Anatomical organization of the memory underlying sensitization in the siphon-withdrawal reflex circuit of {\it Aplysia californica}

Previous studies have shown that short-term sensitization of the Aplysia siphon-withdrawal reflex circuit results in multiple sites of change in synaptic efficacy. In this dissertation I have used a realistic modeling approach (using an integrate-and-fire scheme), in conjunction with electrophysiological experiments, to evaluate the contribution of each site of plasticity to the sensitized response.^ This dissertation contains a detailed description of methodology for the construction of the model circuit, consisting of the LFS motor neurons and ten interneurons known to convey excitatory input to them. The model replicates closely the natural motor neuron firing response to a brief tactile stimulus.^ The various circuit elements have different roles for producing circuit output. For example, the sensory connections onto the motor neuron are important for the production of the phasic response, while the polysynaptic interneuronal connections are important for producing the tonic response.^ The multiple sites of plasticity that produce changes in circuit output also have specialized roles. Presynaptic facilitation of the sensory neuron to LFS connection enhances only the phasic component of the motor neuron firing response. The sensory neuron to interneuron connections primarily enhance the tonic component of the motor neuron firing response. Also, the L29 posttetanic potentiation and the L30 presynaptic inhibition primarily enhance the tonic component of the motor neuron firing response. Finally, the information content at the various sites of plasticity can shift with changes in stimulus intensity. This suggests that while the sites of plasticity encoding memory are fixed, the information content at these sites can be dynamic, shifting in anatomical location with changes in the intensity of the test stimulus.^ These sites of plasticity also produce specific changes in the behavioral response. Sensory-LFS plasticity selectively increases the amplitude of the behavioral response, and has no effect on the duration of the behavioral response. Interneuronal plasticity (L29 and L30) affects both the amplitude and duration of the behavioral response. Other sensory plasticity also affect both the amplitude and duration of the behavioral response, presumably by increasing the recruitment of the interneurons, which provide all of the effect on duration of the behavioral response. ^

Long-term synaptic facilitation of tail sensorimotor connections in {\it Aplysia\/}

Long-term sensitization in Aplysia is a well studied model for the examination of the cellular and molecules mechanisms of long-term memory. Several lines of evidence suggest long-term sensitization is mediated at least partially by long-term synaptic facilitation between the sensory and motor neurons. The sensitization training and one of its analogues, serotonin (5-HT), can induce long-term facilitation. In this study, another analogue to long-term sensitization training has been developed. Stimulation of peripheral nerves of pleural-pedal ganglia preparation induced long-term facilitation at both 24 hr and 48 hr. This is the first report that long-term facilitation in Aplysia persists for more than 24 hr, which is consistent with the observation that long-term sensitization lasts for more than one day. Thus, the data support the hypothesis that long-term facilitation is an important mechanism for long-term sensitization.^ One of the major differences between short-term and long-term facilitation is that long-term facilitation requires protein synthesis. Therefore, the effects of anisomycin, a protein synthesis inhibitor, on long-term facilitation was examined. Long-term facilitation induced by nerve stimulation was inhibited by 2 $\mu$M anisomycin, which inhibits $\sim$90% of protein synthesis. Nevertheless, at higher concentration (20 $\mu$M), anisomycin induced long-term facilitation by itself, which raises an interesting question about the function of anisomycin other than protein synthesis inhibition.^ Since protein synthesis is critical for long-term facilitation, a major goal is to identify and functionally characterize the molecules whose mRNA levels are altered during the formation of long-term facilitation. Behavioral training or its analogues (nerve stimulation and 5-HT) increases the level of mRNA of calmodulin (CaM). Thus, the role of Ca$\sp{2+}$-CaM-dependent protein kinase II (CaMKII), a major substrate of CaM, in long-term facilitation induced by nerve stimulation was examined. KN-62, a specific CaMKII inhibitor, did not block either the induction or the maintenance of long-term facilitation induced by nerve stimulation. These data indicate that CaMKII may not be involved in long-term facilitation. Another protein whose mRNA level of a molecule was increased by the behavioral training and the treatment of 5-HT is Aplysia tolloid/BMP-1-like protein 1 (apTBL-1). Tolloid in Drosophila and BMP-1 in human tissues are believed to be secreted as a metalloprotease to activate TGF-$\beta.$ Thus, the long-term effects of recombinant human TGF-$\beta1$ on synaptic strength were examined. Treatment of ganglia with TGF-$\beta1$ produced long-term facilitation, but not short-term or intermediate-term facilitation ($\le$4 hr). In addition, TGF-$\beta1$ and 5-HT were not additive in producing long-term facilitation, which indicates an interaction between two cascades. Moreover, 5-HT-induced facilitation (at both 24 hr and 48 hr) and nerve stimulation-induced facilitation (at 24 hr) were inhibited by TGF-$\beta$ sRII, a TGF-$\beta$ inhibitor. These results suggest that TGF-$\beta$ is part of the cascade of events underlying long-term sensitization, and also indicate that a signaling molecule used in development may also have functions in adult neuronal plasticity. ^

Steady streaming in a two-dimensional box model of a passive cochlea

Acoustic stimulation of the cochlea leads to a travelling wave in the cochlear fluids and on the basilar membrane (BM). It has long been suspected that this travelling wave leads to a steady streaming flow in the cochlea. Theoretical investigations suggested that the steady streaming might be of physiological relevance. Here, we present a quantitative study of the steady streaming in a computational model of a passive cochlea. The structure of the streaming flow is illustrated and the sources of streaming are closely investigated. We describe a source of streaming which has not been considered in the cochlea by previous authors. This source is also related to a steady axial displacement of the BM which leads to a local stretching of this compliant structure. We present theoretical predictions for the streaming intensity which account for these new phenomena. It is shown that these predictions compare well with our numerical results and that there may be steady streaming velocities of the order of millimetres per second. Our results indicate that steady streaming should be more relevant to low-frequency hearing because the strength of the streaming flow rapidly decreases for higher frequencies.

