Effects of diet and exercise on metabolic syndrome and the underlying factors = Efectos de la dieta y el ejercicio sobre el síndrome metabólico y sus factores

Introducción. El número de personas que padecen síndrome metabólico ha incrementado a nivel mundial durante las últimas dos décadas. Existen numerosos estudios que tratan de comparar prevalencias según los diferentes criterios y estimaciones del riesgo metabólico. De ellos se puede concluir que el principal hallazgo ha sido recalcar la necesidad de una definición estándar universal. A pesar de estas discrepancias no hay lugar a duda sobre el problema de salud pública que esto conlleva. Se necesitan medidas y estrategias urgentes para prevenir y controlar esta emergente epidemia global y para ello se debe prestar especial atención a los cambios en el estilo de vida, fundamentalmente dieta y ejercicio. A pesar de todo, existe a día de hoy una importante controversia sobre el tipo de ejercicio más efectivo y su combinación con la dieta para conseguir mejoras en la salud. Objetivos. Estudiar los índices de riesgo metabólico empleados en la literatura científica y las terapias basadas en dieta y ejercicio para el tratamiento de los factores del síndrome metabólico en adultos con sobrepeso. Diseño de investigación. Los datos empleados en el análisis de esta tesis son, primeramente un estudio piloto, y posteriormente parte del estudio “Programas de Nutrición y Actividad Física para el tratamiento de la obesidad” (PRONAF). El estudio PRONAF es un proyecto consistente en un estudio clínico sobre programas de nutrición y actividad física para el sobrepeso y la obesidad, desarrollado en España durante varios años de intervenciones. Fue diseñado, en parte, para tratar de comparar protocolos de entrenamiento de resistencia, cargas y combinado en igualdad de volumen e intensidad, con el objetivo de evaluar su impacto en los factores de riesgo y la prevalencia del síndrome metabólico en personas con sobrepeso y obesidad. El diseño experimental es un control aleatorio y el protocolo incluye 3 modos de ejercicio (entrenamiento de resistencia, con cargas y combinado) y restricción dietética sobre diversas variables determinantes del estado de salud. Las principales variables para la investigación que comprende esta tesis fueron: actividad física habitual, marcadores de grasa corporal, niveles de insulina, glucosa, triglicéridos, colesterol total, colesterol HDL, colesterol LDL, presión arterial y parámetros relacionados con el ejercicio. Conclusiones. A) Los índices de riesgo metabólico estudiados presentan resultados contradictorios en relación al riesgo metabólico en un individuo, dependiendo de los métodos matemáticos empleados para el cálculo y de las variables introducidas, tanto en mujeres sanas como en adultos en sobrepeso. B) El protocolo de entrenamiento combinado (de cargas y de resistencia) junto con la dieta equilibrada propuesto en este estudio fue la mejor estrategia para la mejora del riesgo de síndrome metabólico en adultos con sobrepeso. C) Los protocolos de entrenamiento supervisado de resistencia, con cargas y combinado junto con la restricción nutricional, no obtuvieron mejoras sobre el perfil lipídico, más allá de los cambios conseguidos con el protocolo de dieta y recomendaciones generales de actividad física habitual en clínica, en adultos con sobrepeso. Background. Over the past two decades, a striking increase in the number of people with the MetS worldwide has taken place. Many studies compare prevalences using different criteria and metabolic risk estimation formulas, and perhaps their main achievement is to reinforce the need for a standardized international definition. Although these discrepancies, there is no doubt it is a public health problem. There is urgent need for strategies to prevent and manage the emerging global epidemic, special consideration should be given to behavioral and lifestyle, mainly diet and exercise. However, there is still controversy about the most effective type of exercise and diet combination to achieve improvements. Objectives. To study the metabolic risk scores used in the literature and the diet and exercise therapies for the treatment of the MetS factors in overweight adults. Research design. The data used in the analysis was collected firstly in a pilot study and lately, as a part of the “Programas de Nutrición y Actividad física para el tratamiento de la obesidad” study (PRONAF). The PRONAF Study is a clinical research project in nutrition and physical activity programs for overweight and obesity, carried out in Spain (2008-2011). Was designed, in part, to attempt to match the volume and intensity of endurance, strength and combined training protocols in order to evaluate their impact on risk factors and MetS prevalence in overweight and obese people. The design and protocol included three exercise modes (endurance, strength and combined training) and diet restriction, in a randomized controlled trial concerning diverse health status variables. The main variables under investigation were habitual physical activity, markers of body fat, fasting serum levels of insulin, glucose, triglycerides, total, LDL and HDL cholesterol, blood pressure and diet and exercise parameters. Main outcomes. A) The metabolic risk scores studied presented contradictory results in relation to the metabolic risk of an individual, depending on the mathematical method used and the variables included, both in healthy women and overweight adults. B) The protocol proposed for combination of strength and endurance training combined with a balance diet was the optimal strategy for the improvement of MetS risk in overweight adults. C) The intervention program of endurance, strength or combined supervised training protocol with diet restriction did not achieved further improvements in lipid profile than a habitual clinical practice protocol including dietary advice and standard physical activity recommendations, in overweight adults.

