Phage display selection of ligand residues important for Src homology 3 domain binding specificity.

The Src homology 3 (SH3) domain is a 50-aa modular unit present in many cellular proteins involved in intracellular signal transduction. It functions to direct protein-protein interactions through the recognition of proline-rich motifs on associated proteins. SH3 domains are important regulatory elements that have been demonstrated to specify distinct regulatory pathways important for cell growth, migration, differentiation, and responses to the external milieu. By the use of synthetic peptides, ligands have been shown to consist of a minimum core sequence and to bind to SH3 domains in one of two pseudosymmetrical orientations, class I and class II. The class I sites have the consensus sequence ZP(L/P)PP psi P whereas the class II consensus is PP psi PPZ (where psi is a hydrophobic residue and Z is a SH3 domain-specific residue). We previously showed by M13 phage display that the Src, Fyn, Lyn, and phosphatidylinositol 3-kinase (PI3K) SH3 domains preferred the same class I-type core binding sequence, RPLPP psi P. These results failed to explain the specificity for cellular proteins displayed by SH3 domains in cells. In the current study, class I and class II core ligand sequences were displayed on the surface of bacteriophage M13 with five random residues placed either N- or C-terminal of core ligand residues. These libraries were screened for binding to the Src, Fyn, Lyn, Yes, and PI3K SH3 domains. By this approach, additional ligand residue preferences were identified that can increase the affinity of SH3 peptide ligands at least 20-fold compared with core peptides. The amino acids selected in the flanking sequences were similar for Src, Fyn, and Yes SH3 domains; however, Lyn and PI3K SH3 domains showed distinct binding specificities. These results indicate that residues that flank the core binding sequences shared by many SH3 domains are important determinants of SH3 binding affinity and selectivity.

A protein-binding domain, EH, identified in the receptor tyrosine kinase substrate Eps15 and conserved in evolution.

In this report we structurally and functionally define a binding domain that is involved in protein association and that we have designated EH (for Eps15 homology domain). This domain was identified in the tyrosine kinase substrate Eps15 on the basis of regional conservation with several heterogeneous proteins of yeast and nematode. The EH domain spans about 70 amino acids and shows approximately 60% overall amino acid conservation. We demonstrated the ability of the EH domain to specifically bind cytosolic proteins in normal and malignant cells of mesenchymal, epithelial, and hematopoietic origin. These observations prompted our search for additional EH-containing proteins in mammalian cells. Using an EH domain-specific probe derived from the eps15 cDNA, we cloned and characterized a cDNA encoding an EH-containing protein with overall similarity to Eps15; we designated this protein Eps15r (for Eps15-related). Structural comparison of Eps15 and Eps15r defines a family of signal transducers possessing extensive networking abilities including EH-mediated binding and association with Src homology 3-containing proteins.

Domain Globalization: Using Languages to Support Technical and Social Coordination

When a project is realized in a globalized environment, multiple stakeholders from different organizations work on the same system. Depending on the stakeholders and their organizations, various (possibly overlapping) concerns are raised in the development of the system. In this context a Domain Specific Language (DSL) supports the work of a group of stakeholders who are responsible for addressing a specific set of concerns. This chapter identifies the open challenges arising from the coordination of globalized domain-specific languages. We identify two types of coordination: technical coordination and social coordination. After presenting an overview of the current state of the art, we discuss first the open challenges arising from the composition of multiple DSLs, and then the open challenges associated to the collaboration in a globalized environment.

Independent component analysis for domain independent watermarking

A new principled domain independent watermarking framework is presented. The new approach is based on embedding the message in statistically independent sources of the covertext to mimimise covertext distortion, maximise the information embedding rate and improve the method's robustness against various attacks. Experiments comparing the performance of the new approach, on several standard attacks show the current proposed approach to be competitive with other state of the art domain-specific methods.

ArchWiSeN: uma estratégia baseada em modelos para desenvolvimento de aplicações para redes de sensores e atuadores sem fio

Wireless Sensor and Actuator Networks (WSAN) are a key component in Ubiquitous Computing Systems and have many applications in different knowledge domains. Programming for such networks is very hard and requires developers to know the available sensor platforms specificities, increasing the learning curve for developing WSAN applications. In this work, an MDA (Model-Driven Architecture) approach for WSAN applications development called ArchWiSeN is proposed. The goal of such approach is to facilitate the development task by providing: (i) A WSAN domain-specific language, (ii) a methodology for WSAN application development; and (iii) an MDA infrastructure composed of several software artifacts (PIM, PSMs and transformations). ArchWiSeN allows the direct contribution of domain experts in the WSAN application development without the need of specialized knowledge on WSAN platforms and, at the same time, allows network experts to manage the application requirements without the need for specific knowledge of the application domain. Furthermore, this approach also aims to enable developers to express and validate functional and non-functional requirements of the application, incorporate services offered by WSAN middleware platforms and promote reuse of the developed software artifacts. In this sense, this Thesis proposes an approach that includes all WSAN development stages for current and emerging scenarios through the proposed MDA infrastructure. An evaluation of the proposal was performed by: (i) a proof of concept encompassing three different scenarios performed with the usage of the MDA infrastructure to describe the WSAN development process using the application engineering process, (ii) a controlled experiment to assess the use of the proposed approach compared to traditional method of WSAN application development, (iii) the analysis of ArchWiSeN support of middleware services to ensure that WSAN applications using such services can achieve their requirements ; and (iv) systematic analysis of ArchWiSeN in terms of desired characteristics for MDA tool when compared with other existing MDA tools for WSAN.