Application of a computational model for complex fluvial ecosystems: The population dynamics of zebra mussel Dreissena polymorpha as a case study

The potential and adaptive flexibility of population dynamic P-systems (PDP) to study population dynamics suggests that they may be suitable for modelling complex fluvial ecosystems, characterized by a composition of dynamic habitats with many variables that interact simultaneously. Using as a model a reservoir occupied by the zebra mussel Dreissena polymorpha, we designed a computational model based on P systems to study the population dynamics of larvae, in order to evaluate management actions to control or eradicate this invasive species. The population dynamics of this species was simulated under different scenarios ranging from the absence of water flow change to a weekly variation with different flow rates, to the actual hydrodynamic situation of an intermediate flow rate. Our results show that PDP models can be very useful tools to model complex, partially desynchronized, processes that work in parallel. This allows the study of complex hydroecological processes such as the one presented, where reproductive cycles, temperature and water dynamics are involved in the desynchronization of the population dynamics both, within areas and among them. The results obtained may be useful in the management of other reservoirs with similar hydrodynamic situations in which the presence of this invasive species has been documented.

A numerical model for inert gas transport in the lung based on fractal airway morphology

Patients suffering from cystic fibrosis (CF) show thick secretions, mucus plugging and bronchiectasis in bronchial and alveolar ducts. This results in substantial structural changes of the airway morphology and heterogeneous ventilation. Disease progression and treatment effects are monitored by so-called gas washout tests, where the change in concentration of an inert gas is measured over a single or multiple breaths. The result of the tests based on the profile of the measured concentration is a marker for the severity of the ventilation inhomogeneity strongly affected by the airway morphology. However, it is hard to localize underlying obstructions to specific parts of the airways, especially if occurring in the lung periphery. In order to support the analysis of lung function tests (e.g. multi-breath washout), we developed a numerical model of the entire airway tree, coupling a lumped parameter model for the lung ventilation with a 4th-order accurate finite difference model of a 1D advection-diffusion equation for the transport of an inert gas. The boundary conditions for the flow problem comprise the pressure and flow profile at the mouth, which is typically known from clinical washout tests. The natural asymmetry of the lung morphology is approximated by a generic, fractal, asymmetric branching scheme which we applied for the conducting airways. A conducting airway ends when its dimension falls below a predefined limit. A model acinus is then connected to each terminal airway. The morphology of an acinus unit comprises a network of expandable cells. A regional, linear constitutive law describes the pressure-volume relation between the pleural gap and the acinus. The cyclic expansion (breathing) of each acinus unit depends on the resistance of the feeding airway and on the flow resistance and stiffness of the cells themselves. Special care was taken in the development of a conservative numerical scheme for the gas transport across bifurcations, handling spatially and temporally varying advective and diffusive fluxes over a wide range of scales. Implicit time integration was applied to account for the numerical stiffness resulting from the discretized transport equation. Local or regional modification of the airway dimension, resistance or tissue stiffness are introduced to mimic pathological airway restrictions typical for CF. This leads to a more heterogeneous ventilation of the model lung. As a result the concentration in some distal parts of the lung model remains increased for a longer duration. The inert gas concentration at the mouth towards the end of the expirations is composed of gas from regions with very different washout efficiency. This results in a steeper slope of the corresponding part of the washout profile.

Loss of Nogo-A-expressing neurons in a rat model of Parkinson's disease

The myelin-associated protein Nogo-A is among the most potent neurite growth inhibitors in the adult CNS. Recently, Nogo-A expression was demonstrated in a number of neuronal subpopulations of the adult and developing CNS but at present, little is known about the expression of Nogo-A in the nigrostriatal system, a brain structure severely affected in Parkinson's disease (PD). The present study sought to characterize the expression pattern of Nogo-A immunoreactive (ir) cells in the adult ventral mesencephalon of control rats and in the 6-hydroxydopamine (6-OHDA) rat model of PD. Immunohistochemical analyses of normal adult rat brain showed a distinct expression of Nogo-A in the ventral mesencephalon, with the highest level in the substantia nigra pars compacta (SNc) where it co-localized with dopaminergic neurons. Analyses conducted 1week and 1 month after unilateral striatal injections of 6-OHDA disclosed a severe loss of the number of Nogo-A-ir cells in the SNc. Notably, at 1week after treatment, more dopaminergic neurons expressing Nogo-A were affected by the 6-OHDA toxicity than Nogo-A-negative dopaminergic neurons. However, at later time points more of the surviving dopaminergic neurons expressed Nogo-A. In the striatum, both small and large Nogo-A-positive cells were detected. The large cells were identified as cholinergic interneurons. Our results suggest yet unidentified functions of Nogo-A in the CNS beyond the inhibition of axonal regeneration and plasticity, and may indicate a role for Nogo-A in PD.

The Effects of Credit Risk on Dynamic Portfolio Management: A New Computational Approach

The study investigates the role of credit risk in a continuous time stochastic asset allocation model, since the traditional dynamic framework does not provide credit risk flexibility. The general model of the study extends the traditional dynamic efficiency framework by explicitly deriving the optimal value function for the infinite horizon stochastic control problem via a weighted volatility measure of market and credit risk. The model's optimal strategy was then compared to that obtained from a benchmark Markowitz-type dynamic optimization framework to determine which specification adequately reflects the optimal terminal investment returns and strategy under credit and market risks. The paper shows that an investor's optimal terminal return is lower than typically indicated under the traditional mean-variance framework during periods of elevated credit risk. Hence I conclude that, while the traditional dynamic mean-variance approach may indicate the ideal, in the presence of credit-risk it does not accurately reflect the observed optimal returns, terminal wealth and portfolio selection strategies.

Dynamic chanel model LMS updating for RSS-based localization

Received signal strength-based localization systems usually rely on a calibration process that aims at characterizing the propagation channel. However, due to the changing environmental dynamics, the behavior of the channel may change after some time, thus, recalibration processes are necessary to maintain the positioning accuracy. This paper proposes a dynamic calibration method to initially calibrate and subsequently update the parameters of the propagation channel model using a Least Mean Squares approach. The method assumes that each anchor node in the localization infrastructure is characterized by its own propagation channel model. In practice, a set of sniffers is used to collect RSS samples, which will be used to automatically calibrate each channel model by iteratively minimizing the positioning error. The proposed method is validated through numerical simulation, showing that the positioning error of the mobile nodes is effectively reduced. Furthermore, the method has a very low computational cost; therefore it can be used in real-time operation for wireless resource-constrained nodes.

