Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones.

α-Synuclein aggregation and accumulation in Lewy bodies are implicated in progressive loss of dopaminergic neurons in Parkinson disease and related disorders. In neurons, the Hsp70s and their Hsp40-like J-domain co-chaperones are the only known components of chaperone network that can use ATP to convert cytotoxic protein aggregates into harmless natively refolded polypeptides. Here we developed a protocol for preparing a homogeneous population of highly stable β-sheet enriched toroid-shaped α-Syn oligomers with a diameter typical of toxic pore-forming oligomers. These oligomers were partially resistant to in vitro unfolding by the bacterial Hsp70 chaperone system (DnaK, DnaJ, GrpE). Moreover, both bacterial and human Hsp70/Hsp40 unfolding/refolding activities of model chaperone substrates were strongly inhibited by the oligomers but, remarkably, not by unstructured α-Syn monomers even in large excess. The oligomers acted as a specific competitive inhibitor of the J-domain co-chaperones, indicating that J-domain co-chaperones may preferably bind to exposed bulky misfolded structures in misfolded proteins and, thus, complement Hsp70s that bind to extended segments. Together, our findings suggest that inhibition of the Hsp70/Hsp40 chaperone system by α-Syn oligomers may contribute to the disruption of protein homeostasis in dopaminergic neurons, leading to apoptosis and tissue loss in Parkinson disease and related neurodegenerative diseases.

Efficient self-synchronised blind audio watermarking system based on time domain and FFT amplitude modification

Many audio watermarking schemes divide the audio signal into several blocks such that part of the watermark is embedded into each of them. One of the key issues in these block-oriented watermarking schemes is to preserve the synchronisation, i.e. to recover the exact position of each block in the mark recovery process. In this paper, a novel time domain synchronisation technique is presented together with a new blind watermarking scheme which works in the Discrete Fourier Transform (DFT or FFT) domain. The combined scheme provides excellent imperceptibility results whilst achieving robustness against typical attacks. Furthermore, the execution of the scheme is fast enough to be used in real-time applications. The excellent transparency of the embedding algorithm makes it particularly useful for professional applications, such as the embedding of monitoring information in broadcast signals. The scheme is also compared with some recent results of the literature.

A System-Level Simulation Model for a Protocol Processor

As the development of integrated circuit technology continues to follow Moore’s law the complexity of circuits increases exponentially. Traditional hardware description languages such as VHDL and Verilog are no longer powerful enough to cope with this level of complexity and do not provide facilities for hardware/software codesign. Languages such as SystemC are intended to solve these problems by combining the powerful expression of high level programming languages and hardware oriented facilities of hardware description languages. To fully replace older languages in the desing flow of digital systems SystemC should also be synthesizable. The devices required by modern high speed networks often share the same tight constraints for e.g. size, power consumption and price with embedded systems but have also very demanding real time and quality of service requirements that are difficult to satisfy with general purpose processors. Dedicated hardware blocks of an application specific instruction set processor are one way to combine fast processing speed, energy efficiency, flexibility and relatively low time-to-market. Common features can be identified in the network processing domain making it possible to develop specialized but configurable processor architectures. One such architecture is the TACO which is based on transport triggered architecture. The architecture offers a high degree of parallelism and modularity and greatly simplified instruction decoding. For this M.Sc.(Tech) thesis, a simulation environment for the TACO architecture was developed with SystemC 2.2 using an old version written with SystemC 1.0 as a starting point. The environment enables rapid design space exploration by providing facilities for hw/sw codesign and simulation and an extendable library of automatically configured reusable hardware blocks. Other topics that are covered are the differences between SystemC 1.0 and 2.2 from the viewpoint of hardware modeling, and compilation of a SystemC model into synthesizable VHDL with Celoxica Agility SystemC Compiler. A simulation model for a processor for TCP/IP packet validation was designed and tested as a test case for the environment.

