Identification of neuronal alterations induced by Shank3 mutations using iPS cells from Phelan-McDermid Patients' Fibroblasts

A família de proteínas Shank é o principal conjunto de proteinas de suporte e está localizada na densidade pós-sináptica das sinapses excitatórias. Existem 3 genes na família Shank, Shank1, Shank2 e Shank3 e são caracterizados por múltiplos domínios repetidos de anquirina próximo ao N-terminal seguido pelos domínios Src homologo 3 e PDZ, uma região longa rica em prolina e um domínio de motivo α estéril próximo ao C-terminal. Shank proteínas conectam duas subunidades de receptors glutamatérgicos, recetores NMDA e recetores metabotrópicos de glutamato do tipo-I (mGluRs). O domínio PDZ da Shank conecta-se ao C-terminal do GKAP e este, liga-se, ao complexo recetor PSD-95-NMDA. Por outro lado, a proteína Homer interage com o domínio rico em prolina para confirmar a associação entre a proteína Shank com o mGluR tipo-I. A proteína específica em estudo, Shank3, é haploinsuficiente em pacientes com sindrome Phelan-McDermid devido à deleções no braço comprido do cromossoma 22 levando à danos intelectuais, ausência ou atraso no discurso, comportamentos semelhantes ao autismo, hipotonia e características dismórficas. Neste trabalho, investigamos o papel da Shank3 na função sináptica para compreender a relação entre alterações nesta proteína e as características neurológicas presente em Pacientes com síndrome Phelan-McDermid. Foram utilizados dois modelos diferentes, ratinhos knockout Shank3 e hiPSC de pacientes com PMS. Ratinhos geneticamente modificados são ferramentas uteis no estudo de genes e na compreensão dos mecanismos que experiências in vitro não são capazes de reproduzir, mas de maneira a compreender melhor as patologias humanas, decidimos trabalhar também com células humanas. Os fibroblastos dos pacientes com síndrome Phelan-McDermid fora reprogramados em hiPS cells, diferenciados em neurónios e comparados com os neurónios obtidos a partir de doadores saudavéis e da mesma idade. A reprogramação em iPSC foi realizada por infecção de lentivirus com quatro genes de reprogramação OCT4, c-MYC, SOX2 e KFL4 para posteriormente serem diferenciados em neurónios, com cada passo sendo positivamente confirmado através de marcadores neuronais. Através dos neurónios diferenciados, analisamos a expressão de proteínas sinápticas. Pacientes com haploinsuficiencia na proteína Shank3 apresentam níveis elevados de proteína mGluR5 e decrescidos de proteína Homer sugerindo que a haploinsuficiencia leva a desregulação do complexo mGluR5-Homer-Shank3 conduzindo também, a defeitos na maturação sináptica. Assim, a expressão da proteína mGluR5 está alterada nos pacientes com PMS podendo estar relacionada com defeitos encontrados na diferenciação neuronal e maturação sináptica observados nos neurónios de pacientes. Conclusivamente, iPS cells representam um modelo fundamental no estudo da proteína Shank3 e a sua influência no sindrome de Phelan-McDermid.

Semantics of logic programs with explicit negation

After a historical introduction, the bulk of the thesis concerns the study of a declarative semantics for logic programs. The main original contributions are: ² WFSX (Well–Founded Semantics with eXplicit negation), a new semantics for logic programs with explicit negation (i.e. extended logic programs), which compares favourably in its properties with other extant semantics. ² A generic characterization schema that facilitates comparisons among a diversity of semantics of extended logic programs, including WFSX. ² An autoepistemic and a default logic corresponding to WFSX, which solve existing problems of the classical approaches to autoepistemic and default logics, and clarify the meaning of explicit negation in logic programs. ² A framework for defining a spectrum of semantics of extended logic programs based on the abduction of negative hypotheses. This framework allows for the characterization of different levels of scepticism/credulity, consensuality, and argumentation. One of the semantics of abduction coincides with WFSX. ² O–semantics, a semantics that uniquely adds more CWA hypotheses to WFSX. The techniques used for doing so are applicable as well to the well–founded semantics of normal logic programs. ² By introducing explicit negation into logic programs contradiction may appear. I present two approaches for dealing with contradiction, and show their equivalence. One of the approaches consists in avoiding contradiction, and is based on restrictions in the adoption of abductive hypotheses. The other approach consists in removing contradiction, and is based in a transformation of contradictory programs into noncontradictory ones, guided by the reasons for contradiction.

