Identification of putative noncoding RNAs among the RIKEN mouse full-length cDNA collection

With the sequencing and annotation of genomes and transcriptomes of several eukaryotes, the importance of noncoding RNA (ncRNA)-RNA molecules that are not translated to protein products-has become more evident. A subclass of ncRNA transcripts are encoded by highly regulated, multi-exon, transcriptional units, are processed like typical protein-coding mRNAs and are increasingly implicated in regulation of many cellular functions in eukaryotes. This study describes the identification of candidate functional ncRNAs from among the RIKEN mouse full-length cDNA collection, which contains 60,770 sequences, by using a systematic computational filtering approach. We initially searched for previously reported ncRNAs and found nine murine ncRNAs and homologs of several previously described nonmouse ncRNAs. Through our computational approach to filter artifact-free clones that lack protein coding potential, we extracted 4280 transcripts as the largest-candidate set. Many clones in the set had EST hits, potential CpG islands surrounding the transcription start sites, and homologies with the human genome. This implies that many candidates are indeed transcribed in a regulated manner. Our results demonstrate that ncRNAs are a major functional subclass of processed transcripts in mammals.

Toward an atomistic understanding of the immune synapse:large-scale molecular dynamics simulation of a membrane-embedded TCR-pMHC-CD4 complex

T-cell activation requires interaction of T-cell receptors (TCR) with peptide epitopes bound by major histocompatibility complex (MHC) proteins. This interaction occurs at a special cell-cell junction known as the immune or immunological synapse. Fluorescence microscopy has shown that the interplay among one agonist peptide-MHC (pMHC), one TCR and one CD4 provides the minimum complexity needed to trigger transient calcium signalling. We describe a computational approach to the study of the immune synapse. Using molecular dynamics simulation, we report here on a study of the smallest viable model, a TCR-pMHC-CD4 complex in a membrane environment. The computed structural and thermodynamic properties are in fair agreement with experiment. A number of biomolecules participate in the formation of the immunological synapse. Multi-scale molecular dynamics simulations may be the best opportunity we have to reach a full understanding of this remarkable supra-macromolecular event at a cell-cell junction.

Sensemaking tools for understanding research literatures:design, implementation and user evaluation

This paper describes the work undertaken in the Scholarly Ontologies Project. The aim of the project has been to develop a computational approach to support scholarly sensemaking, through interpretation and argumentation, enabling researchers to make claims: to describe and debate their view of a document's key contributions and relationships to the literature. The project has investigated the technicalities and practicalities of capturing conceptual relations, within and between conventional documents in terms of abstract ontological structures. In this way, we have developed a new kind of index to distributed digital library systems. This paper reports a case study undertaken to test the sensemaking tools developed by the Scholarly Ontologies project. The tools used were ClaiMapper, which allows the user to sketch argument maps of individual papers and their connections, ClaiMaker, a server on which such models can be stored and saved, which provides interpretative services to assist the querying of argument maps across multiple papers and ClaimFinder, a novice interface to the search services in ClaiMaker.

Quantifying protein folding pathways

A deep understanding of the proteins folding dynamics can be get quantifying folding landscape by calculating how the number of microscopic configurations (entropy) varies with the energy of the chain, Ω=Ω(E). Because of the incredibly large number of microstates available to a protein, direct enumeration of Ω(E) is not possible on realistic computer simulations. An estimate of Ω(E) can be obtained by use of a combination of statistical mechanics and thermodynamics. By combining different definitions of entropy that are valid for a system whose probability for occupying a state is given by the canonical Boltzmann probability, computers allow the determination of Ω(E). ^ The energy landscapes of two similar, but not identical model proteins were studied. One protein contains no kinetic tracks. Results show a smooth funnel for the folding landscape. That allows the contour determination of the folding funnel. Also it was presented results for the folding landscape for a modified protein with kinetic traps. Final results show that the computational approach is able to distinguish and explore regions of the folding landscape that are due to kinetic traps from the native state folding funnel.^

Fermion Mass Generation without Spontaneous Symmetry Breaking

The conventional mechanism of fermion mass generation in the Standard Model involves Spontaneous Symmetry Breaking (SSB). In this thesis, we study an alternate mechanism for the generation of fermion masses that does not require SSB, in the context of lattice field theories. Being inherently strongly coupled, this mechanism requires a non-perturbative approach like the lattice approach.