Embedded Service Bus for Internet of Things Interoperability

Internet of Things (IoT) technologies are developing rapidly, and therefore there exist several standards of interconnection protocols and platforms. The existence of heterogeneous protocols and platforms has become a critical challenge for IoT system developers. To mitigate this challenge, few alliances and organizations have taken the initiative to build a framework that helps to integrate application silos. Some of these frameworks focus only on a specific domain like home automation. However, the resource constraints in the large proportion of connected devices make it difficult to build an interoperable system using such frameworks. Therefore, a general purpose, lightweight interoperability framework that can be used for a range of devices is required. To tackle the heterogeneous nature, this work introduces an embedded, distributed and lightweight service bus, Lightweight IoT Service bus Architecture (LISA), which fits inside the network stack of a small real-time operating system for constrained nodes. LISA provides a uniform application programming interface for an IoT system on a range of devices with variable resource constraints. It hides platform and protocol variations underneath it, thus facilitating interoperability in IoT implementations. LISA is inspired by the Network on Terminal Architecture, a service centric open architecture by Nokia Research Center. Unlike many other interoperability frameworks, LISA is designed specifically for resource constrained nodes and it provides essential features of a service bus for easy service oriented architecture implementation. The presented architecture utilizes an intermediate computing layer, a Fog layer, between the small nodes and the cloud, thereby facilitating the federation of constrained nodes into subnetworks. As a result of a modular and distributed design, the part of LISA running in the Fog layer handles the heavy lifting to assist the lightweight portion of LISA inside the resource constrained nodes. Furthermore, LISA introduces a new networking paradigm, Node Centric Networking, to route messages across protocol boundaries to facilitate interoperability. This thesis presents a concept implementation of the architecture and creates a foundation for future extension towards a comprehensive interoperability framework for IoT.

The Bern psychopathology scale for the assessment of system-specific psychotic symptoms

The translation from psychiatric core symptoms to brain functions and vice versa is a largely unresolved issue. In particular, the search for disorders of single brain regions explaining classical symptoms has not yielded the expected results. Based on the assumption that the psychopathology of psychosis is related to a functional imbalance of higher-order brain systems, the authors focused on three specific candidate brain circuitries, namely the language, and limbic and motor systems. These domains are of particular interest for understanding the disastrous communication breakdown during psychotic disorders. Core symptoms of psychosis were mapped on these domains by shaping their definitions in order to match the related brain functions. The resulting psychopathological assessment scale was tested for interrater reliability and internal consistency in a group of 168 psychotic patients. The items of the scale were reliable and a principal component analysis (PCA) was best explained by a solution resembling the three candidate systems. Based on the results, the scale was optimized as an instrument to identify patient subgroups characterized by a prevailing dysfunction of one or more of these systems. In conclusion, the scale is apt to distinguish symptom domains related to the activity of defined brain systems. PCA showed a certain degree of independence of the system-specific symptom clusters within the patient group, indicating relative subgroups of psychosis. The scale is understood as a research instrument to investigate psychoses based on a system-oriented approach. Possible immediate advantages in the clinical application of the understanding of psychoses related to system-specific symptom domains are also discussed.

Comparison of objectively measured motor behavior with ratings of the motor behavior domain of the Bern Psychopathology Scale (BPS) in schizophrenia

Motor symptoms in schizophrenia occur frequently and are relevant to diagnosis and antipsychotic therapy. To date motor symptoms are difficult to assess and their pathobiology is a widely unresolved issue. The Bern Psychopathology Scale for the assessment of system-specific psychotic symptoms (BPS) was designed to identify homogenous patient groups by focusing on three domains: language, affectivity and motor behavior. The present study aimed to validate the motor behavior domain of the BPS using wrist actigraphy. In total, 106 patients were rated with the BPS and underwent 24 h continuous actigraphy recording. The ratings of the global severity of the motor behavior domain (GSM) as well as the quantitative and the subjective items of the motor behavior domain of the BPS were significantly associated with actigraphic variables. In contrast, the qualitative items of the motor domain failed to show an association with actigraphy. Likewise, scores of the language and the affectivity domains were not related to actigraphic measures. In conclusion, we provided substantial external validity for global, quantitative and subjective ratings of the BPS motor behavior domain. Thus, the BPS is suitable to assess the dimension of quantitative motor behavior in the schizophrenia spectrum.