Mining protein structure data

The principal topic of this work is the application of data mining techniques, in particular of machine learning, to the discovery of knowledge in a protein database. In the first chapter a general background is presented. Namely, in section 1.1 we overview the methodology of a Data Mining project and its main algorithms. In section 1.2 an introduction to the proteins and its supporting file formats is outlined. This chapter is concluded with section 1.3 which defines that main problem we pretend to address with this work: determine if an amino acid is exposed or buried in a protein, in a discrete way (i.e.: not continuous), for five exposition levels: 2%, 10%, 20%, 25% and 30%. In the second chapter, following closely the CRISP-DM methodology, whole the process of construction the database that supported this work is presented. Namely, it is described the process of loading data from the Protein Data Bank, DSSP and SCOP. Then an initial data exploration is performed and a simple prediction model (baseline) of the relative solvent accessibility of an amino acid is introduced. It is also introduced the Data Mining Table Creator, a program developed to produce the data mining tables required for this problem. In the third chapter the results obtained are analyzed with statistical significance tests. Initially the several used classifiers (Neural Networks, C5.0, CART and Chaid) are compared and it is concluded that C5.0 is the most suitable for the problem at stake. It is also compared the influence of parameters like the amino acid information level, the amino acid window size and the SCOP class type in the accuracy of the predictive models. The fourth chapter starts with a brief revision of the literature about amino acid relative solvent accessibility. Then, we overview the main results achieved and finally discuss about possible future work. The fifth and last chapter consists of appendices. Appendix A has the schema of the database that supported this thesis. Appendix B has a set of tables with additional information. Appendix C describes the software provided in the DVD accompanying this thesis that allows the reconstruction of the present work.

Development of an interface for ontology‐based transformation between features of different types

Dissertation submitted in partial fulfilment of the requirements for the Degree of Master of Science in Geospatial Technologies

Integration of e-learning systems with repositories of learning objects

This paper describes a communication model to integrate repositories of programming problems with other e-Learning software components. The motivation for this work comes from the EduJudge project that aims to connect an existing repository of programming problems to learning management systems. When trying to use the existing repositories of learning objects we realized that they are mainly specialized search engines and lack features for integration with other e-Learning systems. With this model we intend to clarify the main features of a programming problem repository, in order to enable the design and development of software components that use it. The two main points of this model are the definition of programming problems as learning objects and the definition of the core functions exposed by the repository. In both cases, this model follows the existing specifications of the IMS standard and proposes extensions to deal with the special requirements of automatic evaluation and grading of programming exercises. In the definition of programming problems as learning objects we introduced a new schema for meta-data. This schema is used to represent meta-data related to automatic evaluation that cannot be conveniently represented using the standard: the type of automatic evaluation; the requirements of the evaluation engine; or the roles of different assets - tests cases, program solutions, etc. In the definition of the core functions we used two different web services flavours - SOAP and REST - and described each function as an operation for each type of interface. We describe also the data types of the arguments of each operation. These data types consist mainly on learning objects and their identifications, but include also usage reports and queries using XQuery.

Extending the learning object definition to represent programming problems

The present generation of eLearning platforms values the interchange of learning objects standards. Nevertheless, for specialized domains these standards are insufficient to fully describe all the assets, especially when they are used as input for other eLearning services. To address this issue we extended an existing learning objects standard to the particular requirements of a specialized domain, namely the automatic evaluation of programming problems. The focus of this paper is the definition of programming problems as learning objects. We introduce a new schema to represent metadata related to automatic evaluation that cannot be conveniently represented using existing standards, such as: the type of automatic evaluation; the requirements of the evaluation engine; or the roles of different assets - tests cases, program solutions, etc. This new schema is being used in an interoperable repository of learning objects, called crimsonHex.