Functional, structural and phylogenetic analysis of domains underlying the Al sensitivity of the aluminum-activated malate/anion transporter, TaALMT1.

Triticum aestivum aluminum-activated malate transporter (TaALMT1) is the founding member of a unique gene family of anion transporters (ALMTs) that mediate the efflux of organic acids. A small sub-group of root-localized ALMTs, including TaALMT1, is physiologically associated with in planta aluminum (Al) resistance. TaALMT1 exhibits significant enhancement of transport activity in response to extracellular Al. In this study, we integrated structure–function analyses of structurally altered TaALMT1 proteins expressed in Xenopus oocytes with phylogenic analyses of the ALMT family. Our aim is to re-examine the role of protein domains in terms of their potential involvement in the Al-dependent enhancement (i.e. Al-responsiveness) of TaALMT1 transport activity, as well as the roles of all its 43 negatively charged amino acid residues. Our results indicate that the N-domain, which is predicted to form the conductive pathway, mediates ion transport even in the absence of the C-domain. However, segments in both domains are involved in Al3+ sensing. We identified two regions, one at the N-terminus and a hydrophobic region at the C-terminus, that jointly contribute to the Al-response phenotype. Interestingly, the characteristic motif at the N-terminus appears to be specific for Al-responsive ALMTs. Our study highlights the need to include a comprehensive phylogenetic analysis when drawing inferences from structure–function analyses, as a significant proportion of the functional changes observed for TaALMT1 are most likely the result of alterations in the overall structural integrity of ALMT family proteins rather than modifications of specific sites involved in Al3+ sensing.

Self-organizing cultured neural networks: Image analysis techniques for longitudinal tracking and modeling of the underlying network structure

Esta tesis estudia la evolución estructural de conjuntos de neuronas como la capacidad de auto-organización desde conjuntos de neuronas separadas hasta que forman una red (clusterizada) compleja. Esta tesis contribuye con el diseño e implementación de un algoritmo no supervisado de segmentación basado en grafos con un coste computacional muy bajo. Este algoritmo proporciona de forma automática la estructura completa de la red a partir de imágenes de cultivos neuronales tomadas con microscopios de fase con una resolución muy alta. La estructura de la red es representada mediante un objeto matemático (matriz) cuyos nodos representan a las neuronas o grupos de neuronas y los enlaces son las conexiones reconstruidas entre ellos. Este algoritmo extrae también otras medidas morfológicas importantes que caracterizan a las neuronas y a las neuritas. A diferencia de otros algoritmos hasta el momento, que necesitan de fluorescencia y técnicas inmunocitoquímicas, el algoritmo propuesto permite el estudio longitudinal de forma no invasiva posibilitando el estudio durante la formación de un cultivo. Además, esta tesis, estudia de forma sistemática un grupo de variables topológicas que garantizan la posibilidad de cuantificar e investigar la progresión de las características principales durante el proceso de auto-organización del cultivo. Nuestros resultados muestran la existencia de un estado concreto correspondiente a redes con configuracin small-world y la emergencia de propiedades a micro- y meso-escala de la estructura de la red. Finalmente, identificamos los procesos físicos principales que guían las transformaciones morfológicas de los cultivos y proponemos un modelo de crecimiento de red que reproduce el comportamiento cuantitativamente de las observaciones experimentales. ABSTRACT The thesis analyzes the morphological evolution of assemblies of living neurons, as they self-organize from collections of separated cells into elaborated, clustered, networks. In particular, it contributes with the design and implementation of a graph-based unsupervised segmentation algorithm, having an associated very low computational cost. The processing automatically retrieves the whole network structure from large scale phase-contrast images taken at high resolution throughout the entire life of a cultured neuronal network. The network structure is represented by a mathematical object (a matrix) in which nodes are identified neurons or neurons clusters, and links are the reconstructed connections between them. The algorithm is also able to extract any other relevant morphological information characterizing neurons and neurites. More importantly, and at variance with other segmentation methods that require fluorescence imaging from immunocyto- chemistry techniques, our measures are non invasive and entitle us to carry out a fully longitudinal analysis during the maturation of a single culture. In turn, a systematic statistical analysis of a group of topological observables grants us the possibility of quantifying and tracking the progression of the main networks characteristics during the self-organization process of the culture. Our results point to the existence of a particular state corresponding to a small-world network configuration, in which several relevant graphs micro- and meso-scale properties emerge. Finally, we identify the main physical processes taking place during the cultures morphological transformations, and embed them into a simplified growth model that quantitatively reproduces the overall set of experimental observations.