Hybrid Approach Combining Machine Learning and a Rule-Based Expert System for Text Categorization

This paper discusses a novel hybrid approach for text categorization that combines a machine learning algorithm, which provides a base model trained with a labeled corpus, with a rule-based expert system, which is used to improve the results provided by the previous classifier, by filtering false positives and dealing with false negatives. The main advantage is that the system can be easily fine-tuned by adding specific rules for those noisy or conflicting categories that have not been successfully trained. We also describe an implementation based on k-Nearest Neighbor and a simple rule language to express lists of positive, negative and relevant (multiword) terms appearing in the input text. The system is evaluated in several scenarios, including the popular Reuters-21578 news corpus for comparison to other approaches, and categorization using IPTC metadata, EUROVOC thesaurus and others. Results show that this approach achieves a precision that is comparable to top ranked methods, with the added value that it does not require a demanding human expert workload to train

OntoTag - A Linguistic and Ontological Annotation Model Suitable for the Semantic Web

OntoTag - A Linguistic and Ontological Annotation Model Suitable for the Semantic Web 1. INTRODUCTION. LINGUISTIC TOOLS AND ANNOTATIONS: THEIR LIGHTS AND SHADOWS Computational Linguistics is already a consolidated research area. It builds upon the results of other two major ones, namely Linguistics and Computer Science and Engineering, and it aims at developing computational models of human language (or natural language, as it is termed in this area). Possibly, its most well-known applications are the different tools developed so far for processing human language, such as machine translation systems and speech recognizers or dictation programs. These tools for processing human language are commonly referred to as linguistic tools. Apart from the examples mentioned above, there are also other types of linguistic tools that perhaps are not so well-known, but on which most of the other applications of Computational Linguistics are built. These other types of linguistic tools comprise POS taggers, natural language parsers and semantic taggers, amongst others. All of them can be termed linguistic annotation tools. Linguistic annotation tools are important assets. In fact, POS and semantic taggers (and, to a lesser extent, also natural language parsers) have become critical resources for the computer applications that process natural language. Hence, any computer application that has to analyse a text automatically and ‘intelligently’ will include at least a module for POS tagging. The more an application needs to ‘understand’ the meaning of the text it processes, the more linguistic tools and/or modules it will incorporate and integrate. However, linguistic annotation tools have still some limitations, which can be summarised as follows: 1. Normally, they perform annotations only at a certain linguistic level (that is, Morphology, Syntax, Semantics, etc.). 2. They usually introduce a certain rate of errors and ambiguities when tagging. This error rate ranges from 10 percent up to 50 percent of the units annotated for unrestricted, general texts. 3. Their annotations are most frequently formulated in terms of an annotation schema designed and implemented ad hoc. A priori, it seems that the interoperation and the integration of several linguistic tools into an appropriate software architecture could most likely solve the limitations stated in (1). Besides, integrating several linguistic annotation tools and making them interoperate could also minimise the limitation stated in (2). Nevertheless, in the latter case, all these tools should produce annotations for a common level, which would have to be combined in order to correct their corresponding errors and inaccuracies. Yet, the limitation stated in (3) prevents both types of integration and interoperation from being easily achieved. In addition, most high-level annotation tools rely on other lower-level annotation tools and their outputs to generate their own ones. For example, sense-tagging tools (operating at the semantic level) often use POS taggers (operating at a lower level, i.e., the morphosyntactic) to identify the grammatical category of the word or lexical unit they are annotating. Accordingly, if a faulty or inaccurate low-level annotation tool is to be used by other higher-level one in its process, the errors and inaccuracies of the former should be minimised in advance. Otherwise, these errors and inaccuracies would be transferred to (and even magnified in) the annotations of the high-level annotation tool. Therefore, it would be quite useful to find a way to (i) correct or, at least, reduce the errors and the inaccuracies of lower-level linguistic tools; (ii) unify the annotation schemas of different linguistic annotation tools or, more generally speaking, make these tools (as well as their annotations) interoperate. Clearly, solving (i) and (ii) should ease the automatic annotation of web pages by means of linguistic tools, and their transformation into Semantic Web pages (Berners-Lee, Hendler and Lassila, 2001). Yet, as stated above, (ii) is a type of interoperability problem. There again, ontologies (Gruber, 1993; Borst, 1997) have been successfully applied thus far to solve several interoperability problems. Hence, ontologies should help solve also the problems and limitations of linguistic annotation tools aforementioned. Thus, to summarise, the main aim of the present work was to combine somehow these separated approaches, mechanisms and tools for annotation from Linguistics and Ontological Engineering (and the Semantic Web) in a sort of hybrid (linguistic and ontological) annotation model, suitable for both areas. This hybrid (semantic) annotation model should (a) benefit from the advances, models, techniques, mechanisms and tools of these two areas; (b) minimise (and even solve, when possible) some of the problems found in each of them; and (c) be suitable for the Semantic Web. The concrete goals that helped attain this aim are presented in the following section. 2. GOALS OF THE PRESENT WORK As mentioned above, the main goal of this work was to specify a hybrid (that is, linguistically-motivated and ontology-based) model of annotation suitable for the Semantic Web (i.e. it had to produce a semantic annotation of web page contents). This entailed that the tags included in the annotations of the model had to (1) represent linguistic concepts (or linguistic categories, as they are termed in ISO/DCR (2008)), in order for this model to be linguistically-motivated; (2) be ontological terms (i.e., use an ontological vocabulary), in order for the model to be ontology-based; and (3) be structured (linked) as a collection of ontology-based triples, as in the usual Semantic Web languages (namely RDF(S) and OWL), in order for the model to be considered suitable for the Semantic Web. Besides, to be useful for the Semantic Web, this model should provide a way to automate the annotation of web pages. As for the present work, this requirement involved reusing the linguistic annotation tools purchased by the OEG research group (http://www.oeg-upm.net), but solving beforehand (or, at least, minimising) some of their limitations. Therefore, this model had to minimise these limitations by means of the integration of several linguistic annotation tools into a common architecture. Since this integration required the interoperation of tools and their annotations, ontologies were proposed as the main technological component to make them effectively interoperate. From the very beginning, it seemed that the formalisation of the elements and the knowledge underlying linguistic annotations within an appropriate set of ontologies would be a great step forward towards the formulation of such a model (henceforth referred to as OntoTag). Obviously, first, to combine the results of the linguistic annotation tools that operated at the same level, their annotation schemas had to be unified (or, preferably, standardised) in advance. This entailed the unification (id. standardisation) of their tags (both their representation and their meaning), and their format or syntax. Second, to merge the results of the linguistic annotation tools operating at different levels, their respective annotation schemas had to be (a) made interoperable and (b) integrated. And third, in order for the resulting annotations to suit the Semantic Web, they had to be specified by means of an ontology-based vocabulary, and structured by means of ontology-based triples, as hinted above. Therefore, a new annotation scheme had to be devised, based both on ontologies and on this type of triples, which allowed for