In order to explore this mechanism, we study a simple lattice model with a four-fermion interaction that has massless fermions at weak couplings and massive fermions at strong couplings, but without any spontaneous symmetry breaking. Prior work on this type of mass generation mechanism in 4D, was done long ago using either mean-field theory or Monte-Carlo calculations on small lattices. In this thesis, we have developed a new computational approach that enables us to perform large scale quantum Monte-Carlo calculations to study the phase structure of this theory. In 4D, our results confirm prior results, but differ in some quantitative details of the phase diagram. In contrast, in 3D, we discover a new second order critical point using calculations on lattices up to size $ 60^3$. Such large scale calculations are unprecedented. The presence of the critical point implies the existence of an alternate mechanism of fermion mass generation without any SSB, that could be of interest in continuum quantum field theory.

Is phraseology the third articulation of language? Fresh insights into a theoretical conundrum

Is phraseology the third articulation of language? Fresh insights into a theoretical conundrum Jean-Pierre Colson University of Louvain (Louvain-la-Neuve, Belgium) Although the notion of phraseology is now used across a wide range of linguistic disciplines, its definition and the classification of phraseological units remain a subject of intense debate. It is generally agreed that phraseology implies polylexicality, but this term is problematic as well, because it brings us back to one of the most controversial topics in modern linguistics: the definition of a word. On the other hand, another widely accepted principle of language is the double articulation or duality of patterning (Martinet 1960): the first articulation consists of morphemes and the second of phonemes. The very definition of morphemes, however, also poses several problems, and the situation becomes even more confused if we wish to take phraseology into account. In this contribution, I will take the view that a corpus-based and computational approach to phraseology may shed some new light on this theoretical conundrum. A better understanding of the basic units of meaning is necessary for more efficient language learning and translation, especially in the case of machine translation. Previous research (Colson 2011, 2012, 2013, 2014), Corpas Pastor (2000, 2007, 2008, 2013, 2015), Corpas Pastor & Leiva Rojo (2011), Leiva Rojo (2013), has shown the paramount importance of phraseology for translation. A tentative step towards a coherent explanation of the role of phraseology in language has been proposed by Mejri (2006): it is postulated that a third articulation of language intervenes at the level of words, including simple morphemes, sequences of free and bound morphemes, but also phraseological units. I will present results from experiments with statistical associations of morphemes across several languages, and point out that (mainly) isolating languages such as Chinese are interesting for a better understanding of the interplay between morphemes and phraseological units. Named entities, in particular, are an extreme example of intertwining cultural, statistical and linguistic elements. Other examples show that the many borrowings and influences that characterize European languages tend to give a somewhat blurred vision of the interplay between morphology and phraseology. From a statistical point of view, the cpr-score (Colson 2016) provides a methodology for adapting the automatic extraction of phraseological units to the morphological structure of each language. The results obtained can therefore be used for testing hypotheses about the interaction between morphology, phraseology and culture. Experiments with the cpr-score on the extraction of Chinese phraseological units show that results depend on how the basic units of meaning are defined: a morpheme-based approach yields good results, which corroborates the claim by Beck and Mel'čuk (2011) that the association of morphemes into words may be similar to the association of words into phraseological units. A cross-linguistic experiment carried out for English, French, Spanish and Chinese also reveals that the results are quite compatible with Mejri’s hypothesis (2006) of a third articulation of language. Such findings, if confirmed, also corroborate the notion of statistical semantics in language. To illustrate this point, I will present the PhraseoRobot (Colson 2016), a computational tool for extracting phraseological associations around key words from the media, such as Brexit. The results confirm a previous study on the term globalization (Colson 2016): a significant part of sociolinguistic associations prevailing in the media is related to phraseology in the broad sense, and can therefore be partly extracted by means of statistical scores. References Beck, D. & I. Mel'čuk (2011). Morphological phrasemes and Totonacan verbal morphology. Linguistics 49/1: 175-228. Colson, J.