Self-organizing cultured neural networks: Image analysis techniques for longitudinal tracking and modeling of the underlying network structure (versión actualizada)

Esta tesis estudia la evolución estructural de conjuntos de neuronas como la capacidad de auto-organización desde conjuntos de neuronas separadas hasta que forman una red (clusterizada) compleja. Esta tesis contribuye con el diseño e implementación de un algoritmo no supervisado de segmentación basado en grafos con un coste computacional muy bajo. Este algoritmo proporciona de forma automática la estructura completa de la red a partir de imágenes de cultivos neuronales tomadas con microscopios de fase con una resolución muy alta. La estructura de la red es representada mediante un objeto matemático (matriz) cuyos nodos representan a las neuronas o grupos de neuronas y los enlaces son las conexiones reconstruidas entre ellos. Este algoritmo extrae también otras medidas morfológicas importantes que caracterizan a las neuronas y a las neuritas. A diferencia de otros algoritmos hasta el momento, que necesitan de fluorescencia y técnicas inmunocitoquímicas, el algoritmo propuesto permite el estudio longitudinal de forma no invasiva posibilitando el estudio durante la formación de un cultivo. Además, esta tesis, estudia de forma sistemática un grupo de variables topológicas que garantizan la posibilidad de cuantificar e investigar la progresión de las características principales durante el proceso de auto-organización del cultivo. Nuestros resultados muestran la existencia de un estado concreto correspondiente a redes con configuracin small-world y la emergencia de propiedades a micro- y meso-escala de la estructura de la red. Finalmente, identificamos los procesos físicos principales que guían las transformaciones morfológicas de los cultivos y proponemos un modelo de crecimiento de red que reproduce el comportamiento cuantitativamente de las observaciones experimentales. ABSTRACT The thesis analyzes the morphological evolution of assemblies of living neurons, as they self-organize from collections of separated cells into elaborated, clustered, networks. In particular, it contributes with the design and implementation of a graph-based unsupervised segmentation algorithm, having an associated very low computational cost. The processing automatically retrieves the whole network structure from large scale phase-contrast images taken at high resolution throughout the entire life of a cultured neuronal network. The network structure is represented by a mathematical object (a matrix) in which nodes are identified neurons or neurons clusters, and links are the reconstructed connections between them. The algorithm is also able to extract any other relevant morphological information characterizing neurons and neurites. More importantly, and at variance with other segmentation methods that require fluorescence imaging from immunocyto- chemistry techniques, our measures are non invasive and entitle us to carry out a fully longitudinal analysis during the maturation of a single culture. In turn, a systematic statistical analysis of a group of topological observables grants us the possibility of quantifying and tracking the progression of the main networks characteristics during the self-organization process of the culture. Our results point to the existence of a particular state corresponding to a small-world network configuration, in which several relevant graphs micro- and meso-scale properties emerge. Finally, we identify the main physical processes taking place during the cultures morphological transformations, and embed them into a simplified growth model that quantitatively reproduces the overall set of experimental observations.