Using mobile device detection approaches to augment the accuracy of web delivery content

Recent studies of mobile Web trends show a continuous explosion of mobile-friendly content. However, the increasing number and heterogeneity of mobile devices poses several challenges for Web programmers who want to automatically get the delivery context and adapt the content to mobile devices. In this process, the devices detection phase assumes an important role where an inaccurate detection could result in a poor mobile experience for the enduser. In this paper we compare the most promising approaches for mobile device detection. Based on this study, we present an architecture for a system to detect and deliver uniform m-Learning content to students in a Higher School. We focus mainly on the devices capabilities repository manageable and accessible through an API. We detail the structure of the capabilities XML Schema that formalizes the data within the devices capabilities XML repository and the REST Web Service API for selecting the correspondent devices capabilities data according to a specific request. Finally, we validate our approach by presenting the access and usage statistics of the mobile web interface of the proposed system such as hits and new visitors, mobile platforms, average time on site and rejection rate.

PExIL: Programming Exercises Interoperability Language

Several standards appeared in recent years to formalize the metadata of learning objects, but they are still insufficient to fully describe a specialized domain. In particular, the programming exercise domain requires interdependent resources (e.g. test cases, solution programs, exercise description) usually processed by different services in the programming exercise life-cycle. Moreover, the manual creation of these resources is time-consuming and error-prone leading to what is an obstacle to the fast development of programming exercises of good quality. This paper focuses on the definition of an XML dialect called PExIL (Programming Exercises Interoperability Language). The aim of PExIL is to consolidate all the data required in the programming exercise life-cycle, from when it is created to when it is graded, covering also the resolution, the evaluation and the feedback. We introduce the XML Schema used to formalize the relevant data of the programming exercise life-cycle. The validation of this approach is made through the evaluation of the usefulness and expressiveness of the PExIL definition. In the former we present the tools that consume the PExIL definition to automatically generate the specialized resources. In the latter we use the PExIL definition to capture all the constraints of a set of programming exercises stored in a learning objects repository.

Using the Common Cartridge profile to enhance learning content interoperability

The concept of Learning Object (LO) is crucial for the standardization on eLearning. The latest LO standard from IMS Global Learning Consortium is the IMS Common Cartridge (IMS CC) that organizes and distributes digital learning content. By analyzing this new specification we considered two interoperability levels: content and communication. A common content format is the backbone of interoperability and is the basis for content exchange among eLearning systems. Communication is more than just exchanging content; it includes also accessing to specialized systems and services and reporting on content usage. This is particularly important when LOs are used for evaluation. In this paper we analyze the Common Cartridge profile based on the two interoperability levels we proposed. We detail its data model that comprises a set of derived schemata referenced on the CC schema and we explore the use of the IMS Learning Tools Interoperability (LTI) to allow remote tools and content to be integrated into a Learning Management System (LMS). In order to test the applicability of IMS CC for automatic evaluation we define a representation of programming exercises using this standard. This representation is intended to be the cornerstone of a network of eLearning systems where students can solve computer programming exercises and obtain feedback automatically. The CC learning object is automatically generated based on a XML dialect called PExIL that aims to consolidate all the data need to describe resources within the programming exercise life-cycle. Finally, we test the generated cartridge on the IMS CC online validator to verify its conformance with the IMS CC specification.

Using device detection techniques in M-learning scenarios

Recent studies of mobile Web trends show the continued explosion of mobile-friend content. However, the wide number and heterogeneity of mobile devices poses several challenges for Web programmers, who want automatic delivery of context and adaptation of the content to mobile devices. Hence, the device detection phase assumes an important role in this process. In this chapter, the authors compare the most used approaches for mobile device detection. Based on this study, they present an architecture for detecting and delivering uniform m-Learning content to students in a Higher School. The authors focus mainly on the XML device capabilities repository and on the REST API Web Service for dealing with device data. In the former, the authors detail the respective capabilities schema and present a new caching approach. In the latter, they present an extension of the current API for dealing with it. Finally, the authors validate their approach by presenting the overall data and statistics collected through the Google Analytics service, in order to better understand the adherence to the mobile Web interface, its evolution over time, and the main weaknesses.

