Identification of Drosophila heart-specific Cis-Regulatory Modules under Hox control

Cardiac morphogenesis is a complex process governed by evolutionarily conserved transcription factors and signaling molecules. The Drosophila cardiac tube is linear, made of 52 pairs of cardiomyocytes (CMs), which express specific transcription factor genes that have human homologues implicated in Congenital Heart Diseases (CHDs) (NKX2-5, GATA4 and TBX5). The Drosophila cardiac tube is linear and composed of a rostral portion named aorta and a caudal one called heart, distinguished by morphological and functional differences controlled by Hox genes, key regulators of axial patterning. Overexpression and inactivation of the Hox gene abdominal-A (abd-A), which is expressed exclusively in the heart, revealed that abd-A controls heart identity. The aim of our work is to isolate the heart-specific cisregulatory sequences of abd-A direct target genes, the realizator genes granting heart identity. In each segment of the heart, four pairs of cardiomyocytes (CMs) express tinman (tin), homologous to NKX2-5, and acquire strong contractile and automatic rhythmic activities. By tyramide amplified FISH, we found that seven genes, encoding ion channels, pumps or transporters, are specifically expressed in the Tin-CMs of the heart. We initially used online available tools to identify their heart-specific cisregutatory modules by looking for Conserved Non-coding Sequences containing clusters of binding sites for various cardiac transcription factors, including Hox proteins. Based on these data we generated several reporter gene constructs and transgenic embryos, but none of them showed reporter gene expression in the heart. In order to identify additional abd-A target genes, we performed microarray experiments comparing the transcriptomes of aorta versus heart and identified 144 genes overexpressed in the heart. In order to find the heart-specific cis-regulatory regions of these target genes we developed a new bioinformatic approach where prediction is based on pattern matching and ordered statistics. We first retrieved Conserved Noncoding Sequences from the alignment between the D.melanogaster and D.pseudobscura genomes. We scored for combinations of conserved occurrences of ABD-A, ABD-B, TIN, PNR, dMEF2, MADS box, T-box and E-box sites and we ranked these results based on two independent strategies. On one hand we ranked the putative cis-regulatory sequences according to best scored ABD-A biding sites, on the other hand we scored according to conservation of binding sites. We integrated and ranked again the two lists obtained independently to produce a final rank. We generated nGFP reporter construct flies for in vivo validation. We identified three 1kblong heart-specific enhancers. By in vivo and in vitro experiments we are determining whether they are direct abd-A targets, demonstrating the role of a Hox gene in the realization of heart identity. The identified abd-A direct target genes may be targets also of the NKX2-5, GATA4 and/or TBX5 homologues tin, pannier and Doc genes, respectively. The identification of sequences coregulated by a Hox protein and the homologues of transcription factors causing CHDs, will provide a mean to test whether these factors function as Hox cofactors granting cardiac specificity to Hox proteins, increasing our knowledge on the molecular mechanisms underlying CHDs. Finally, it may be investigated whether these Hox targets are involved in CHDs.

Development of control-oriented models of Dual Clutch Transmission systems

A control-oriented model of a Dual Clutch Transmission was developed for real-time Hardware In the Loop (HIL) applications, to support model-based development of the DCT controller. The model is an innovative attempt to reproduce the fast dynamics of the actuation system while maintaining a step size large enough for real-time applications. The model comprehends a detailed physical description of hydraulic circuit, clutches, synchronizers and gears, and simplified vehicle and internal combustion engine sub-models. As the oil circulating in the system has a large bulk modulus, the pressure dynamics are very fast, possibly causing instability in a real-time simulation; the same challenge involves the servo valves dynamics, due to the very small masses of the moving elements. Therefore, the hydraulic circuit model has been modified and simplified without losing physical validity, in order to adapt it to the real-time simulation requirements. The results of offline simulations have been compared to on-board measurements to verify the validity of the developed model, that was then implemented in a HIL system and connected to the TCU (Transmission Control Unit). Several tests have been performed: electrical failure tests on sensors and actuators, hydraulic and mechanical failure tests on hydraulic valves, clutches and synchronizers, and application tests comprehending all the main features of the control performed by the TCU. Being based on physical laws, in every condition the model simulates a plausible reaction of the system. The first intensive use of the HIL application led to the validation of the new safety strategies implemented inside the TCU software. A test automation procedure has been developed to permit the execution of a pattern of tests without the interaction of the user; fully repeatable tests can be performed for non-regression verification, allowing the testing of new software releases in fully automatic mode.