Subtyping schizophrenia: A comparison of positive/negative and system-specific approaches

BACKGROUND Schizophrenia is a heterogeneous disorder. Over the years, different approaches have been proposed to approach this heterogeneity by categorizing symptom patterns. The study aimed to compare positive/negative and system-specific approaches to subtyping. METHODS We used the Positive and Negative Syndrome Scale (PANSS) and Bern Psychopathology Scale (BPS), which consists of subscales for three domains (language, affect and motor behavior) that are hypothesized to be related to specific brain circuits, to assess cross-sectional psychopathological characteristics in a sample of 100 inpatients with schizophrenia spectrum disorders. We then categorized participants into positive/negative and system-specific subgroups to allow comparisons of the two approaches. RESULTS The analyses revealed correlations between the PANSS positive subscore and the BPS affective subscore (r=.446, p<.001) and between the PANSS negative subscore and the BPS motor behavior subscore (r=.227, p=.023). As regards the positive and negative subtype, more participants were classified as positive in the language-dominant subtype (30.3%) and affect-dominant subtype (30.3%), whereas more were classified as negative in the motor behavior-dominant subtype (44.4%). However, most patients met the criteria for the mixed subtype. CONCLUSIONS The results suggest that the positive/negative and system-specific approaches can be regarded as complementary. Future studies should examine both approaches in a longitudinal assessment of psychopathological symptoms and link them with qualitative-phenomenological approaches.

Automatic Categorization for Improving Spanish into Spanish Sign Language Machine Translation

This paper describes a preprocessing module for improving the performance of a Spanish into Spanish Sign Language (Lengua de Signos Espanola: LSE) translation system when dealing with sparse training data. This preprocessing module replaces Spanish words with associated tags. The list with Spanish words (vocabulary) and associated tags used by this module is computed automatically considering those signs that show the highest probability of being the translation of every Spanish word. This automatic tag extraction has been compared to a manual strategy achieving almost the same improvement. In this analysis, several alternatives for dealing with non-relevant words have been studied. Non-relevant words are Spanish words not assigned to any sign. The preprocessing module has been incorporated into two well-known statistical translation architectures: a phrase-based system and a Statistical Finite State Transducer (SFST). This system has been developed for a specific application domain: the renewal of Identity Documents and Driver's License. In order to evaluate the system a parallel corpus made up of 4080 Spanish sentences and their LSE translation has been used. The evaluation results revealed a significant performance improvement when including this preprocessing module. In the phrase-based system, the proposed module has given rise to an increase in BLEU (Bilingual Evaluation Understudy) from 73.8% to 81.0% and an increase in the human evaluation score from 0.64 to 0.83. In the case of SFST, BLEU increased from 70.6% to 78.4% and the human evaluation score from 0.65 to 0.82.

Energy and power aware scheduling algorithm modeling for battery powered embedded systems