-P. (2011). La traduction spécialisée basée sur les corpus : une expérience dans le domaine informatique. In : Sfar, I. & S. Mejri, La traduction de textes spécialisés : retour sur des lieux communs. Synergies Tunisie n° 2. Gerflint, Agence universitaire de la Francophonie, p. 115-123. Colson, J.-P. (2012). Traduire le figement en langue de spécialité : une expérience de phraséologie informatique. In : Mogorrón Huerta, P. & S. Mejri (dirs.), Lenguas de especialidad, traducción, fijación / Langues spécialisées, figement et traduction. Encuentros Mediterráneos / Rencontres Méditerranéennes, N°4. Universidad de Alicante, p. 159-171. Colson, J.-P. (2013). Pratique traduisante et idiomaticité : l’importance des structures semi-figées. In : Mogorrón Huerta, P., Gallego Hernández, D., Masseau, P. & Tolosa Igualada, M. (eds.), Fraseología, Opacidad y Traduccíon. Studien zur romanischen Sprachwissenschaft und interkulturellen Kommunikation (Herausgegeben von Gerd Wotjak). Frankfurt am Main, Peter Lang, p. 207-218. Colson, J.-P. (2014). La phraséologie et les corpus dans les recherches traductologiques. Communication lors du colloque international Europhras 2014, Association Européenne de Phraséologie. Université de Paris Sorbonne, 10-12 septembre 2014. Colson, J-P. (2016). Set phrases around globalization : an experiment in corpus-based computational phraseology. In: F. Alonso Almeida, I. Ortega Barrera, E. Quintana Toledo and M. Sánchez Cuervo (eds.), Input a Word, Analyse the World: Selected Approaches to Corpus Linguistics. Newcastle upon Tyne: Cambridge Scholars Publishing, p. 141-152. Corpas Pastor, G. (2000). Acerca de la (in)traducibilidad de la fraseología. In: G. Corpas Pastor (ed.), Las lenguas de Europa: Estudios de fraseología, fraseografía y traducción. Granada: Comares, p. 483-522. Corpas Pastor, G. (2007). Europäismen - von Natur aus phraseologische Äquivalente? Von blauem Blut und sangre azul. In: M. Emsel y J. Cuartero Otal (eds.), Brücken: Übersetzen und interkulturelle Kommunikationen. Festschrift für Gerd Wotjak zum 65. Geburtstag, Fráncfort: Peter Lang, p. 65-77. Corpas Pastor, G. (2008). Investigar con corpus en traducción: los retos de un nuevo paradigma [Studien zur romanische Sprachwissenschaft und interkulturellen Kommunikation, 49], Fráncfort: Peter Lang. Corpas Pastor, G. (2013). Detección, descripción y contraste de las unidades fraseológicas mediante tecnologías lingüísticas. In Olza, I. & R. Elvira Manero (eds.) Fraseopragmática. Berlin: Frank & Timme, p. 335-373. Leiva Rojo, J. (2013). La traducción de unidades fraseológicas (alemán-español/español-alemán) como parámetro para la evaluación y revisión de traducciones. In: Mellado Blanco, C., Buján, P, Iglesias N.M., Losada M.C. & A. Mansilla (eds), La fraseología del alemán y el español: lexicografía y traducción. ELS, Etudes Linguistiques / Linguistische Studien, Band 11. München: Peniope, p. 31-42. Leiva Rojo, J. & G. Corpas Pastor (2011). Placing Italian idioms in a foreign milieu: a case study. In: Pamies Bertrán, A., Luque Nadal, L., Bretana, J. &; M. Pazos (eds), (2011). Multilingual phraseography. Second Language Learning and Translation Applications. Baltmannsweiler: Schneider Verlag (Colección: Phraseologie und Parömiologie, 28), p. 289-298. Martinet, A. (1966). Eléments de linguistique générale. Paris: Colin. Mejri, S. (2006). Polylexicalité, monolexicalité et double articulation. Cahiers de Lexicologie 2: 209-221.

Meshfree Method for Prediction of Thermal Properties of Porous Ceramic Materials

In the presented thesis work, meshfree method with distance fields is applied to create a novel computational approach which enables inclusion of the realistic geometric models of the microstructure and liberates Finite Element Analysis(FEA) from thedependance on and limitations of meshing of fine microstructural feature such as splats and porosity.Manufacturing processes of ceramics produce materials with complex porosity microstructure.Geometry of pores, their size and location substantially affect macro scale physical properties of the material. Complex structure and geometry of the pores severely limit application of modern Finite Element Analysis methods because they require construction of spatial grids (meshes) that conform to the geometric shape of the structure. As a result, there are virtually no effective tools available for predicting overall mechanical and thermal properties of porous materials based on their microstructure. This thesis is a separate handling and controls of geometric and physical computational models that are seamlessly combined at solution run time. Using the proposedapproach we will determine the effective thermal conductivity tensor of real porous ceramic materials featuring both isotropic and anisotropic thermal properties. This work involved development and implementation of numerical algorithms, data structure, and software.