Considering cycling for commuting : the role of mode familiarity : an exploration on the (circular) relation between cycling behaviours and attitudes toward cycling in Vitoria-Gasteiz, Spain

¿La gente utiliza la bicicleta porque les gusta? ¿O es el propio hecho de usarla la razón por la que les gusta hacerlo? ¿O es una combinación de las dos? Este tipo de preguntas reflejan un problema que se puede llamar ‘el círculo de la consideración de la bicicleta’: para poder considerar el uso de la bicicleta en el conjunto de posibles opciones a escoger, un individuo tiene que tener creencias positivas sobre ella, sobre todo en el caso de ‘contextos de bajo uso’. Pero parece poco probable que se formen creencias positivas cuando hay bajos niveles de familiaridad al modo, es decir, con un bajo conocimiento de sus características, su funcionamiento y del imaginario asociado; al mismo tiempo, la familiaridad irá alcanzando niveles más altos conforme aumente el tiempo y la intensidad con la que se utilice la bicicleta a lo largo de la vida de los individuos. El problema parece un circulo recursivo huevo-gallina, ya que es difícil que alguien considere el usar la bicicleta en lugares donde su uso es una práctica poco extendida. En estos lugares, y dentro del conglomerado actual de tecnologías, infraestructuras, reglas, prácticas de los usuarios y preferencias culturales que se han desarrollado alrededor del automóvil (el actual "sistema socio-técnico de la movilidad urbana", Urry 2004; Geels 2005, 2012) usar la bicicleta es considerado por la mayoría como algo difícil, inseguro, y anormal. Como consecuencia, los procesos de aumento de familiaridad con la bicicleta permanecen inactivos. La tesis asume la familiaridad como una fuente de información e influencia sobre las creencias positivas sobre la bicicleta. En ‘contextos de bajo uso’, sin familiaridad al uso de la bicicleta, estas creencias sólo pueden surgir de ciertos rasgos personales (afecto, valores, identidades, voluntad, etc.). Tal como han evidenciado investigaciones recientes, en estos contextos la posibilidad de considerar el uso de la bicicleta (y su eventual adopción), se circunscribe principalmente a los ‘entusiastas’, a los que están dispuestos a “ir contra corriente” (Horton & Parkin 2012), limitando el alcance de las políticas de promoción. La investigación llevada a cabo en esta tesis ofrece un nuevo enfoque al problema del ‘círculo de la consideración de la bicicleta’. Para ello, plantea un modelo en el que se introduce a la familiaridad como un constructo que media entre el comportamiento final –qué modo de transporte elige el individuo– y el conjunto de constructos psicosociales que preceden la elección modal (creencias y actitudes). La familiaridad al uso de la bicicleta se concibe como una medida de la intensidad relativa del uso de una bicicleta, real y percibida (basándose en Diana & Mokhtarian 2009) que puede formarse de manera distinta según sus fines (utilitarios o no utilitarios). El constructo familiaridad con el modo bicicleta está relacionado con la cantidad de tiempo, la intensidad y la regularidad con la que un individuo ha hecho uso de la bicicleta a lo largo de su vida. La familiaridad se concibe así como una condición que permite definir adecuadamente el contexto en el que se toman las decisiones modales de los individuos, en línea con investigaciones que postulan patrones de causalidad alternativos entre los procesos cognitivos de elección y los comportamientos modales (Tardif 1977; Dobson et al. 1978; Golob et al. 1979; Golob 2001; Schwanen et al. 2012; Diana et al. 2009; Vij & Walker 2014). De este modo se plantea que el esquema unidireccional actitudesconductas podría no ser completamente valido en el caso de la consideración de la bicicleta, explorando la hipótesis que sean las propias conductas a influenciar la formación de las actitudes. En esta tesis, el constructo de familiaridad se articula teórica y metodológicamente, y se emplea un instrumento de diseño transversal para contrastarlo. Los resultados de una encuesta telefónica a una muestra representativa de 736 personas en la ciudad española de Vitoria-Gasteiz proveen evidencias que sugieren –aunque de forma preliminar– que la familiaridad juega un papel de mediadora en la relación entre la utilización de la bicicleta y la formación de las creencias y actitudes hacia el su uso. La tesis emplea mediciones para cada individuo con respecto tanto a su consideración como a su familiaridad al uso de la bicicleta. Éstas mediciones se definen haciendo uso del análisis factorial exploratorio (AFE). Por un lado, el AFE arroja una estructura del constructo ‘consideración’ formada por cuatro factores, tres de ellos asociados con elementos positivos y uno con elementos negativos: (1) de cómo el uso de la bicicleta se considera verde e inteligente (G&S); (2) sobre su carácter agradable y adecuado (P&S); (3) sobre su eficacia como modo de transporte para ir al trabajo (E); y (4) sobre los principales inconvenientes de su uso, es decir, las dificultades implícitas (sudoración y estar expuestos a las inclemencias del tiempo) y la sensación de inseguridad que genera (sentirse en riesgo de accidentes y estresarse por el tráfico) (D&T). Por otro lado, la familiaridad al uso de la bicicleta se mide en dos distintas variables ordinales (según se base en el uso utilitario o no utilitario). Como resultado, se puede hablar de que cada individuo se encuentra en una de las siguientes cuatro etapas en orden creciente hacia una familiaridad completa al modo: no familiarizados; apenas familiarizados; moderadamente familiarizados; totalmente familiarizados. El análisis de los datos de los cuatro grupos de sujetos de la muestra, –definidos de acuerdo con cada una de las cuatro etapas de familiaridad definidas– ha evidenciado la existencia de diferencias intergrupo estadísticamente significativas, especialmente para la medida relacionada con el uso utilitario. Asimismo, las personas en los niveles inferiores de familiaridad tienen una consideración menor de los aspectos positivos de la bicicleta y por el contrario presentan preocupaciones mayores hacia las características negativas respecto a aquellas personas que están más familiarizados en el uso utilitario. El uso, aunque esporádico, de una bicicleta para fines utilitarios (ir de compras, hacer recados, etc.), a diferencia de no usarla en absoluto, aparece asociado a unas puntuaciones significativamente más altas en los tres factores positivos (G&S, E, P&S), mientras que parece estar asociado a puntuaciones significativamente más bajas en el factor relacionado con las características negativas (D&U). Aparecen resultados similares cuando se compara un uso moderado, con uno esporádico, sobre todo con respecto a la consideración de las características negativas. Los resultados de esta tesis están en línea con la literatura anterior que se ha basado en variables similares (por ejemplo, de Geus et al. 2008; Stinson & Bhat 2003, 2004; Hunt & Abraham 2006; y van Bekkum et al. 2011a, entre otros), pero en este estudio las diferencias se observan en un contexto de bajo uso y se derivan de un análisis de toda la población de personas que se desplazan a su lugar de trabajo o estudio, lo cual eleva la fiabilidad de los resultados. La posibilidad de que unos niveles más altos de uso de la bicicleta para fines utilitarios puedan llevar a niveles más positivos de su consideración abre el camino a implicaciones teóricas y de políticas que se discuten en la tesis. Con estos resultados se argumenta que el enfoque convencional basado en el cambio de actitudes puede no ser el único y prioritario para lograr cambios a la hora de fomentar el uso de la bicicleta. Los resultados apuntan al potencial de otros esquemas de causalidad, basados en patrones de influencia más descentrados y distribuidos, y que adopten una mirada más positiva hacia los hábitos de transporte, conceptualizándolos como “inteligencia encarnada y pre-reflexiva” (Schwanen et al. 2012). Tales esquemas conducen a un enfoque más práctico para la promoción del uso de la bicicleta, con estrategias que podrían basarse en acciones de ‘degustación’ de su uso o de mayor ‘exposición’ a su uso. Is the fact that people like cycling the reason for them to cycle? Or is the fact that they do cycle the reason for them to like cycling? Or is a combination of the two? This kind of questions reflect a problem that can be called ‘the cycle of cycling consideration’: in order to consider cycling in the set of possible options to be chosen, an individual needs to have positive beliefs about it, especially in the case of ‘low-cycling contexts’. However, positive beliefs seem unlikely to be formed with low levels of mode familiarity, say, with a low acquaintance with mode features, functioning and images; at the same time, higher levels of familiarity are likely to be reached if cycling is practised over relative threshold levels of intensities and extensively across individual life courses. The problem looks like a chicken-egg recursive cycle, since the latter condition is hardly met in places where cycling is little practised. In fact, inside the current conglomerate of technologies, infrastructures, regulations, user practices, cultural preferences that have grown around the automobile (the current “socio-technical system of urban mobility”, Urry 2004; Geels 2005, 2012) cycling is commonly considered as difficult, unsafe, and abnormal. Consequently, the processes of familiarity forming remain disabled, and, as a result, beliefs cannot rely on mode familiarity as a source of information and influence. Without cycling familiarity, origins of positive beliefs are supposed to rely only on personal traits (affect, values, identities, willingness, etc.), which, in low-cycling contexts, confine the possibility of cycling consideration (and eventual adoption) mainly to ‘cycling enthusiasts’ who are willing to “go against the grain” (Horton & Parkin 2012), as it results from previous research. New research conducted by author provides theoretical insights for a different approach of the cycling consideration problem in which the presence of the new construct of cycling familiarity is hypothesised in the relationship between mode choice behaviour and the set of psychosocial constructs that are supposed to precede it (beliefs and attitudes). Cycling familiarity is conceived as a measure of the real and the perceived relative intensity of use of a bicycle (building upon Diana & Mokhtarian 2009) which may be differently formed for utilitarian or non-utilitarian purposes. The construct is assumed to be related to the amount of time, the intensity and the regularity an individual spends in using a bicycle for the two distinct categories of purposes, gaining in this way a certain level of acquaintance with the mode. Familiarity with a mode of transport is conceived as an enabling condition to properly define the decision-making context in which individual travel mode choices are taken, in line with rather disperse research efforts postulating inverse relationships between mode behaviours and mode choices (Tardiff 1977; Dobson et al. 1978; Golob et al. 1979; Golob 2001; Schwanen et al. 2012; Diana et al. 2009; Vij & Walker 2014). The new construct is built theoretically and methodologically, and a cross-sectional design instrument is employed. Results from a telephone survey in a representative sample of 736 commuters in the Spanish city of Vitoria-Gasteiz, provide suggestive –although preliminary– evidence on the role of mode familiarity as a mediator in the relationship between cycling use and the formation of beliefs and attitudes toward cycling. Measures of both cycling consideration and cycling familiarity are defined making use of exploratory factor analysis. On the one hand, four distinct cycling consideration measures are created, based on attitude expressions on four underlying factors relating to the cycling commuting behaviour: on how cycling commuting is considered green and smart (G&S); on its pleasant and suited character (P&S); on its efficiency as a mode of transport for commuting (E); and on the main drawbacks of its use, namely the difficulties implied (sweating and being exposed to adverse weather conditions) and the sense of unsafety it generates (feeling at risk of accidents and getting stressed by traffic) (D&U). On the other hand, dimensions of cycling familiarity are measured on two distinct ordinal variables (whether based on the utilitarian or non-utilitarian use) comprising four stages to a complete mode familiarity: not familiar; barely familiar; moderately familiar; fully familiar. For each of the four stages of cycling familiarity defined, statistical significant differences are found, especially for the measure related to the utilitarian use. Consistently, people at the lower levels of cycling familiarity have a lower consideration of the positive aspects of cycling and conversely they exhibit higher concerns towards the negative characteristics than those individuals that are more familiar in utilitarian cycling. Using a bicycle occasionally for practical purposes, as opposed to not using it at all, seems associated to significant higher scores in the three positive factors (G&S, E, P&S) while it appears to be associated to significant lower scores in the factor relating with the negative characteristics of cycling commuting (D&U). A same pattern also occurs with a moderate use, as opposed to an occasional one, especially for the consideration of the negative characteristics. The results are in line with previous literature based on similar variables (e.g. de Geus et al. 2008; Stinson & Bhat 2003, 2004; Hunt & Abraham 2006; and van Bekkum et al. 2011a, among others), but in this study the differences are observed in a low-cycling context and derive from an analysis of the entire population of commuters, which rises the reliability of results.