the combination and the integration of the annotations of any set of linguistic annotation tools. This annotation scheme was considered a fundamental part of the model proposed here, and its development was, accordingly, another major objective of the present work. All these goals, aims and objectives could be re-stated more clearly as follows: Goal 1: Development of a set of ontologies for the formalisation of the linguistic knowledge relating linguistic annotation. Sub-goal 1.1: Ontological formalisation of the EAGLES (1996a; 1996b) de facto standards for morphosyntactic and syntactic annotation, in a way that helps respect the it, Attribute, Value> triple structure recommended for annotations in these works (which is isomorphic to the triple structures used in the context of the Semantic Web). Sub-goal 1.2: Incorporation into this preliminary ontological formalisation of other existing standards and standard proposals relating the levels mentioned above, such as those currently under development within ISO/TC 37 (the ISO Technical Committee dealing with Terminology, which deals also with linguistic resources and annotations). Sub-goal 1.3: Generalisation and extension of the recommendations in EAGLES (1996a; 1996b) and ISO/TC 37 to the semantic level, for which no ISO/TC 37 standards have been developed yet. Sub-goal 1.4: Ontological formalisation of the generalisations and/or extensions obtained in the previous sub-goal as generalisations and/or extensions of the corresponding ontology (or ontologies). Sub-goal 1.5: Ontological formalisation of the knowledge required to link, combine and unite the knowledge represented in the previously developed ontology (or ontologies). Goal 2: Development of OntoTag’s annotation scheme, a standard-based abstract scheme for the hybrid (linguistically-motivated and ontological-based) annotation of texts. Sub-goal 2.1: Development of the standard-based morphosyntactic annotation level of OntoTag’s scheme. This level should include, and possibly extend, the recommendations of EAGLES (1996a) and also the recommendations included in the ISO/MAF (2008) standard draft. Sub-goal 2.2: Development of the standard-based syntactic annotation level of the hybrid abstract scheme. This level should include, and possibly extend, the recommendations of EAGLES (1996b) and the ISO/SynAF (2010) standard draft. Sub-goal 2.3: Development of the standard-based semantic annotation level of OntoTag’s (abstract) scheme. Sub-goal 2.4: Development of the mechanisms for a convenient integration of the three annotation levels already mentioned. These mechanisms should take into account the recommendations included in the ISO/LAF (2009) standard draft. Goal 3: Design of OntoTag’s (abstract) annotation architecture, an abstract architecture for the hybrid (semantic) annotation of texts (i) that facilitates the integration and interoperation of different linguistic annotation tools, and (ii) whose results comply with OntoTag’s annotation scheme. Sub-goal 3.1: Specification of the decanting processes that allow for the classification and separation, according to their corresponding levels, of the results of the linguistic tools annotating at several different levels. Sub-goal 3.2: Specification of the standardisation processes that allow (a) complying with the standardisation requirements of OntoTag’s annotation scheme, as well as (b) combining the results of those linguistic tools that share some level of annotation. Sub-goal 3.3: Specification of the merging processes that allow for the combination of the output annotations and the interoperation of those linguistic tools that share some level of annotation. Sub-goal 3.4: Specification of the merge processes that allow for the integration of the results and the interoperation of those tools performing their annotations at different levels. Goal 4: Generation of OntoTagger’s schema, a concrete instance of OntoTag’s abstract scheme for a concrete set of linguistic annotations. These linguistic annotations result from the tools and the resources available in the research group, namely • Bitext’s DataLexica (http://www.bitext.com/EN/datalexica.asp), • LACELL’s (POS) tagger (http://www.um.es/grupos/grupo-lacell/quees.php), • Connexor’s FDG (http://www.connexor.eu/technology/machinese/glossary/fdg/), and • EuroWordNet (Vossen et al., 1998). This schema should help evaluate OntoTag’s underlying hypotheses, stated below. Consequently, it should implement, at least, those levels of the abstract scheme dealing with the annotations of the set of tools considered in this implementation. This includes the morphosyntactic, the syntactic and the semantic levels. Goal 5: Implementation of OntoTagger’s configuration, a concrete instance of OntoTag’s abstract architecture for this set of linguistic tools and annotations. This configuration (1) had to use the schema generated in the previous goal; and (2) should help support or refute the hypotheses of this work as well (see the next section). Sub-goal 5.1: Implementation of the decanting processes that facilitate the classification and separation of the results of those linguistic resources that provide annotations at several different levels (on the one hand, LACELL’s tagger operates at the morphosyntactic level and, minimally, also at the semantic level; on the other hand, FDG operates at the morphosyntactic and the syntactic levels and, minimally, at the semantic level as well). Sub-goal 5.2: Implementation of the standardisation processes that allow (i) specifying the results of those linguistic tools that share some level of annotation according to the requirements of OntoTagger’s schema, as well as (ii) combining these shared level results. In particular, all the tools selected perform morphosyntactic annotations and they had to be conveniently combined by means of these processes. Sub-goal 5.3: Implementation of the merging processes that allow for the combination (and possibly the improvement) of the annotations and the interoperation of the tools that share some level of annotation (in particular, those relating the morphosyntactic level, as in the previous sub-goal). Sub-goal 5.4: Implementation of the merging processes that allow for the integration of the different standardised and combined annotations aforementioned, relating all the levels considered. Sub-goal 5.5: Improvement of the semantic level of this configuration by adding a named entity recognition, (sub-)classification and annotation subsystem, which also uses the named entities annotated to populate a domain ontology, in order to provide a concrete application of the present work in the two areas involved (the Semantic Web and Corpus Linguistics). 3. MAIN RESULTS: ASSESSMENT OF ONTOTAG’S UNDERLYING HYPOTHESES The model developed in the present thesis tries to shed some light on (i) whether linguistic annotation tools can effectively interoperate; (ii) whether their results can be combined and integrated; and, if they can, (iii) how they can, respectively, interoperate and be combined and integrated. Accordingly, several hypotheses had to be supported (or rejected) by the development of the OntoTag model and OntoTagger (its implementation). The hypotheses underlying OntoTag are surveyed below. Only one of the hypotheses (H.6) was rejected; the other five could be confirmed. H.1 The annotations of different levels (or layers) can be integrated into a sort of overall, comprehensive, multilayer and multilevel annotation, so that their elements can complement and refer to each other. • CONFIRMED by the development of: o OntoTag’s annotation scheme, o OntoTag’s annotation architecture, o OntoTagger’s (XML, RDF, OWL) annotation schemas, o OntoTagger’s configuration. H.2 Tool-dependent annotations can be mapped onto a sort of tool-independent annotations and, thus, can be standardised. • CONFIRMED by means of the standardisation phase incorporated into OntoTag and OntoTagger for the annotations yielded by the tools. H.3 Standardisation should ease: H.3.1: The interoperation of linguistic tools. H.3.2: The comparison, combination (at the same level and layer) and integration (at different levels or layers) of annotations. • H.3 was CONFIRMED by means of the development of OntoTagger’s ontology-based configuration: o Interoperation, comparison, combination and integration of the annotations of three different linguistic tools (Connexor’s FDG, Bitext’s DataLexica and LACELL’s tagger); o Integration of EuroWordNet-based, domain-ontology-based and named entity annotations at the semantic level. o Integration of morphosyntactic, syntactic and semantic annotations. H.4 Ontologies and Semantic Web technologies (can) play a crucial role in the standardisation of linguistic annotations, by providing consensual vocabularies and standardised formats for annotation (e.g., RDF triples). • CONFIRMED by means of the development of OntoTagger’s RDF-triple-based annotation schemas. H.5 The rate of errors introduced by a linguistic tool at a given level, when annotating, can be reduced automatically by contrasting and combining its results with the ones coming from other tools, operating at the same level. However, these other tools might be built following a different technological (stochastic vs. rule-based, for example) or theoretical (dependency vs. HPS-grammar-based, for instance) approach. • CONFIRMED by the results yielded by the evaluation of OntoTagger. H.6 Each linguistic level can be managed and annotated independently. • REJECTED: OntoTagger’s experiments and the dependencies observed among the morphosyntactic annotations, and between them and the syntactic annotations. In fact, Hypothesis H.6 was already rejected when OntoTag’s ontologies were developed. We observed then that several linguistic units stand on an interface between levels, belonging thereby to both of them (such as morphosyntactic units, which belong to both the morphological level and the syntactic level). Therefore, the annotations of these levels overlap and cannot be handled independently when merged into a unique multileveled annotation. 