WW Domains of the Yes-Kinase-Associated-Protein (YAP) Transcriptional Regulator Behave as Independent Units with Different Binding Preferences for PPxY Motif-Containing Ligands

YAP is a WW domain-containing effector of the Hippo tumor suppressor pathway, and the object of heightened interest as a potent oncogene and stemness factor. YAP has two major isoforms that differ in the number of WW domains they harbor. Elucidating the degree of co-operation between these WW domains is important for a full understanding of the molecular function of YAP. We present here a detailed biophysical study of the structural stability and binding properties of the two YAP WW domains aimed at investigating the relationship between both domains in terms of structural stability and partner recognition. We have carried out a calorimetric study of the structural stability of the two YAP WW domains, both isolated and in a tandem configuration, and their interaction with a set of functionally relevant ligands derived from PTCH1 and LATS kinases. We find that the two YAP WW domains behave as independent units with different binding preferences, suggesting that the presence of the second WW domain might contribute to modulate target recognition between the two YAP isoforms. Analysis of structural models and phage-display studies indicate that electrostatic interactions play a critical role in binding specificity. Together, these results are relevant to understand of YAP function and open the door to the design of highly specific ligands of interest to delineate the functional role of each WW domain in YAP signaling.This work was supported by the Spanish Ministry of Education and Science [grant BIO2009-13261-CO2], the Spanish Ministry of Economy and Competitivity [grant BIO2012-39922-CO2] including FEDER (European Funds for Regional Development) funds and the Governement of Andalusia [grant CVI-5915]. Marius Sudol was supported by PA Breast Cancer Coalition Grants (#60707 and #920093) plus the Geisinger Clinic

Neonatal Diagnosis of Prader-Willi Syndrome

A síndrome de Prader-Willi tem uma prevalência aproximada de 1:25000 nascimentos. No período neonatal há hipotonia severa, atraso de crescimento e dificuldade alimentar que persistem durante o primeiro ano de vida. O quadro clínico inicial contrasta com a bulimia que se evidencia mais tarde e que, não controlada, pode conduzir à obesidade mórbida. Descrevem-se as características clínicas, o diagnóstico genético e os cuidados específicos a ter na promoção da saúde a propósito de cinco crianças com síndrome de Prader Willi, cujo diagnóstico foi feito no período neonatal

Contagem numérica em estudantes com síndromes de X-Frágil e Prader-Willi Numerical counting in students with fragile X and Prader-Willi Syndromes

as dificuldades de aprendizagem matemática constituem um campo bastante complexo e ainda relativamente pouco explorado. Pesquisas com síndromes associadas ao baixo desempenho matemático indicam que há diferentes perfis cognitivos subjacentes às dificuldades na matemática e nos mostram que nem toda dificuldade de aprendizagem matemática é originada da mesma maneira. Este estudo teve como objetivo investigar as características dos princípios da contagem numérica em dois estudantes: um com síndrome do X-Frágil (SXF) e outro com síndrome de Prader-Willi (SPW). Foram feitas observações em sala de aula e no espaço escolar e investigaram-se os princípios numéricos em cinco situações matemáticas diferentes com intenção de observar os seguintes princípios numéricos: correspondência um a um, ordem constante, cardinalidade, abstração e irrelevância da ordem. Concluiu-se que o princípio da correspondência um a um (termo a termo) mostra-se em desenvolvimento mais lento do que nas crianças da mesma faixa etária, enquanto que os princípios da abstração e irrelevância da ordem são os menos desenvolvidos nas duas crianças estudadas. Crianças com estas síndromes estão em salas de aulas regulares e o conhecimento sobre suas habilidades cognitivas e sua apropriação de conceitos e conteúdos matemáticos se torna necessário para garantir uma inclusão que favoreça o sucesso matemático.<br>Difficulties in learning mathematics are a complex issue that is still relatively unexplored. Research into syndromes associated with low mathematical performance indicate that different cognitive profiles underlie learning difficulties in math and show that not all such difficulties have the same origins. This study aimed to investigate characteristics of the principles of numerical counting in two students: one with Fragile X syndrome (FXS) and another with Prader-Willi syndrome (PWS). Observations were made in the classroom and on the school playground. Five different mathematical situations were used to investigate five numerical principles: one to one correspondence, constant order, cardinality, abstraction and irrelevance of order. It was concluded that the principle of one to one correspondence in these children appears later than in their peers, and the principles of abstraction and irrelevance of order are the least developed in these children. There are children with syndromes such as these enrolled in regular classrooms. In order to ensure inclusion that encourages mathematical success, it is important to gain knowledge about their cognitive abilities and how they appropriate concepts and mathematical content