Energy management has always been recognized as a challenge in mobile systems, especially in modern OS-based mobile systems where multi-functioning are widely supported. Nowadays, it is common for a mobile system user to run multiple applications simultaneously while having a target battery lifetime in mind for a specific application. Traditional OS-level power management (PM) policies make their best effort to save energy under performance constraint, but fail to guarantee a target lifetime, leaving the painful trading off between the total performance of applications and the target lifetime to the user itself. This thesis provides a new way to deal with the problem. It is advocated that a strong energy-aware PM scheme should first guarantee a user-specified battery lifetime to a target application by restricting the average power of those less important applications, and in addition to that, maximize the total performance of applications without harming the lifetime guarantee. As a support, energy, instead of CPU or transmission bandwidth, should be globally managed as the first-class resource by the OS. As the first-stage work of a complete PM scheme, this thesis presents the energy-based fair queuing scheduling, a novel class of energy-aware scheduling algorithms which, in combination with a mechanism of battery discharge rate restricting, systematically manage energy as the first-class resource with the objective of guaranteeing a user-specified battery lifetime for a target application in OS-based mobile systems. Energy-based fair queuing is a cross-application of the traditional fair queuing in the energy management domain. It assigns a power share to each task, and manages energy by proportionally serving energy to tasks according to their assigned power shares. The proportional energy use establishes proportional share of the system power among tasks, which guarantees a minimum power for each task and thus, avoids energy starvation on any task. Energy-based fair queuing treats all tasks equally as one type and supports periodical time-sensitive tasks by allocating each of them a share of system power that is adequate to meet the highest energy demand in all periods. However, an overly conservative power share is usually required to guarantee the meeting of all time constraints. To provide more effective and flexible support for various types of time-sensitive tasks in general purpose operating systems, an extra real-time friendly mechanism is introduced to combine priority-based scheduling into the energy-based fair queuing. Since a method is available to control the maximum time one time-sensitive task can run with priority, the power control and time-constraint meeting can be flexibly traded off. A SystemC-based test-bench is designed to assess the algorithms. Simulation results show the success of the energy-based fair queuing in achieving proportional energy use, time-constraint meeting, and a proper trading off between them. La gestión de energía en los sistema móviles está considerada hoy en día como un reto fundamental, notándose, especialmente, en aquellos terminales que utilizando un sistema operativo implementan múltiples funciones. Es común en los sistemas móviles actuales ejecutar simultaneamente diferentes aplicaciones y tener, para una de ellas, un objetivo de tiempo de uso de la batería. Tradicionalmente, las políticas de gestión de consumo de potencia de los sistemas operativos hacen lo que está en sus manos para ahorrar energía y satisfacer sus requisitos de prestaciones, pero no son capaces de proporcionar un objetivo de tiempo de utilización del sistema, dejando al usuario la difícil tarea de buscar un compromiso entre prestaciones y tiempo de utilización del sistema. Esta tesis, como contribución, proporciona una nueva manera de afrontar el problema. En ella se establece que un esquema de gestión de consumo de energía debería, en primer lugar, garantizar, para una aplicación dada, un tiempo mínimo de utilización de la batería que estuviera especificado por el usuario, restringiendo la potencia media consumida por las aplicaciones que se puedan considerar menos importantes y, en segundo lugar, maximizar las prestaciones globales sin comprometer la garantía de utilización de la batería. Como soporte de lo anterior, la energía, en lugar del tiempo de CPU o el ancho de banda, debería gestionarse globalmente por el sistema operativo como recurso de primera clase. Como primera fase en el desarrollo completo de un esquema de gestión de consumo, esta tesis presenta un algoritmo de planificación de encolado equitativo (fair queueing) basado en el consumo de energía, es decir, una nueva clase de algoritmos de planificación que, en combinación con mecanismos que restrinjan la tasa de descarga de una batería, gestionen de forma sistemática la energía como recurso de primera clase, con el objetivo de garantizar, para una aplicación dada, un tiempo de uso de la batería, definido por el usuario, en sistemas móviles empotrados. El encolado equitativo de energía es una extensión al dominio de la energía del encolado equitativo tradicional. Esta clase de algoritmos asigna una reserva de potencia a cada tarea y gestiona la energía sirviéndola de manera proporcional a su reserva. Este uso proporcional de la energía garantiza que cada tarea reciba una porción de potencia y evita que haya tareas que se vean privadas de recibir energía por otras con un comportamiento más ambicioso. Esta clase de algoritmos trata a todas las tareas por igual y puede planificar tareas periódicas en tiempo real asignando a cada una de ellas una reserva de potencia que es adecuada para proporcionar la mayor de las cantidades de energía demandadas por período. Sin embargo, es posible demostrar que sólo se consigue cumplir con los requisitos impuestos por todos los plazos temporales con reservas de potencia extremadamente conservadoras. En esta tesis, para proporcionar un soporte más flexible y eficiente para diferentes tipos de tareas de tiempo real junto con el resto de tareas, se combina un mecanismo de planificación basado en prioridades con el encolado equitativo basado en energía. En esta clase de algoritmos, gracias al método introducido, que controla el tiempo que se ejecuta con prioridad una tarea de tiempo real, se puede establecer un compromiso entre el cumplimiento de los requisitos de tiempo real y el consumo de potencia. Para evaluar los algoritmos, se ha diseñado en SystemC un banco de pruebas. Los resultados muestran que el algoritmo de encolado equitativo basado en el consumo de energía consigue el balance entre el uso proporcional a la energía reservada y el cumplimiento de los requisitos de tiempo real.