4. OTHER MAIN RESULTS AND CONTRIBUTIONS First, interoperability is a hot topic for both the linguistic annotation community and the whole Computer Science field. The specification (and implementation) of OntoTag’s architecture for the combination and integration of linguistic (annotation) tools and annotations by means of ontologies shows a way to make these different linguistic annotation tools and annotations interoperate in practice. Second, as mentioned above, the elements involved in linguistic annotation were formalised in a set (or network) of ontologies (OntoTag’s linguistic ontologies). • On the one hand, OntoTag’s network of ontologies consists of − The Linguistic Unit Ontology (LUO), which includes a mostly hierarchical formalisation of the different types of linguistic elements (i.e., units) identifiable in a written text; − The Linguistic Attribute Ontology (LAO), which includes also a mostly hierarchical formalisation of the different types of features that characterise the linguistic units included in the LUO; − The Linguistic Value Ontology (LVO), which includes the corresponding formalisation of the different values that the attributes in the LAO can take; − The OIO (OntoTag’s Integration Ontology), which  Includes the knowledge required to link, combine and unite the knowledge represented in the LUO, the LAO and the LVO;  Can be viewed as a knowledge representation ontology that describes the most elementary vocabulary used in the area of annotation. • On the other hand, OntoTag’s ontologies incorporate the knowledge included in the different standards and recommendations for linguistic annotation released so far, such as those developed within the EAGLES and the SIMPLE European projects or by the ISO/TC 37 committee: − As far as morphosyntactic annotations are concerned, OntoTag’s ontologies formalise the terms in the EAGLES (1996a) recommendations and their corresponding terms within the ISO Morphosyntactic Annotation Framework (ISO/MAF, 2008) standard; − As for syntactic annotations, OntoTag’s ontologies incorporate the terms in the EAGLES (1996b) recommendations and their corresponding terms within the ISO Syntactic Annotation Framework (ISO/SynAF, 2010) standard draft; − Regarding semantic annotations, OntoTag’s ontologies generalise and extend the recommendations in EAGLES (1996a; 1996b) and, since no stable standards or standard drafts have been released for semantic annotation by ISO/TC 37 yet, they incorporate the terms in SIMPLE (2000) instead; − The terms coming from all these recommendations and standards were supplemented by those within the ISO Data Category Registry (ISO/DCR, 2008) and also of the ISO Linguistic Annotation Framework (ISO/LAF, 2009) standard draft when developing OntoTag’s ontologies. Third, we showed that the combination of the results of tools annotating at the same level can yield better results (both in precision and in recall) than each tool separately. In particular, 1. OntoTagger clearly outperformed two of the tools integrated into its configuration, namely DataLexica and FDG in all the combination sub-phases in which they overlapped (i.e. POS tagging, lemma annotation and morphological feature annotation). As far as the remaining tool is concerned, i.e. LACELL’s tagger, it was also outperformed by OntoTagger in POS tagging and lemma annotation, and it did not behave better than OntoTagger in the morphological feature annotation layer. 2. As an immediate result, this implies that a) This type of combination architecture configurations can be applied in order to improve significantly the accuracy of linguistic annotations; and b) Concerning the morphosyntactic level, this could be regarded as a way of constructing more robust and more accurate POS tagging systems. Fourth, Semantic Web annotations are usually performed by humans or else by machine learning systems. Both of them leave much to be desired: the former, with respect to their annotation rate; the latter, with respect to their (average) precision and recall. In this work, we showed how linguistic tools can be wrapped in order to annotate automatically Semantic Web pages using ontologies. This entails their fast, robust and accurate semantic annotation. As a way of example, as mentioned in Sub-goal 5.5, we developed a particular OntoTagger module for the recognition, classification and labelling of named entities, according to the MUC and ACE tagsets (Chinchor, 1997; Doddington et al., 2004). These tagsets were further specified by means of a domain ontology, namely the Cinema Named Entities Ontology (CNEO). This module was applied to the automatic annotation of ten different web pages containing cinema reviews (that is, around 5000 words). In addition, the named entities annotated with this module were also labelled as instances (or individuals) of the classes included in the CNEO and, then, were used to populate this domain ontology. • The statistical results obtained from the evaluation of this particular module of OntoTagger can be summarised as follows. On the one hand, as far as recall (R) is concerned, (R.1) the lowest value was 76,40% (for file 7); (R.2) the highest value was 97, 50% (for file 3); and (R.3) the average value was 88,73%. On the other hand, as far as the precision rate (P) is concerned, (P.1) its minimum was 93,75% (for file 4); (R.2) its maximum was 100% (for files 1, 5, 7, 8, 9, and 10); and (R.3) its average value was 98,99%. • These results, which apply to the tasks of named entity annotation and ontology population, are extraordinary good for both of them. They can be explained on the basis of the high accuracy of the annotations provided by OntoTagger at the lower levels (mainly at the morphosyntactic level). However, they should be conveniently qualified, since they might be too domain- and/or language-dependent. It should be further experimented how our approach works in a different domain or a different language, such as French, English, or German. • In any case, the results of this application of Human Language Technologies to Ontology Population (and, accordingly, to Ontological Engineering) seem very promising and encouraging in order for these two areas to collaborate and complement each other in the area of semantic annotation. Fifth, as shown in the State of the Art of this work, there are different approaches and models for the semantic annotation of texts, but all of them focus on a particular view of the semantic level. Clearly, all these approaches and models should be integrated in order to bear a coherent and joint semantic annotation level. OntoTag shows how (i) these semantic annotation layers could be integrated together; and (ii) they could be integrated with the annotations associated to other annotation levels. Sixth, we identified some recommendations, best practices and lessons learned for annotation standardisation, interoperation and merge. They show how standardisation (via ontologies, in this case) enables the combination, integration and interoperation of different linguistic tools and their annotations into a multilayered (or multileveled) linguistic annotation, which is one of the hot topics in the area of Linguistic Annotation. And last but not least, OntoTag’s annotation scheme and OntoTagger’s annotation schemas show a way to formalise and annotate coherently and uniformly the different units and features associated to the different levels and layers of linguistic annotation. This is a great scientific step ahead towards the global standardisation of this area, which is the aim of ISO/TC 37 (in particular, Subcommittee 4, dealing with the standardisation of linguistic annotations and resources).