A group decision-making methodology with incomplete individual beliefs applied to e-Democracy

We consider the situation where there are several alternatives for investing a quantity of money to achieve a set of objectives. The choice of which alternative to apply depends on how citizens and political representatives perceive that such objectives should be achieved. All citizens with the right to vote can express their preferences in the decision-making process. These preferences may be incomplete. Political representatives represent the citizens who have not taken part in the decision-making process. The weight corresponding to political representatives depends on the number of citizens that have intervened in the decision-making process. The methodology we propose needs the participants to specify for each alternative how they rate the different attributes and the relative importance of attributes. On the basis of this information an expected utility interval is output for each alternative. To do this, an evidential reasoning approach is applied. This approach improves the insightfulness and rationality of the decision-making process using a belief decision matrix for problem modeling and the Dempster?Shafer theory of evidence for attribute aggregation. Finally, we propose using the distances of each expected utility interval from the maximum and the minimum utilities to rank the alternative set. The basic idea is that an alternative is ranked first if its distance to the maximum utility is the smallest, and its distance to the minimum utility is the greatest. If only one of these conditions is satisfied, a distance ratio is then used.

The underlying pathway structure of biochemical reaction networks

Bioinformatics is yielding extensive, and in some cases complete, genetic and biochemical information about individual cell types and cellular processes, providing the composition of living cells and the molecular structure of its components. These components together perform integrated cellular functions that now need to be analyzed. In particular, the functional definition of biochemical pathways and their role in the context of the whole cell is lacking. In this study, we show how the mass balance constraints that govern the function of biochemical reaction networks lead to the translation of this problem into the realm of linear algebra. The functional capabilities of biochemical reaction networks, and thus the choices that cells can make, are reflected in the null space of their stoichiometric matrix. The null space is spanned by a finite number of basis vectors. We present an algorithm for the synthesis of a set of basis vectors for spanning the null space of the stoichiometric matrix, in which these basis vectors represent the underlying biochemical pathways that are fundamental to the corresponding biochemical reaction network. In other words, all possible flux distributions achievable by a defined set of biochemical reactions are represented by a linear combination of these basis pathways. These basis pathways thus represent the underlying pathway structure of the defined biochemical reaction network. This development is significant from a fundamental and conceptual standpoint because it yields a holistic definition of biochemical pathways in contrast to definitions that have arisen from the historical development of our knowledge about biochemical processes. Additionally, this new conceptual framework will be important in defining, characterizing, and studying biochemical pathways from the rapidly growing information on cellular function.

Neural systems underlying learning and representation of global motion

We demonstrate performance-related changes in cortical and cerebellar activity. The largest learning-dependent changes were observed in the anterior lateral cerebellum, where the extent and intensity of activation correlated inversely with psychophysical performance. After learning had occurred (a few minutes), the cerebellar activation almost disappeared; however, it was restored when the subjects were presented with a novel, untrained direction of motion for which psychophysical performance also reverted to chance level. Similar reductions in the extent and intensity of brain activations in relation to learning occurred in the superior colliculus, anterior cingulate, and parts of the extrastriate cortex. The motion direction-sensitive middle temporal visual complex was a notable exception, where there was an expansion of the cortical territory activated by the trained stimulus. Together, these results indicate that the learning and representation of visual motion discrimination are mediated by different, but probably interacting, neuronal subsystems.

Mechanisms underlying kainate receptor-mediated disinhibition in the hippocampus

Kainate (KA) receptor activation depresses stimulus-evoked γ-aminobutyric acid (GABA-mediated) synaptic transmission onto CA1 pyramidal cells of the hippocampus and simultaneously increases the frequency of spontaneous GABA release through an increase in interneuronal spiking. To determine whether these two effects are independent, we examined the mechanism by which KA receptor activation depresses the stimulus-evoked, inhibitory postsynaptic current (IPSC). Bath application of the α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)/KA receptor agonist KA in the presence of the AMPA receptor antagonist GYKI 53655 caused a large increase in spontaneous GABA release and a coincident depression of the evoked IPSC. The depressant action on the evoked IPSC was reduced, but not abolished, by the GABAB receptor antagonist SCH 50911, suggesting that the KA-induced increase in spontaneous GABA release depresses the evoked IPSC through activation of presynaptic GABAB receptors. KA had no resolvable effect on the potassium-induced increase in miniature IPSC frequency, suggesting that KA does not act through a direct effect on the release machinery or presynaptic calcium influx. KA caused a decrease in pyramidal cell input resistance, which was reduced by GABAA receptor antagonists. KA also caused a reduction in the size of responses to iontophoretically applied GABA, which was indistinguishable from the SCH 50911-resistant, residual depression of the evoked IPSC. These results suggest that KA receptor activation depresses the evoked IPSC indirectly by increasing interneuronal spiking and GABA release, leading to activation of presynaptic GABAB receptors, which depress GABA release, and postsynaptic GABAA receptors, which increase passive shunting.

Comment on “Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Diseases in Male Mice” and “Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Trends and Scientific Gaps”

Peer reviewed

Neural mechanisms underlying binocular fusion and stereopsis: Position vs. phase

The visual system utilizes binocular disparity to discriminate the relative depth of objects in space. Since the striate cortex is the first site along the central visual pathways at which signals from the left and right eyes converge onto a single neuron, encoding of binocular disparity is thought to begin in this region. There are two possible mechanisms for encoding binocular disparity through simple cells in the striate cortex: a difference in receptive field (RF) position between the two eyes (RF position disparity) and a difference in RF profile between the two eyes (RF phase disparity). Although there have been studies supporting each of the two encoding mechanisms, both mechanisms have not been examined in a single study. Therefore, the relative roles of the two mechanisms have not been determined. To address this issue, we have mapped left and right eye RFs of simple cells in the cat’s striate cortex using binary m-sequence noise, and then we have estimated RF position and phase disparities. We find that RF position disparities are generally limited to small values that are not sufficient to encode large binocular disparities. In contrast, RF phase disparities cover a wide range of binocular disparities and exhibit dependencies on orientation and spatial frequency in a manner expected for a mechanism that encodes binocular disparity. These results indicate that binocular disparity is mainly encoded through RF phase disparity. However, RF position disparity may play a significant role for cells with high spatial frequency selectivity, which are constrained to small RF phase disparities.

