Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions

Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions

The nature of discrimination learning in pigeons

The results from five experiments are considered in relation to two of Spence's (1937, 1938) proposals concerning discrimination learning. In Experiments 1 and 2, we investigated whether his ideas about the interaction between excitatory and inhibitory generalization gradients can be used to understand how animals solve a complex patterning discrimination. The results supported a development of his proposals as put forward by Pearce (1994), provided a modification was made to Pearce's rule for determining the shape of the generalization gradient. In Experiments 3, 4, and 5, we examined whether animals would pay more attention to stimuli that are relevant, rather than irrelevant, to the solution of a discrimination. The results supported this proposal for stimuli comprising visual patterns, but not for those comprising plain colors. The results also indicated that change of attention was a consequence of preliminary receptor-exposure acts, as envisaged by Spence, and not of more central changes in attention. Copyright 2008 Psychonomic Society, Inc

A self-initiated cue-reward learning procedure for neural recording in rodents

Background: Single-unit recording in Pavlovian conditioning tasks requires the use of within-subject designs as well as sampling a considerable number of trials per trial type and session, which increases the total trial count. Pavlovian conditioning, on the other hand, requires a long average intertrial interval (ITI) relative to cue duration for cue-specific learning to occur. These requirements combined can make the session duration unfeasibly long. New method: To circumvent this issue, we developed a self-initiated variant of the Pavlovian magazine-approach procedure in rodents. Unlike the standard procedure, where the animals passively receive the trials, the self-initiated procedure grants animals agency to self-administer and self-pace trials from a predetermined, pseudorandomized list. Critically, whereas in the standard procedure the typical ITI is in the order of minutes, our procedure uses a much shorter ITI (10 s). Results: Despite such a short ITI, discrimination learning in the self-initiated procedure is comparable to that observed in the standard procedure with a typical ITI, and superior to that observed in the standard procedure with an equally short ITI. Comparison with existing method(s): The self-initiated procedure permits delivering 100 trials in a ∼1-h session, almost doubling the number of trials safely attainable over that period with the standard procedure. Conclusions: The self-initiated procedure enhances the collection of neural correlates of cue-reward learning while producing good discrimination performance. Other advantages for neural recording studies include ensuring that at the start of each trial the animal is engaged, attentive and in the same location within the conditioning chamber

Periapical biomechanics and the role of cyclic biting force in apical retrograde fluid movement

10.1111/j.1365-2591.2005.00986.xInternational Endodontic Journal389597-603IENJ

O círculo vicioso da violência sexual: do ofendido ao ofensor

O presente trabalho discute o fenômeno da violência sexual contra crianças e adolescentes pondo em foco o autor do ato. Objetivou-se compreender o processo de formação da violência empregada, tendo em vista a experiência de violência anteriormente sofrida pelo autor, com base em uma visão fenomenológico-existencial. Para ilustração, foram inseridos trechos de atendimentos psicoterápicos realizados com um autor de violência sexual, de trinta e um anos, preso há onze anos em regime fechado. Foram realizadas vinte e nove sessões, que fizeram parte do Projeto Invertendo a Rota, vinculado ao CEPAJ/UCG. Concluiu-se, por meio dos atendimentos, que a imagem do abuso sexual sofrido na infância influenciou a forma como o sujeito cometeu a violência na idade adulta. Com o trabalho psicoterápico, percebeu-se ainda que o sujeito pôde ampliar percepções construídas acerca de si mesmo e do outro, começando, assim, um processo de ressignificação de sua própria história