WWW Programming using computational logic systems (and the PiLLoW/Ciao library)

We discuss from a practical point of view a number of issues involved in writing Internet and WWW applications using LP/CLP systems. We describe Pd_l_oW, a public-domain Internet and WWW programming library for LP/CLP systems which we argüe significantly simplifies the process of writing such applications. Pd_l_oW provides facilities for generating HTML structured documents, producing HTML forms, writing form handlers, accessing and parsing WWW documents, and accessing code posted at HTTP addresses. We also describe the architecture of some application classes, using a high-level model of client-server interaction, active modules. We then propose an architecture for automatic LP/CLP code downloading for local execution, using generic browsers. Finally, we also provide an overview of related work on the topic. The PiLLoW library has been developed in the context of the &- Prolog and CIAO systems, but it has been adapted to a number of popular LP/CLP systems, supporting most of its functionality.

The PiLLoW/Ciao library for INTERNET/WWW programming using computational logic systems

We discuss from a practical point of view a number of issues involved in writing Internet and WWW applications using LP/CLP systems. We describe PiLLoW, an Internet and WWW programming library for LP/CLP systems which we argüe significantly simplifies the process of writing such applications. PiLLoW provides facilities for generating HTML structured documents, producing HTML forms, writing form handlers, accessing and parsing WWW documents, and accessing code posted at HTTP addresses. We also describe the architecture of some application classes, using a high-level model of client-server interaction, active modules. Finally we describe an architecture for automatic LP/CLP code downloading for local execution, using generic browsers. The PiLLoW library has been developed in the context of the &-Prolog and CIAO systems, but it has been adapted to a number of popular LP/CLP systems, supporting most of its functionality.