Chest Breadths to Predict Individuals' Age - A Case Based View

It is well known that rib cage dimensions depend on the gender and vary with the age of the individual. Under this setting it is therefore possible to assume that a computational approach to the problem may be thought out and, consequently, this work will focus on the development of an Artificial Intelligence grounded decision support system to predict individual’s age, based on such measurements. On the one hand, using some basic image processing techniques it were extracted such descriptions from chest X-rays (i.e., its maximum width and height). On the other hand, the computational framework was built on top of a Logic Programming Case Base approach to knowledge representation and reasoning, which caters for the handling of incomplete, unknown, or even contradictory information. Furthermore, clustering methods based on similarity analysis among cases were used to distinguish and aggregate collections of historical data in order to reduce the search space, therefore enhancing the cases retrieval and the overall computational process. The accuracy of the proposed model is satisfactory, close to 90%.

Methods for objective and interpretative evaluation of function and motor control: gait in perturbed condition and in the aquatic therapy

Gait analysis allows to characterize motor function, highlighting deviations from normal motor behavior related to an underlying pathology. The widespread use of wearable inertial sensors has opened the way to the evaluation of ecological gait, and a variety of methodological approaches and algorithms have been proposed for the characterization of gait from inertial measures (e.g. for temporal parameters, motor stability and variability, specific pathological alterations). However, no comparative analysis of their performance (i.e. accuracy, repeatability) was available yet, in particular, analysing how this performance is affected by extrinsic (i.e. sensor location, computational approach, analysed variable, testing environmental constraints) and intrinsic (i.e. functional alterations resulting from pathology) factors. The aim of the present project was to comparatively analyze the influence of intrinsic and extrinsic factors on the performance of the numerous algorithms proposed in the literature for the quantification of specific characteristics (i.e. timing, variability/stability) and alterations (i.e. freezing) of gait. Considering extrinsic factors, the influence of sensor location, analyzed variable, and computational approach on the performance of a selection of gait segmentation algorithms from a literature review was analysed in different environmental conditions (e.g. solid ground, sand, in water). Moreover, the influence of altered environmental conditions (i.e. in water) was analyzed as referred to the minimum number of stride necessary to obtain reliable estimates of gait variability and stability metrics, integrating what already available in the literature for over ground gait in healthy subjects. Considering intrinsic factors, the influence of specific pathological conditions (i.e. Parkinson’s Disease) was analyzed as affecting the performance of segmentation algorithms, with and without freezing. Finally, the analysis of the performance of algorithms for the detection of gait freezing showed how results depend on the domain of implementation and IMU position.

Synthesis and characterization of novel selective NKCC1 inhibitors for the treatment of down syndrome and brain disorders characterized by depolarizing GABAergic transmission.

Proper GABAergic transmission through Cl-permeable GABAA receptors is fundamental for physiological brain development and function. Indeed, defective GABAergic signaling – due to a high NKCC1/KCC2 expression ratio – has been implicated in several neurodevelopmental disorders (e.g., Down syndrome, DS, Autism spectrum disorders, ASD). Interestingly, NKCC1 inhibition by the FDA-approved diuretic drug bumetanide reverts cognitive deficits in the TS65Dn mouse models of DS and core symptoms in other models of brain disorders. However, the required chronic treatment with bumetanide is burdened by its diuretic side effects caused by the antagonization of the kidney Cl importer NKCC2. This may lead to hypokalemia, while jeopardizing drug compliance. Crucially, these issues would be solved by selective NKCC1 inhibitors, thus devoid of the diuretic effect of bumetanide. To this aim, starting from bumetanide’s structure, we applied a ligand-based computational approach to design new molecular entities that we tested in vitro for their capacity to selectively block NKCC1. Extensive synthetic efforts and structure-activity relationships analyses allowed us to improve in vitro potency and overall drug-like properties of the initially identified chemical hits. As a result, we identified a new highly potent NKCC1 inhibitor (ARN23746) that displayed excellent solubility, metabolic stability, and no significant effect on NKCC2 in vitro. Moreover, this novel and selective NKCC1 inhibitor was able to rescue cognitive deficits in DS mice and social/repetitive behaviors in ASD mice, with no diuretic effect and no overt toxicity upon chronic treatment in adult animals. Thus, ARN23746 a selective NKCC1 inhibitor devoid of the diuretic effect – represents a suitable and solid therapeutic strategy for the treatment of Down syndrome and all the brain neurological disorders characterized by depolarizing GABAergic transmission.