Making programming exercises interoperable with PExIL

Several standards have appeared in recent years to formalize the metadata of learning objects, but they are still insufficient to fully describe a specialized domain. In particular, the programming exercise domain requires interdependent resources (e.g. test cases, solution programs, exercise description) usually processed by different services in the programming exercise lifecycle. Moreover, the manual creation of these resources is time-consuming and error-prone, leading to an obstacle to the fast development of programming exercises of good quality. This chapter focuses on the definition of an XML dialect called PExIL (Programming Exercises Interoperability Language). The aim of PExIL is to consolidate all the data required in the programming exercise lifecycle from when it is created to when it is graded, covering also the resolution, the evaluation, and the feedback. The authors introduce the XML Schema used to formalize the relevant data of the programming exercise lifecycle. The validation of this approach is made through the evaluation of the usefulness and expressiveness of the PExIL definition. In the former, the authors present the tools that consume the PExIL definition to automatically generate the specialized resources. In the latter, they use the PExIL definition to capture all the constraints of a set of programming exercises stored in a learning objects repository.

Towards a flexible and transparent database evolution

Applications refactorings that imply the schema evolution are common activities in programming practices. Although modern object-oriented databases provide transparent schema evolution mechanisms, those refactorings continue to be time consuming tasks for programmers. In this paper we address this problem with a novel approach based on aspect-oriented programming and orthogonal persistence paradigms, as well as our meta-model. An overview of our framework is presented. This framework, a prototype based on that approach, provides applications with aspects of persistence and database evolution. It also provides a new pointcut/advice language that enables the modularization of the instance adaptation crosscutting concern of classes, which were subject to a schema evolution. We also present an application that relies on our framework. This application was developed without any concern regarding persistence and database evolution. However, its data is recovered in each execution, as well as objects, in previous schema versions, remain available, transparently, by means of our framework.

Evolution of the application and database with aspects

Generally, the evolution process of applications has impact on their underlining data models, thus becoming a time-consuming problem for programmers and database administrators. In this paper we address this problem within an aspect-oriented approach, which is based on a meta-model for orthogonal persistent programming systems. Applying reflection techniques, our meta-model aims to be simpler than its competitors. Furthermore, it enables database multi-version schemas. We also discuss two case studies in order to demonstrate the advantages of our approach.

An Approach To Publish a Data Warehouse Content as Linked Data

Mestrado em Engenharia Informática - Área de Especialização em Tecnologias do Conhecimento e Decisão

A DCAP for the social and solidarity economy

This article presents a work-in-progress version of a Dublin Core Application Profile (DCAP) developed to serve the Social and Solidarity Economy (SSE). Studies revealed that this community is interested in implementing both internal interoperability between their Web platforms to build a global SSE e-marketplace, and external interoperability among their Web platforms and external ones. The Dublin Core Application Profile for Social and Solidarity Economy (DCAP-SSE) serves this purpose. SSE organisations are submerged in the market economy but they have specificities not taken into account in this economy. The DCAP-SSE integrates terms from well-known metadata schemas, Resource Description Framework (RDF) vocabularies or ontologies, in order to enhance interoperability and take advantage of the benefits of the Linked Open Data ecosystem. It also integrates terms from the new essglobal RDF vocabulary which was created with the goal to respond to the SSE-specific needs. The DCAP-SSE also integrates five new Vocabulary Encoding Schemes to be used with DCAP-SSE properties. The DCAP development was based on a method for the development of application profiles (Me4MAP). We believe that this article has an educational value since it presents the idea that it is important to base DCAP developments on a method. This article shows the main results of applying such a method.