Control of muscle relaxation during anesthesia: a novel approach for clinical routine

During general anesthesia drugs are administered to provide hypnosis, ensure analgesia, and skeletal muscle relaxation. In this paper, the main components of a newly developed controller for skeletal muscle relaxation are described. Muscle relaxation is controlled by administration of neuromuscular blocking agents. The degree of relaxation is assessed by supramaximal train-of-four stimulation of the ulnar nerve and measuring the electromyogram response of the adductor pollicis muscle. For closed-loop control purposes, a physiologically based pharmacokinetic and pharmacodynamic model of the neuromuscular blocking agent mivacurium is derived. The model is used to design an observer-based state feedback controller. Contrary to similar automatic systems described in the literature this controller makes use of two different measures obtained in the train-of-four measurement to maintain the desired level of relaxation. The controller is validated in a clinical study comparing the performance of the controller to the performance of the anesthesiologist. As presented, the controller was able to maintain a preselected degree of muscle relaxation with excellent precision while minimizing drug administration. The controller performed at least equally well as the anesthesiologist.

Personalized Tuning of a Reinforcement Learning Control Algorithm for Glucose Regulation

Artificial pancreas is in the forefront of research towards the automatic insulin infusion for patients with type 1 diabetes. Due to the high inter- and intra-variability of the diabetic population, the need for personalized approaches has been raised. This study presents an adaptive, patient-specific control strategy for glucose regulation based on reinforcement learning and more specifically on the Actor-Critic (AC) learning approach. The control algorithm provides daily updates of the basal rate and insulin-to-carbohydrate (IC) ratio in order to optimize glucose regulation. A method for the automatic and personalized initialization of the control algorithm is designed based on the estimation of the transfer entropy (TE) between insulin and glucose signals. The algorithm has been evaluated in silico in adults, adolescents and children for 10 days. Three scenarios of initialization to i) zero values, ii) random values and iii) TE-based values have been comparatively assessed. The results have shown that when the TE-based initialization is used, the algorithm achieves faster learning with 98%, 90% and 73% in the A+B zones of the Control Variability Grid Analysis for adults, adolescents and children respectively after five days compared to 95%, 78%, 41% for random initialization and 93%, 88%, 41% for zero initial values. Furthermore, in the case of children, the daily Low Blood Glucose Index reduces much faster when the TE-based tuning is applied. The results imply that automatic and personalized tuning based on TE reduces the learning period and improves the overall performance of the AC algorithm.

Soporte de redes activas para un servicio integrado de multipunto fiable con control de congestión

Las limitaciones de las tecnologías de red actuales, identificadas en la Agencia de Proyectos de Investigación Avanzados para la Defensa (DARPA) durante 1995, han originado recientemente una propuesta de modelo de red denominado Redes Activas. En este modelo, los nodos proporcionan un entorno de ejecución sobre el que se ejecuta el código asociado a cada paquete. El objetivo es disponer de una tecnología de red que permita que nuevos servicios de red sean desarrollados e instalados rápidamente sin modificar los nodos de la red. Un servicio de red que se puede beneficiar de esta tecnología es la transmisión de datos en multipunto con diferentes grados fiabilidad. Las propuestas actuales de servicios de multipunto fiable proporcionan una solución específica para cada clase de aplicaciones, y los protocolos existentes extremo a extremo sufren de limitaciones técnicas relacionadas con una fiabilidad limitada, y con la ausencia de mecanismos de control de congestión efectivos. Esta tesis realiza propuestas originales conducentes a solucionar parte de las limitaciones actuales en el ámbito de Redes Activas y multipunto fiable con control de congestión. En primer lugar, se especificará un servicio genérico de multipunto fiable que, basándose en los requisitos de una serie de aplicaciones consideradas relevantes, proporcione diferentes clases de sesiones y grados de fiabilidad. Partiendo de la definición del servicio genérico especificado, se diseñará un protocolo de comunicaciones sobre la tecnología de Redes Activas que proporcione dicho servicio. El protocolo diseñado estará dotado de un mecanismo de control de congestión para que la fuente ajuste dinámicamente el tráfico inyectado a las condiciones de carga de la red. En esta tesis se pretende también profundizar en el estudio y análisis de la tecnología de Redes Activas, experimentando con dicha tecnología para proporcionar una realimentación a sus diseñadores. Dicha experimentación se realizará en tres ámbitos: el de los servicios y protocolos que puede soportar, el del modelo y arquitectura de las Redes Activas y el de las plataformas de ejecución disponibles. Como aportación adicional de este trabajo, se validarán los objetivos anteriores mediante una implementación piloto de las entidades de protocolo y de su interfaz de servicio sobre uno de los entornos de ejecución disponibles. Abstract The limitations of current networking technologies identified in the Defense Advance Research Projects Agency (DARPA) along 1995 have led to a recent proposal of a new network model called Active Networks. In this model, the nodes provide an execution environment over which the code used to process each packet is executed. The objective is a network technology that allows the fast design and deployment of new network services without requiring the modification of the network nodes. One network service that could benefit from this technology is the transmission of multicast data with different types of loss tolerance. The current proposals for reliable multicast services provide specific solutions for each application class, and existing end-to-end protocols suffer from technical drawbacks related to limited reliability and lack of an effective congestion control mechanism. This thesis contains original proposals that aim to solve part of the current drawbacks in the scope of Active Networks and reliable multicast with congestion control. Firstly, a generic reliable multicast network service will be specified. This service will be designed from the requirements of a relevant set of applications, and will provide different session classes and different types of reliability. Then, a network protocol based on Active Network technology will be designed such that it provides the specified network service. This protocol will incorporate a congestion control mechanism capable of performing an automatic adjustment of the traffic injected by the source to the available network capacity. This thesis will also contribute to a deeper study and analysis of Active Network technology, by experimenting with the technology in order to provide feedback to its designers. This experimentation will be done attending to three different scopes: support of Active Network for services and protocols, Active Network model and architecture, and currently available Active Network execution environments. As an additional contribution of this work, the previous objectives will be validated through a prototype implementation of the protocol entities and the service interface based on one of the current execution environments.