Semi-supervised subspace clustering and applications to neuroscience

Machine learning techniques are used for extracting valuable knowledge from data. Nowa¬days, these techniques are becoming even more important due to the evolution in data ac¬quisition and storage, which is leading to data with different characteristics that must be exploited. Therefore, advances in data collection must be accompanied with advances in machine learning techniques to solve new challenges that might arise, on both academic and real applications. There are several machine learning techniques depending on both data characteristics and purpose. Unsupervised classification or clustering is one of the most known techniques when data lack of supervision (unlabeled data) and the aim is to discover data groups (clusters) according to their similarity. On the other hand, supervised classification needs data with supervision (labeled data) and its aim is to make predictions about labels of new data. The presence of data labels is a very important characteristic that guides not only the learning task but also other related tasks such as validation. When only some of the available data are labeled whereas the others remain unlabeled (partially labeled data), neither clustering nor supervised classification can be used. This scenario, which is becoming common nowadays because of labeling process ignorance or cost, is tackled with semi-supervised learning techniques. This thesis focuses on the branch of semi-supervised learning closest to clustering, i.e., to discover clusters using available labels as support to guide and improve the clustering process. Another important data characteristic, different from the presence of data labels, is the relevance or not of data features. Data are characterized by features, but it is possible that not all of them are relevant, or equally relevant, for the learning process. A recent clustering tendency, related to data relevance and called subspace clustering, claims that different clusters might be described by different feature subsets. This differs from traditional solutions to data relevance problem, where a single feature subset (usually the complete set of original features) is found and used to perform the clustering process. The proximity of this work to clustering leads to the first goal of this thesis. As commented above, clustering validation is a difficult task due to the absence of data labels. Although there are many indices that can be used to assess the quality of clustering solutions, these validations depend on clustering algorithms and data characteristics. Hence, in the first goal three known clustering algorithms are used to cluster data with outliers and noise, to critically study how some of the most known validation indices behave. The main goal of this work is however to combine semi-supervised clustering with subspace clustering to obtain clustering solutions that can be correctly validated by using either known indices or expert opinions. Two different algorithms are proposed from different points of view to discover clusters characterized by different subspaces. For the first algorithm, available data labels are used for searching for subspaces firstly, before searching for clusters. This algorithm assigns each instance to only one cluster (hard clustering) and is based on mapping known labels to subspaces using supervised classification techniques. Subspaces are then used to find clusters using traditional clustering techniques. The second algorithm uses available data labels to search for subspaces and clusters at the same time in an iterative process. This algorithm assigns each instance to each cluster based on a membership probability (soft clustering) and is based on integrating known labels and the search for subspaces into a model-based clustering approach. The different proposals are tested using different real and synthetic databases, and comparisons to other methods are also included when appropriate. Finally, as an example of real and current application, different machine learning tech¬niques, including one of the proposals of this work (the most sophisticated one) are applied to a task of one of the most challenging biological problems nowadays, the human brain model¬ing. Specifically, expert neuroscientists do not agree with a neuron classification for the brain cortex, which makes impossible not only any modeling attempt but also the day-to-day work without a common way to name neurons. Therefore, machine learning techniques may help to get an accepted solution to this problem, which can be an important milestone for future research in neuroscience. Resumen Las técnicas de aprendizaje automático se usan para extraer información valiosa de datos. Hoy en día, la importancia de estas técnicas está siendo incluso mayor, debido a que la evolución en la adquisición y almacenamiento de datos está llevando a datos con diferentes características que deben ser explotadas. Por lo tanto, los avances en la recolección de datos deben ir ligados a avances en las técnicas de aprendizaje automático para resolver nuevos retos que pueden aparecer, tanto en aplicaciones académicas como reales. Existen varias técnicas de aprendizaje automático dependiendo de las características de los datos y del propósito. La clasificación no supervisada o clustering es una de las técnicas más conocidas cuando los datos carecen de supervisión (datos sin etiqueta), siendo el objetivo descubrir nuevos grupos (agrupaciones) dependiendo de la similitud de los datos. Por otra parte, la clasificación supervisada necesita datos con supervisión (datos etiquetados) y su objetivo es realizar predicciones sobre las etiquetas de nuevos datos. La presencia de las etiquetas es una característica muy importante que guía no solo el aprendizaje sino también otras tareas relacionadas como la validación. Cuando solo algunos de los datos disponibles están etiquetados, mientras que el resto permanece sin etiqueta (datos parcialmente etiquetados), ni el clustering ni la clasificación supervisada se pueden utilizar. Este escenario, que está llegando a ser común hoy en día debido a la ignorancia o el coste del proceso de etiquetado, es abordado utilizando técnicas de aprendizaje semi-supervisadas. Esta tesis trata la rama del aprendizaje semi-supervisado más cercana al clustering, es decir, descubrir agrupaciones utilizando las etiquetas disponibles como apoyo para guiar y mejorar el proceso de clustering. Otra característica importante de los datos, distinta de la presencia de etiquetas, es la relevancia o no de los atributos de los datos. Los datos se caracterizan por atributos, pero es posible que no todos ellos sean relevantes, o igualmente relevantes, para el proceso de aprendizaje. Una tendencia reciente en clustering, relacionada con la relevancia de los datos y llamada clustering en subespacios, afirma que agrupaciones diferentes pueden estar descritas por subconjuntos de atributos diferentes. Esto difiere de las soluciones tradicionales para el problema de la relevancia de los datos, en las que se busca un único subconjunto de atributos (normalmente el conjunto original de atributos) y se utiliza para realizar el proceso de clustering. La cercanía de este trabajo con el clustering lleva al primer objetivo de la tesis. Como se ha comentado previamente, la validación en clustering es una tarea difícil debido a la ausencia de etiquetas. Aunque existen muchos índices que pueden usarse para evaluar la calidad de las soluciones de clustering, estas validaciones dependen de los algoritmos de clustering utilizados y de las características de los datos. Por lo tanto, en el primer objetivo tres conocidos algoritmos se usan para agrupar datos con valores atípicos y ruido para estudiar de forma crítica cómo se comportan algunos de los índices de validación más conocidos. El objetivo principal de este trabajo sin embargo es combinar clustering semi-supervisado con clustering en subespacios para obtener soluciones de clustering que puedan ser validadas de forma correcta utilizando índices conocidos u opiniones expertas. Se proponen dos algoritmos desde dos puntos de vista diferentes para descubrir agrupaciones caracterizadas por diferentes subespacios. Para el primer algoritmo, las etiquetas disponibles se usan para bus¬car en primer lugar los subespacios antes de buscar las agrupaciones. Este algoritmo asigna cada instancia a un único cluster (hard clustering) y se basa en mapear las etiquetas cono-cidas a subespacios utilizando técnicas de clasificación supervisada. El segundo algoritmo utiliza las etiquetas disponibles para buscar de forma simultánea los subespacios y las agru¬paciones en un proceso iterativo. Este algoritmo asigna cada instancia a cada cluster con una probabilidad de pertenencia (soft clustering) y se basa en integrar las etiquetas conocidas y la búsqueda en subespacios dentro de clustering basado en modelos. Las propuestas son probadas utilizando diferentes bases de datos reales y sintéticas, incluyendo comparaciones con otros métodos cuando resulten apropiadas. Finalmente, a modo de ejemplo de una aplicación real y actual, se aplican diferentes técnicas de aprendizaje automático, incluyendo una de las propuestas de este trabajo (la más sofisticada) a una tarea de uno de los problemas biológicos más desafiantes hoy en día, el modelado del cerebro humano. Específicamente, expertos neurocientíficos no se ponen de acuerdo en una clasificación de neuronas para la corteza cerebral, lo que imposibilita no sólo cualquier intento de modelado sino también el trabajo del día a día al no tener una forma estándar de llamar a las neuronas. Por lo tanto, las técnicas de aprendizaje automático pueden ayudar a conseguir una solución aceptada para este problema, lo cual puede ser un importante hito para investigaciones futuras en neurociencia.