Two case studies on generating administrative process applications with AdminDSL

Some organizations end up reimplementing the same class of business process over and over: an "administrative process", which consists of managing a form through several states and involving various roles in the organization. This results in wasted time that could be dedicated to better understanding the process or dealing with the fine details that are specific to the process. Existing virtual office solutions require specific training and infrastructure andmay result in vendor lock-in. In this paper, we propose using a high-level domain-specific language (AdminDSL) to describe the administrative process and a separate code generator targeting a standard web framework. We have implemented the approach using Xtext, EGL and the Django web framework, and we illustrate it through two case studies: a synthetic examination process which illustrates the architecture of the generated code, and a real-world workplace survey process that identified several future avenues for improvement.

Flexible Computing Systems For AI Acceleration At The Extreme Edge Of The IoT

Embedding intelligence in extreme edge devices allows distilling raw data acquired from sensors into actionable information, directly on IoT end-nodes. This computing paradigm, in which end-nodes no longer depend entirely on the Cloud, offers undeniable benefits, driving a large research area (TinyML) to deploy leading Machine Learning (ML) algorithms on micro-controller class of devices. To fit the limited memory storage capability of these tiny platforms, full-precision Deep Neural Networks (DNNs) are compressed by representing their data down to byte and sub-byte formats, in the integer domain. However, the current generation of micro-controller systems can barely cope with the computing requirements of QNNs. This thesis tackles the challenge from many perspectives, presenting solutions both at software and hardware levels, exploiting parallelism, heterogeneity and software programmability to guarantee high flexibility and high energy-performance proportionality. The first contribution, PULP-NN, is an optimized software computing library for QNN inference on parallel ultra-low-power (PULP) clusters of RISC-V processors, showing one order of magnitude improvements in performance and energy efficiency, compared to current State-of-the-Art (SoA) STM32 micro-controller systems (MCUs) based on ARM Cortex-M cores. The second contribution is XpulpNN, a set of RISC-V domain specific instruction set architecture (ISA) extensions to deal with sub-byte integer arithmetic computation. The solution, including the ISA extensions and the micro-architecture to support them, achieves energy efficiency comparable with dedicated DNN accelerators and surpasses the efficiency of SoA ARM Cortex-M based MCUs, such as the low-end STM32M4 and the high-end STM32H7 devices, by up to three orders of magnitude. To overcome the Von Neumann bottleneck while guaranteeing the highest flexibility, the final contribution integrates an Analog In-Memory Computing accelerator into the PULP cluster, creating a fully programmable heterogeneous fabric that demonstrates end-to-end inference capabilities of SoA MobileNetV2 models, showing two orders of magnitude performance improvements over current SoA analog/digital solutions.

Survival and quality of life of patients with oral and oropharyngeal cancer at 1-year follow-up of tumor resection

OBJECTIVE: This study aimed to assess the survival and life quality evolution of patients subjected to surgical excision of oral and oropharyngeal squamous cell carcinoma. MATERIAL AND METHODS: Forty-seven patients treated at a Brazilian healthcare unit specialized in head and neck surgery between 2006 and 2007 were enrolled in the study. The gathering of data comprised reviewing hospital files and applying the University of Washington Quality of Life (UW-QOL) questionnaire previously and 1 year after the surgery. Comparative analysis used Poisson regression to assess factors associated with survival and a paired t-test to compare preoperative and 1-year postoperative QOL ratings. RESULTS: 1 year after surgery, 7 patients were not found (dropout of the cohort); 15 had died and 25 fulfilled the UW-QOL again. The risk of death was associated with having regional metastasis previously to surgery (relative risk=2.18; 95% confidence interval=1.09-5.17) and tumor size T3 or T4 (RR=2.30; 95%CI=1.05-5.04). Survivors presented significantly (p<0.05) poorer overall and domain-specific ratings of quality of life. Chewing presented the largest reduction: from 74.0 before surgery to 34.0 one year later. Anxiety was the only domain whose average rating increased (from 36.0 to 70.7). CONCLUSIONS: The prospective assessment of survival and quality of life may contribute to anticipate interventions aimed at reducing the incidence of functional limitations in patients with oral and oropharyngeal cancer.