Automatic Understanding of ATC Speech: Study of Prospectives and Field Experiments for Several Controller Positions

Although there has been a lot of interest in recognizing and understanding air traffic control (ATC) speech, none of the published works have obtained detailed field data results. We have developed a system able to identify the language spoken and recognize and understand sentences in both Spanish and English. We also present field results for several in-tower controller positions. To the best of our knowledge, this is the first time that field ATC speech (not simulated) is captured, processed, and analyzed. The use of stochastic grammars allows variations in the standard phraseology that appear in field data. The robust understanding algorithm developed has 95% concept accuracy from ATC text input. It also allows changes in the presentation order of the concepts and the correction of errors created by the speech recognition engine improving it by 17% and 25%, respectively, absolute in the percentage of fully correctly understood sentences for English and Spanish in relation to the percentages of fully correctly recognized sentences. The analysis of errors due to the spontaneity of the speech and its comparison to read speech is also carried out. A 96% word accuracy for read speech is reduced to 86% word accuracy for field ATC data for Spanish for the "clearances" task confirming that field data is needed to estimate the performance of a system. A literature review and a critical discussion on the possibilities of speech recognition and understanding technology applied to ATC speech are also given.

Exploring differences between phonetic classes in Sleep Apnoea Syndrome Patients using automatic speech processing techniques

This work is part of an on-going collaborative project between the medical and signal processing communities to promote new research efforts on automatic OSA (Obstructive Apnea Syndrome) diagnosis. In this paper, we explore the differences noted in phonetic classes (interphoneme) across groups (control/apnoea) and analyze their utility for OSA detection

Automatic Adaptation of Airport Surface Surveillance to Sensor Quality

This paper describes a novel method to enhance current airport surveillance systems used in Advanced Surveillance Monitoring Guidance and Control Systems (A-SMGCS). The proposed method allows for the automatic calibration of measurement models and enhanced detection of nonideal situations, increasing surveillance products integrity. It is based on the definition of a set of observables from the surveillance processing chain and a rule based expert system aimed to change the data processing methods

Automatic Inference of Determinacy and Mutual Exclusion for Logic Programs Using Mode and Type Analyses

We propose an analysis for detecting procedures and goals that are deterministic (i.e., that produce at most one solution at most once),or predicates whose clause tests are mutually exclusive (which implies that at most one of their clauses will succeed) even if they are not deterministic. The analysis takes advantage of the pruning operator in order to improve the detection of mutual exclusion and determinacy. It also supports arithmetic equations and disequations, as well as equations and disequations on terms,for which we give a complete satisfiability testing algorithm, w.r.t. available type information. Information about determinacy can be used for program debugging and optimization, resource consumption and granularity control, abstraction carrying code, etc. We have implemented the analysis and integrated it in the CiaoPP system, which also infers automatically the mode and type information that our analysis takes as input. Experiments performed on this implementation show that the analysis is fairly accurate and efficient.

An automatic translation scheme from prolog to the andorra kernel language

The Andorra family of languages (which includes the Andorra Kernel Language -AKL) is aimed, in principie, at simultaneously supporting the programming styles of Prolog and committed choice languages. On the other hand, AKL requires a somewhat detailed specification of control by the user. This could be avoided by programming in Prolog to run on AKL. However, Prolog programs cannot be executed directly on AKL. This is due to a number of factors, from more or less trivial syntactic differences to more involved issues such as the treatment of cut and making the exploitation of certain types of parallelism possible. This paper provides basic guidelines for constructing an automatic compiler of Prolog programs into AKL, which can bridge those differences. In addition to supporting Prolog, our style of translation achieves independent and-parallel execution where possible, which is relevant since this type of parallel execution preserves, through the translation, the user-perceived "complexity" of the original Prolog program.