Computational methods to create and analyze a digital gene expression atlas of embryo development from microscopy images

Abstract The creation of atlases, or digital models where information from different subjects can be combined, is a field of increasing interest in biomedical imaging. When a single image does not contain enough information to appropriately describe the organism under study, it is then necessary to acquire images of several individuals, each of them containing complementary data with respect to the rest of the components in the cohort. This approach allows creating digital prototypes, ranging from anatomical atlases of human patients and organs, obtained for instance from Magnetic Resonance Imaging, to gene expression cartographies of embryo development, typically achieved from Light Microscopy. Within such context, in this PhD Thesis we propose, develop and validate new dedicated image processing methodologies that, based on image registration techniques, bring information from multiple individuals into alignment within a single digital atlas model. We also elaborate a dedicated software visualization platform to explore the resulting wealth of multi-dimensional data and novel analysis algo-rithms to automatically mine the generated resource in search of bio¬logical insights. In particular, this work focuses on gene expression data from developing zebrafish embryos imaged at the cellular resolution level with Two-Photon Laser Scanning Microscopy. Disposing of quantitative measurements relating multiple gene expressions to cell position and their evolution in time is a fundamental prerequisite to understand embryogenesis multi-scale processes. However, the number of gene expressions that can be simultaneously stained in one acquisition is limited due to optical and labeling constraints. These limitations motivate the implementation of atlasing strategies that can recreate a virtual gene expression multiplex. The developed computational tools have been tested in two different scenarios. The first one is the early zebrafish embryogenesis where the resulting atlas constitutes a link between the phenotype and the genotype at the cellular level. The second one is the late zebrafish brain where the resulting atlas allows studies relating gene expression to brain regionalization and neurogenesis. The proposed computational frameworks have been adapted to the requirements of both scenarios, such as the integration of partial views of the embryo into a whole embryo model with cellular resolution or the registration of anatom¬ical traits with deformable transformation models non-dependent on any specific labeling. The software implementation of the atlas generation tool (Match-IT) and the visualization platform (Atlas-IT) together with the gene expression atlas resources developed in this Thesis are to be made freely available to the scientific community. Lastly, a novel proof-of-concept experiment integrates for the first time 3D gene expression atlas resources with cell lineages extracted from live embryos, opening up the door to correlate genetic and cellular spatio-temporal dynamics. La creación de atlas, o modelos digitales, donde la información de distintos sujetos puede ser combinada, es un campo de creciente interés en imagen biomédica. Cuando una sola imagen no contiene suficientes datos como para describir apropiadamente el organismo objeto de estudio, se hace necesario adquirir imágenes de varios individuos, cada una de las cuales contiene información complementaria respecto al resto de componentes del grupo. De este modo, es posible crear prototipos digitales, que pueden ir desde atlas anatómicos de órganos y pacientes humanos, adquiridos por ejemplo mediante Resonancia Magnética, hasta cartografías de la expresión genética del desarrollo de embrionario, típicamente adquiridas mediante Microscopía Optica. Dentro de este contexto, en esta Tesis Doctoral se introducen, desarrollan y validan nuevos métodos de procesado de imagen que, basándose en técnicas de registro de imagen, son capaces de alinear imágenes y datos provenientes de múltiples individuos en un solo atlas digital. Además, se ha elaborado una plataforma de visualization específicamente diseñada para explorar la gran cantidad de datos, caracterizados por su multi-dimensionalidad, que resulta de estos métodos. Asimismo, se han propuesto novedosos algoritmos de análisis y minería de datos que permiten inspeccionar automáticamente los atlas generados en busca de conclusiones biológicas significativas. En particular, este trabajo se centra en datos de expresión genética del desarrollo embrionario del pez cebra, adquiridos mediante Microscopía dos fotones con resolución celular. Disponer de medidas cuantitativas que relacionen estas expresiones genéticas con las posiciones celulares y su evolución en el tiempo es un prerrequisito fundamental para comprender los procesos multi-escala característicos de la morfogénesis. Sin embargo, el número de expresiones genéticos que pueden ser simultáneamente etiquetados en una sola adquisición es reducido debido a limitaciones tanto ópticas como del etiquetado. Estas limitaciones requieren la implementación de estrategias de creación de atlas que puedan recrear un multiplexado virtual de expresiones genéticas. Las herramientas computacionales desarrolladas han sido validadas en dos escenarios distintos. El primer escenario es el desarrollo embrionario temprano del pez cebra, donde el atlas resultante permite constituir un vínculo, a nivel celular, entre el fenotipo y el genotipo de este organismo modelo. El segundo escenario corresponde a estadios tardíos del desarrollo del cerebro del pez cebra, donde el atlas resultante permite relacionar expresiones genéticas con la regionalización del cerebro y la formación de neuronas. La plataforma computacional desarrollada ha sido adaptada a los requisitos y retos planteados en ambos escenarios, como la integración, a resolución celular, de vistas parciales dentro de un modelo consistente en un embrión completo, o el alineamiento entre estructuras de referencia anatómica equivalentes, logrado mediante el uso de modelos de transformación deformables que no requieren ningún marcador específico. Está previsto poner a disposición de la comunidad científica tanto la herramienta de generación de atlas (Match-IT), como su plataforma de visualización (Atlas-IT), así como las bases de datos de expresión genética creadas a partir de estas herramientas. Por último, dentro de la presente Tesis Doctoral, se ha incluido una prueba conceptual innovadora que permite integrar los mencionados atlas de expresión genética tridimensionales dentro del linaje celular extraído de una adquisición in vivo de un embrión. Esta prueba conceptual abre la puerta a la posibilidad de correlar, por primera vez, las dinámicas espacio-temporales de genes y células.

An approach to automatic learning assessment based on the computational theory of perceptions

E-learning systems output a huge quantity of data on a learning process. However, it takes a lot of specialist human resources to manually process these data and generate an assessment report. Additionally, for formative assessment, the report should state the attainment level of the learning goals defined by the instructor. This paper describes the use of the granular linguistic model of a phenomenon (GLMP) to model the assessment of the learning process and implement the automated generation of an assessment report. GLMP is based on fuzzy logic and the computational theory of perceptions. This technique is useful for implementing complex assessment criteria using inference systems based on linguistic rules. Apart from the grade, the model also generates a detailed natural language progress report on the achieved proficiency level, based exclusively on the objective data gathered from correct and incorrect responses. This is illustrated by applying the model to the assessment of Dijkstra’s algorithm learning using a visual simulation-based graph algorithm learning environment, called GRAPHs