Kidosaki redux: Trans-cultural trans-location

This paper concerns a collaborative experiment in architectural design teaching and thinking developed during a workshop held at The University of Queensland in 2000. The programme explored the possibilities and the consequences of relocating location-specific architecture to a different context - a 'Trans-Cultural Trans-Location'. The project involved the careful study by Australia-based students of a house designed for a Japanese family in a dense part of Tokyo by the eminent Japanese architect Tadao Ando, and the subsequent translocation of the ideas that underlay the building to a suburban location in Brisbane, for a theoretical equivalent Australian family. This experimental project examined the universality of architectural concepts, their appreciation and the pedagogical setting. The project raised questions of: - How well do students from one culture comprehend architecture designed specifically for another – which are the areas of misunderstanding and understanding? - How can students transpose architectural ideas from one social and physical context to one that is almost entirely the opposite? - What are the limits of collaboration and exchange in design teaching and how do they reveal similarities, inconsistencies and the unexpected in the aims of the teacher and of the student? These questions suggest that in order to comprehend a design, we must understand the culture within which it originated, and that we must understand the cultures within which we work in order to design. This paper is written in two parts. The first part establishes a framework for discussing the contrast of the cultural settings studied. The second part considers the nature, conduct and results of the Studio Workshop itself.

Rehabilitation of executive dysfunction: A controlled trial of an attention and problem solving treatment group

In this study, the effectiveness of a group-based attention and problem solving (APS) treatment approach to executive impairments in patients with frontal lobe lesions was investigated. Thirty participants with lesions in the frontal lobes, 16 with left frontal (LF) and 14 with right frontal (RF) lesions, were allocated into three groups, each with 10 participants. The APS treatment was initially compared to two other control conditions, an information/education (IE) approach and treatment-as-usual or traditional rehabilitation (TR), with each of the control groups subsequently receiving the APS intervention in a crossover design. This design allowed for an evaluation of the treatment through assessment before and after treatment and on follow up, six months later. There was an improvement on some executive and functional measures after the implementation of the APS programme in the three groups. Size, and to a lesser extent laterality, of lesion affected baseline performance on measures of executive function, but there was no apparent relationship between size, laterality or site of lesion and level of benefit from the treatment intervention. The results were discussed in terms of models of executive functioning and the effectiveness of domain specific interventions in the rehabilitation of executive dysfunction.

MDA-based re-engineering with Object-Z

This paper describes a practical application of MDA and reverse engineering based on a domain-specific modelling language. A well defined metamodel of a domain-specific language is useful for verification and validation of associated tools. We apply this approach to SIFA, a security analysis tool. SIFA has evolved as requirements have changed, and it has no metamodel. Hence, testing SIFA’s correctness is difficult. We introduce a formal metamodelling approach to develop a well-defined metamodel of the domain. Initially, we develop a domain model in EMF by reverse engineering the SIFA implementation. Then we transform EMF to Object-Z using model transformation. Finally, we complete the Object-Z model by specifying system behavior. The outcome is a well-defined metamodel that precisely describes the domain and the security properties that it analyses. It also provides a reliable basis for testing the current SIFA implementation and forward engineering its successor.

Protein targeting to the plasma membrane of adult skeletal muscle fiber: An organized mosaic of functional domains

The plasma membrane of differentiated skeletal muscle fibers comprises the sarcolemma, the transverse (T) tubule network, and the neuromuscular and muscle-tendon junctions. We analyzed the organization of these domains in relation to defined surface markers, beta -dystroglycan, dystrophin, and caveolin-3, These markers were shown to exhibit highly organized arrays along the length of the fiber. Caveolin-3 and beta -dystroglycan/dystrophin showed distinct, but to some extent overlapping, labeling patterns and both markers left transverse tubule openings clear. This labeling pattern revealed microdomains over the entire plasma membrane with the exception of the neuromuscular and muscle-tendon junctions which formed distinct demarcated macrodomains. Our results suggest that the entire plasma membrane of mature muscle comprises a mosaic of T tubule domains together with sareolemmal caveolae and beta -dystroglycan domains. The domains identified with these markers were examined with respect to targeting of viral proteins and other expressed domain-specific markers, We found that each marker protein was targeted to distinct microdomains, The macrodomains were intensely labeled with all our markers. Replacing the cytoplasmic tail of the vesicular stomatitis virus glycoprotein with that of CD4 resulted in retargeting from one domain to another. The domain-specific protein distribution at the muscle cell surface may be generated by targeting pathways requiring specific sorting information but this trafficking is different from the conventional apical-basolateral division. (C) 2001 Academic Press.

Model driven development implementation of a control systems user interfaces specification tool

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Engenharia Informática

Quality in Hospital Administrative Databases

The clinical content of administrative databases includes, among others, patient demographic characteristics, and codes for diagnoses and procedures. The data in these databases is standardized, clearly defined, readily available, less expensive than collected by other means, and normally covers hospitalizations in entire geographic areas. Although with some limitations, this data is often used to evaluate the quality of healthcare. Under these circumstances, the quality of the data, for instance, errors, or it completeness, is of central importance and should never be ignored. Both the minimization of data quality problems and a deep knowledge about this data (e.g., how to select a patient group) are important for users in order to trust and to correctly interpret results. In this paper we present, discuss and give some recommendations for some problems found in these administrative databases. We also present a simple tool that can be used to screen the quality of data through the use of domain specific data quality indicators. These indicators can significantly contribute to better data, to give steps towards a continuous increase of data quality and, certainly, to better informed decision-making.

Software languages engineering: experimental evaluation

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Engenharia Informática