological changes in the chloroplasts, while a combined heat- and light-stress exposure induces both pathomorphologies; suggesting that these stressors act on the dinoflagellate by different mechanisms. Within the first 48 hours of a heat stress (32°C) under low-light conditions, heat stress induced decomposition of thylakoid structures before observation of extensive oxidative damage; thus it is the disorganization of the thylakoids that creates the conditions allowing photo-oxidative-stress. Conversely, during the first 48 hours of a light stress (2007 µmoles m−2 s−1 PAR) at 25°C, condensation or fusion of multiple thylakoid lamellae occurred coincidently with levels of oxidative damage products, implying that photo-oxidative stress causes the structural membrane damage within the chloroplasts. Exposure to combined heat- and light-stresses induced both pathomorphologies, confirming that these stressors acted on the dinoflagellate via different mechanisms. Within 72 hours of exposure to heat and/or light stresses, homeostatic processes (e.g., heat-shock protein and anti-oxidant enzyme response) were evident in the remaining intact dinoflagellates, regardless of the initiating stressor. Understanding the sequence of events during bleaching when triggered by different environmental stressors is important for predicting both severity and consequences of coral bleaching

Avoiding pathologies in very deep networks

Choosing appropriate architectures and regularization strategies of deep networks is crucial to good predictive performance. To shed light on this problem, we analyze the analogous problem of constructing useful priors on compositions of functions. Specifically, we study the deep Gaussian process, a type of infinitely-wide, deep neural network. We show that in standard architectures, the representational capacity of the network tends to capture fewer degrees of freedom as the number of layers increases, retaining only a single degree of freedom in the limit. We propose an alternate network architecture which does not suffer from this pathology. We also examine deep covariance functions, obtained by composing infinitely many feature transforms. Lastly, we characterize the class of models obtained by performing dropout on Gaussian processes.

Development of non-viral vectors for gene therapy for pathologies of the retina

Tese de doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015

Cosmopolitan citizenship and pathologies of pluralism

There are two interconnected questions obscured in the contemporary discourse of legal pluralism. The first concerns the legitimacy of the various forms of pluralism. The second concerns their pathology. If we accept that law does not issue from a unitary source, the problem becomes to characterize the kinds of pluralism in which we find ourselves and to discern their principles of legitimacy. It cannot be taken for granted that they are all legitimate, that is to say, that they can both articulate and fulfill founding principles of justification. That leads to the second question. To celebrate all legal pluralism simply by drawing attention to it as anobservable, documented fact, without considering whether that pluralism conduces to the just and the good, is like speaking of the pluralism of the body’s mechanisms without asking whether any given complex of cells is malignant or benign.