Design, development and field evaluation of a Spanish into sign language translation system

This paper describes the design, development and field evaluation of a machine translation system from Spanish to Spanish Sign Language (LSE: Lengua de Signos Española). The developed system focuses on helping Deaf people when they want to renew their Driver’s License. The system is made up of a speech recognizer (for decoding the spoken utterance into a word sequence), a natural language translator (for converting a word sequence into a sequence of signs belonging to the sign language), and a 3D avatar animation module (for playing back the signs). For the natural language translator, three technological approaches have been implemented and evaluated: an example-based strategy, a rule-based translation method and a statistical translator. For the final version, the implemented language translator combines all the alternatives into a hierarchical structure. This paper includes a detailed description of the field evaluation. This evaluation was carried out in the Local Traffic Office in Toledo involving real government employees and Deaf people. The evaluation includes objective measurements from the system and subjective information from questionnaires. The paper details the main problems found and a discussion on how to solve them (some of them specific for LSE).

Deployment and validation of a smart system for screening of language disorders in primary care

Neuro-evolutive development from birth until the age of six years is a decisive factor in a child?s quality of life. Early detection of development disorders in early childhood can facilitate necessary diagnosis and/or treatment. Primary-care pediatricians play a key role in its detection as they can undertake the preventive and therapeutic actions requested to promote a child?s optimal development. However, the lack of time and little specific knowledge at primary-care avoid to applying continuous early-detection anomalies procedures. This research paper focuses on the deployment and evaluation of a smart system that enhances the screening of language disorders in primary care. Pediatricians get support to proceed with early referral of language disorders. The proposed model provides them with a decision-support tool for referral actions to trigger essential diagnostic and/or therapeutic actions for a comprehensive individual development. The research was conducted by starting from a sample of 60 cases of children with language disorders. Validation was carried out through two complementary steps: first, by including a team of seven experts from the fields of neonatology, pediatrics, neurology and language therapy, and, second, through the evaluation of 21 more previously diagnosed cases. The results obtained show that therapist positively accepted the system proposal in 18 cases (86%) and suggested system redesign for single referral to a speech therapist in three remaining cases.

Desarrollo de aplicaciones basadas en Linux Embedded en una arquitectura basada en Cyclone V SoC (System on Chip) de Altera

We attempt to integrate and start up the set of necessary tools to deploy the design cycle of embedded systems based on Embedded Linux on a "Cyclone V SoC" made by Altera. First, we will analyze the available tools for designing the hardware system of the SoCkit development kit, made by Arrow, which has a "Cyclone V SoC" system (based on a "ARM Cortex-A9 MP Core" architecture). When designing the SoCkit board hardware, we will create a new peripheral to integrate it into the hardware system, so it can be used as any other existent resource of the SoCkit board previously configured. Next, we will analyze the tools to generate an Embedded Linux distribution adapted to the SoCkit board. In order to generate the Linux distribution we will use, on the one hand, a software package from Yocto recommended by Altera; on the other hand, the programs and tools of Altera, Embedded Development Suite. We will integrate all the components needed to build the Embedded Linux distribution, creating a complete and functional system which can be used for developing software applications. Finally, we will study the programs for developing and debugging applications in C or C++ language that will be executed in this hardware platform, then we will program a Linux application as an example to illustrate the use of SoCkit board resources. RESUMEN Se pretende integrar y poner en funcionamiento el conjunto de herramientas necesarias para desplegar el ciclo de diseño de sistemas embebidos basados en "Embedded Linux" sobre una "Cyclone V SoC" de Altera. En primer lugar, se analizarán las diversas herramientas disponibles para diseñar el sistema hardware de la tarjeta de desarrollo SoCkit, fabricada por Arrow, que dispone de un sistema "Cyclone V SoC" (basado en una arquitectura "ARM Cortex A9 MP Core"). En el diseño hardware de la SoCkit se creará un periférico propio y se integrará en el sistema, pudiendo ser utilizado como cualquier otro recurso de la tarjeta ya existente y configurado. A continuación, también se analizarán las herramientas para generar una distribución de "Embedded Linux" adaptado a la placa SoCkit. Para generar la distribución de Linux se utilizará, por una parte, un paquete software de Yocto recomendado por Altera y, por otra parte, las propias herramientas y programas de Altera. Se integrarán todos los componentes necesarios para construir la distribución Linux, creando un sistema completo y funcional que se pueda utilizar para el desarrollo de aplicaciones software. Por último, se estudiarán las herramientas para el diseño y depuración de aplicaciones en lenguaje C ó C++ que se ejecutarán en esta plataforma hardware. Se pretende desarrollar una aplicación de ejemplo para ilustrar el uso de los recursos más utilizados de la SoCkit.