The affected gene underlying the class K glycosylphosphatidylinositol (GPI) surface protein defect codes for the GPI transamidase

The final step in glycosylphosphatidylinositol (GPI) anchoring of cell surface proteins consists of a transamidation reaction in which preassembled GPI donors are substituted for C-terminal signal sequences in nascent polypeptides. In previous studies we described a human K562 cell mutant, termed class K, that accumulates fully assembled GPI units but is unable to transfer them to N-terminally processed proproteins. In further work we showed that, unlike wild-type microsomes, microsomes from these cells are unable to support C-terminal interaction of proproteins with the small nucleophiles hydrazine or hydroxylamine, and that the cells thus are defective in transamidation. In this study, using a modified recombinant vaccinia transient transfection system in conjunction with a composite cDNA prepared by 5′ extension of an existing GenBank sequence, we found that the genetic element affected in these cells corresponds to the human homolog of yGPI8, a gene affected in a yeast mutant strain exhibiting similar accumulation of GPI donors without transfer. hGPI8 gives rise to mRNAs of 1.6 and 1.9 kb, both encoding a protein of 395 amino acids that varies in cells with their ability to couple GPIs to proteins. The gene spans ≈25 kb of DNA on chromosome 1. Reconstitution of class K cells with hGPI8 abolishes their accumulation of GPI precursors and restores C-terminal processing of GPI-anchored proteins. Also, hGPI8 restores the ability of microsomes from the mutant cells to yield an active carbonyl in the presence of a proprotein which is considered to be an intermediate in catalysis by a transamidase.

Fundamental patterns underlying gene expression profiles: Simplicity from complexity

Analysis of previously published sets of DNA microarray gene expression data by singular value decomposition has uncovered underlying patterns or “characteristic modes” in their temporal profiles. These patterns contribute unequally to the structure of the expression profiles. Moreover, the essential features of a given set of expression profiles are captured using just a small number of characteristic modes. This leads to the striking conclusion that the transcriptional response of a genome is orchestrated in a few fundamental patterns of gene expression change. These patterns are both simple and robust, dominating the alterations in expression of genes throughout the genome. Moreover, the characteristic modes of gene expression change in response to environmental perturbations are similar in such distant organisms as yeast and human cells. This analysis reveals simple regularities in the seemingly complex transcriptional transitions of diverse cells to new states, and these provide insights into the operation of the underlying genetic networks.

Molecular mechanisms underlying differential odor responses of a mouse olfactory receptor

The prevailing paradigm for G protein-coupled receptors is that each receptor is narrowly tuned to its ligand and closely related agonists. An outstanding problem is whether this paradigm applies to olfactory receptor (ORs), which is the largest gene family in the genome, in which each of 1,000 different G protein-coupled receptors is believed to interact with a range of different odor molecules from the many thousands that comprise “odor space.” Insights into how these interactions occur are essential for understanding the sense of smell. Key questions are: (i) Is there a binding pocket? (ii) Which amino acid residues in the binding pocket contribute to peak affinities? (iii) How do affinities change with changes in agonist structure? To approach these questions, we have combined single-cell PCR results [Malnic, B., Hirono, J., Sato, T. & Buck, L. B. (1999) Cell 96, 713–723] and well-established molecular dynamics methods to model the structure of a specific OR (OR S25) and its interactions with 24 odor compounds. This receptor structure not only points to a likely odor-binding site but also independently predicts the two compounds that experimentally best activate OR S25. The results provide a mechanistic model for olfactory transduction at the molecular level and show how the basic G protein-coupled receptor template is adapted for encoding the enormous odor space. This combined approach can significantly enhance the identification of ligands for the many members of the OR family and also may shed light on other protein families that exhibit broad specificities, such as chemokine receptors and P450 oxidases.