Automatic parallelization of irregular and pointer-based computations: perspectives from logic and constraint programming

Irregular computations pose some of the most interesting and challenging problems in automatic parallelization. Irregularity appears in certain kinds of numerical problems and is pervasive in symbolic applications. Such computations often use dynamic data structures which make heavy use of pointers. This complicates all the steps of a parallelizing compiler, from independence detection to task partitioning and placement. In the past decade there has been significant progress in the development of parallelizing compilers for logic programming and, more recently, constraint programming. The typical applications of these paradigms frequently involve irregular computations, which arguably makes the techniques used in these compilers potentially interesting. In this paper we introduce in a tutorial way some of the problems faced by parallelizing compilers for logic and constraint programs. These include the need for inter-procedural pointer aliasing analysis for independence detection and having to manage speculative and irregular computations through task granularity control and dynamic task allocation. We also provide pointers to some of the progress made in these áreas. In the associated talk we demónstrate representatives of several generations of these parallelizing compilers.

An automatic translation scheme from CLP to AKL

The Andorra Kernel language scheme was aimed, in principle, at simultaneously supporting the programming styles of Prolog and committed choice languages. Within the constraint programming paradigm, this family of languages could also in principle support the concurrent constraint paradigm. This happens for the Agents Kernel Language (AKL). On the other hand, AKL requires a somewhat detailed specification of control by the user. This could be avoided by programming in CLP to run on AKL. However, CLP programs cannot be executed directly on AKL. This is due to a number of factors, from more or less trivial syntactic differences to more involved issues such as the treatment of cut and making the exploitation of certain types of parallelism possible. This paper provides a translation scheme which is a basis of an automatic compiler of CLP programs into AKL, which can bridge those differences. In addition to supporting CLP, our style of translation achieves independent and-parallel execution where possible, which is relevant since this type of parallel execution preserves, through the translation, the user-perceived "complexity" of the original program.

Advanced predictive quality control strategy involving different facilities

There are many industries that use highly technological solutions to improve quality in all of their products. The steel industry is one example. Several automatic surface-inspection systems are used in the steel industry to identify various types of defects and to help operators decide whether to accept, reroute, or downgrade the material, subject to the assessment process. This paper focuses on promoting a strategy that considers all defects in an integrated fashion. It does this by managing the uncertainty about the exact position of a defect due to different process conditions by means of Gaussian additive influence functions. The relevance of the approach is in making possible consistency and reliability between surface inspection systems. The results obtained are an increase in confidence in the automatic inspection system and an ability to introduce improved prediction and advanced routing models. The prediction is provided to technical operators to help them in their decision-making process. It shows the increase in improvement gained by reducing the 40 % of coils that are downgraded at the hot strip mill because of specific defects. In addition, this technology facilitates an increase of 50 % in the accuracy of the estimate of defect survival after the cleaning facility in comparison to the former approach. The proposed technology is implemented by means of software-based, multi-agent solutions. It makes possible the independent treatment of information, presentation, quality analysis, and other relevant functions.

Improving automatic detection of obstructive sleep apnea through nonlinear analysis of sustained speech

We present a novel approach for the detection of severe obstructive sleep apnea (OSA) based on patients' voices introducing nonlinear measures to describe sustained speech dynamics. Nonlinear features were combined with state-of-the-art speech recognition systems using statistical modeling techniques (Gaussian mixture models, GMMs) over cepstral parameterization (MFCC) for both continuous and sustained speech. Tests were performed on a database including speech records from both severe OSA and control speakers. A 10 % relative reduction in classification error was obtained for sustained speech when combining MFCC-GMM and nonlinear features, and 33 % when fusing nonlinear features with both sustained and continuous MFCC-GMM. Accuracy reached 88.5 % allowing the system to be used in OSA early detection. Tests showed that nonlinear features and MFCCs are lightly correlated on sustained speech, but uncorrelated on continuous speech. Results also suggest the existence of nonlinear effects in OSA patients' voices, which should be found in continuous speech.

A Knowledge Model for Automatic Configuration of Traffic Messages

This paper describes a knowledge model for a configuration problem in the do-main of traffic control. The goal of this model is to help traffic engineers in the dynamic selection of a set of messages to be presented to drivers on variable message signals. This selection is done in a real-time context using data recorded by traffic detectors on motorways. The system follows an advanced knowledge-based solution that implements two abstract problem solving methods according to a model-based approach recently proposed in the knowledge engineering field. Finally, the paper presents a discussion about the advantages and drawbacks found for this problem as a consequence of the applied knowledge modeling ap-proach.