Distributed argumentation technology: advancing risk analysis and regulatory compliance of distributed ledger technologies for transaction and management of securities

Distributed argumentation technology is a computational approach incorporating argumentation reasoning mechanisms within multi-agent systems. For the formal foundations of distributed argumentation technology, in this thesis we conduct a principle-based analysis of structured argumentation as well as abstract multi-agent and abstract bipolar argumentation. The results of the principle-based approach of these theories provide an overview and guideline for further applications of the theories. Moreover, in this thesis we explore distributed argumentation technology using distributed ledgers. We envision an Intelligent Human-input-based Blockchain Oracle (IHiBO), an artificial intelligence tool for storing argumentation reasoning. We propose a decentralized and secure architecture for conducting decision-making, addressing key concerns of trust, transparency, and immutability. We model fund management with agent argumentation in IHiBO and analyze its compliance with European fund management legal frameworks. We illustrate how bipolar argumentation balances pros and cons in legal reasoning in a legal divorce case, and how the strength of arguments in natural language can be represented in structured arguments. Finally, we discuss how distributed argumentation technology can be used to advance risk management, regulatory compliance of distributed ledgers for financial securities, and dialogue techniques.

A computational and geometric approach to phase resetting curves and surfaces

"Vegeu el resum a l'inici del document del fitxer adjunt."

Opportunities for a cultural specific approach in the computational description of music

The current research in Music Information Retrieval (MIR) is showing the potential that the Information Technologies can have in music related applications. Amajor research challenge in that direction is how to automaticallydescribe/annotate audio recordings and how to use the resulting descriptions to discover and appreciate music in new ways. But music is a complex phenomenonand the description of an audio recording has to deal with this complexity. For example, each musicculture has specificities and emphasizes different musicaland communication aspects, thus the musical recordings of each culture should be described differently. At the same time these cultural specificities give us the opportunity to pay attention to musical concepts andfacets that, despite being present in most world musics, are not easily noticed by listeners. In this paper we present some of the work done in the CompMusic project, including ideas and specific examples on how to take advantage of the cultural specificities of differentmusical repertoires. We will use examples from the art music traditions of India, Turkey and China.

A combined computational and functional approach identifies new residues involved in pH-dependent gating of ASIC1a.

Acid-sensing ion channels (ASICs) are key receptors for extracellular protons. These neuronal nonvoltage-gated Na(+) channels are involved in learning, the expression of fear, neurodegeneration after ischemia, and pain sensation. We have applied a systematic approach to identify potential pH sensors in ASIC1a and to elucidate the mechanisms by which pH variations govern ASIC gating. We first calculated the pK(a) value of all extracellular His, Glu, and Asp residues using a Poisson-Boltzmann continuum approach, based on the ASIC three-dimensional structure, to identify candidate pH-sensing residues. The role of these residues was then assessed by site-directed mutagenesis and chemical modification, combined with functional analysis. The localization of putative pH-sensing residues suggests that pH changes control ASIC gating by protonation/deprotonation of many residues per subunit in different channel domains. Analysis of the function of residues in the palm domain close to the central vertical axis of the channel allowed for prediction of conformational changes of this region during gating. Our study provides a basis for the intrinsic ASIC pH dependence and describes an approach that can also be applied to the investigation of the mechanisms of the pH dependence of other proteins.

Modular non-computational-connectionist-hybrid neural network approach to robotic systems

Spiking neural networks are usually limited in their applications due to their complex mathematical models and the lack of intuitive learning algorithms. In this paper, a simpler, novel neural network derived from a leaky integrate and fire neuron model, the ‘cavalcade’ neuron, is presented. A simulation for the neural network has been developed and two basic learning algorithms implemented within the environment. These algorithms successfully learn some basic temporal and instantaneous problems. Inspiration for neural network structures from these experiments are then taken and applied to process sensor information so as to successfully control a mobile robot.