Methodology for developing an advanced communications system for the Deaf in a new domain

A methodology for developing an advanced communications system for the Deaf in a new domain is presented in this paper. This methodology is a user-centred design approach consisting of four main steps: requirement analysis, parallel corpus generation, technology adaptation to the new domain, and finally, system evaluation. During the requirement analysis, both the user and technical requirements are evaluated and defined. For generating the parallel corpus, it is necessary to collect Spanish sentences in the new domain and translate them into LSE (Lengua de Signos Española: Spanish Sign Language). LSE is represented by glosses and using video recordings. This corpus is used for training the two main modules of the advanced communications system to the new domain: the spoken Spanish into the LSE translation module and the Spanish generation from the LSE module. The main aspects to be generated are the vocabularies for both languages (Spanish words and signs), and the knowledge for translating in both directions. Finally, the field evaluation is carried out with deaf people using the advanced communications system to interact with hearing people in several scenarios. In this evaluation, the paper proposes several objective and subjective measurements for evaluating the performance. In this paper, the new considered domain is about dialogues in a hotel reception. Using this methodology, the system was developed in several months, obtaining very good performance: good translation rates (10% Sign Error Rate) with small processing times, allowing face-to-face dialogues.

Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to Eag and cyclic nucleotide-gated channels

We have isolated a novel cDNA, that appears to represent a new class of ion channels, by using the yeast two-hybrid system and the SH3 domain of the neural form of Src (N-src) as a bait. The encoded polypeptide, BCNG-1, is distantly related to cyclic nucleotide-gated channels and the voltage-gated channels, Eag and H-erg. BCNG-1 is expressed exclusively in the brain, as a glycosylated protein of ≈132 kDa. Immunohistochemical analysis indicates that BCNG-1 is preferentially expressed in specific subsets of neurons in the neocortex, hippocampus, and cerebellum, in particular pyramidal neurons and basket cells. Within individual neurons, the BCNG-1 protein is localized to either the dendrites or the axon terminals depending on the cell type. Southern blot analysis shows that several other BCNG-related sequences are present in the mouse genome, indicating the emergence of an entire subfamily of ion channel coding genes. These findings suggest the existence of a new type of ion channel, which is potentially able to modulate membrane excitability in the brain and could respond to regulation by cyclic nucleotides.

Role of the C2A domain of synaptotagmin in transmitter release as determined by specific antibody injection into the squid giant synapse preterminal.

Squid synaptotagmin (Syt) cDNA, including its open reading frame, was cloned and polyclonal antibodies were obtained in rabbits immunized with glutathione S-transferase (GST)-Syt-C2A. Binding assays indicated that the antibody, anti-Syt-C2A, recognized squid Syt and inhibited the Ca(2+)-dependent phospholipid binding to the C2A domain. This antibody, when injected into the preterminal at the squid giant synapse, blocked transmitter release in a manner similar to that previously reported for the presynaptic injection of members of the inositol high-polyphosphate series. The block was not accompanied by any change in the presynaptic action potential or the amplitude or voltage dependence of the presynaptic Ca2+ current. The postsynaptic potential was rather insensitive to repetitive presynaptic stimulation, indicating a direct effect of the antibody on the transmitter release system. Following block of transmitter release, confocal microscopical analysis of the preterminal junction injected with rhodamine-conjugated anti-Syt-C2A demonstrated fluorescent spots at the inner surface of the presynaptic plasmalemma next to the active zones. Structural analysis of the same preparations demonstrated an accumulation of synaptic vesicles corresponding in size and distribution to the fluorescent spots demonstrated confocally. Together with the finding that such antibody prevents Ca2+ binding to a specific receptor in the C2A domain, these results indicate that Ca2+ triggers transmitter release by activating the C2A domain of Syt. We conclude that the C2A domain is directly related to the fusion of synaptic vesicles that results in transmitter release.