Video-based analysis of Gait pathologies

L’analyse de la marche a émergé comme l’un des domaines médicaux le plus im- portants récemment. Les systèmes à base de marqueurs sont les méthodes les plus fa- vorisées par l’évaluation du mouvement humain et l’analyse de la marche, cependant, ces systèmes nécessitent des équipements et de l’expertise spécifiques et sont lourds, coûteux et difficiles à utiliser. De nombreuses approches récentes basées sur la vision par ordinateur ont été développées pour réduire le coût des systèmes de capture de mou- vement tout en assurant un résultat de haute précision. Dans cette thèse, nous présentons notre nouveau système d’analyse de la démarche à faible coût, qui est composé de deux caméras vidéo monoculaire placées sur le côté gauche et droit d’un tapis roulant. Chaque modèle 2D de la moitié du squelette humain est reconstruit à partir de chaque vue sur la base de la segmentation dynamique de la couleur, l’analyse de la marche est alors effectuée sur ces deux modèles. La validation avec l’état de l’art basée sur la vision du système de capture de mouvement (en utilisant le Microsoft Kinect) et la réalité du ter- rain (avec des marqueurs) a été faite pour démontrer la robustesse et l’efficacité de notre système. L’erreur moyenne de l’estimation du modèle de squelette humain par rapport à la réalité du terrain entre notre méthode vs Kinect est très prometteur: les joints des angles de cuisses (6,29◦ contre 9,68◦), jambes (7,68◦ contre 11,47◦), pieds (6,14◦ contre 13,63◦), la longueur de la foulée (6.14cm rapport de 13.63cm) sont meilleurs et plus stables que ceux de la Kinect, alors que le système peut maintenir une précision assez proche de la Kinect pour les bras (7,29◦ contre 6,12◦), les bras inférieurs (8,33◦ contre 8,04◦), et le torse (8,69◦contre 6,47◦). Basé sur le modèle de squelette obtenu par chaque méthode, nous avons réalisé une étude de symétrie sur différentes articulations (coude, genou et cheville) en utilisant chaque méthode sur trois sujets différents pour voir quelle méthode permet de distinguer plus efficacement la caractéristique symétrie / asymétrie de la marche. Dans notre test, notre système a un angle de genou au maximum de 8,97◦ et 13,86◦ pour des promenades normale et asymétrique respectivement, tandis que la Kinect a donné 10,58◦et 11,94◦. Par rapport à la réalité de terrain, 7,64◦et 14,34◦, notre système a montré une plus grande précision et pouvoir discriminant entre les deux cas.

Prise en charge en physiothérapie pour la clientèle âgée avec pathologies chroniques variées

Travail d’intégration

Investigations on pathologies in higher spin field theories

The present thesis deals with the studies on certain aspects of pathological higher field theories .It brings to light some new abnormalities and new samples of abnormal theories and also puts forward a novel approach towards the construction of trouble free theories

Gait termination : a review of experimental methods and the effects of aging and gait pathologies

The study of human gait has expanded and diversified to the extent that it is now possible to identify a substantive literature concerning a variety of gait tasks, such as gait initiation [Halliday SE, Winter DA, Frank JS, Patla AE, Prince F. The initiation of gait in young, elderly, and Parkinson's disease subjects. Gait Posture 1998;8:8–14; Mickelborough J, van der Linden ML, Tallis RC, Ennos AR. Muscle activity during gait initiation in normal elderly people. Gait Posture 2004;19:50–57], stepping over and across obstacles [Patla AE, Prentice SD, Robinson C, Newfold J. Visual control of locomotion: strategies for changing direction and for going over obstacles. J Exp Psych 1991;17:603–34; Chen, HC, Ashton-Miller JA, Alexander NB, Schultz AB. Effect of age and available response time on ability to step over an obstacle. J Gerontol 1994;49:227–33; Sparrow WA, Shinkfield AJ, Chow S, Begg RK. Gait characteristics in stepping over obstacles. Hum Mov Sci 1996;15:605–22; Begg RK, Sparrow WA, Lythgo ND. Time-domain analysis of foot–ground reaction forces in negotiating obstacles. Gait Posture 1998;7:99–109; Patla AE, Rietdyk S. Visual control of limb trajectory over obstacles during locomotion: effect of obstacle height and width. Gait Posture 1993;1:45–60] negotiating raised surfaces such as curbs and stairs [Begg RK, Sparrow WA. Gait characteristics of young and older individuals negotiating a raised surface: implications for the prevention of falls. J Gerontol Med Sci 2000;55A:147–54; Mcfayden BJ, Winter DA. An integrated biomechanical analysis of normal stair ascent and descent. J Biomech 1988;21:733–44]. In addition, increasing research interest in age-related declines in gait that might predispose individuals to falls has engendered a very extensive literature concerning ageing effects on gait. While rapid locomotor adjustments are common in the course of daily activities there has been no previous review of the findings concerning gait adaptations when walking is terminated both rapidly and unexpectedly. The aims of this review were first, to summarise the key research findings and methodological considerations from studies of termination. The second aim was to demonstrate the effects of ageing and gait pathologies on termination with respect to the regulation of step characteristics, lower-limb muscle activation patterns and foot–ground reaction forces.