Identifying quantitative operation principles in metabolic pathways: a systematic method for searching feasible enzyme activity patterns leading to cellular adaptive responses

Background: Optimization methods allow designing changes in a system so that specific goals are attained. These techniques are fundamental for metabolic engineering. However, they are not directly applicable for investigating the evolution of metabolic adaptation to environmental changes. Although biological systems have evolved by natural selection and result in well-adapted systems, we can hardly expect that actual metabolic processes are at the theoretical optimum that could result from an optimization analysis. More likely, natural systems are to be found in a feasible region compatible with global physiological requirements. Results: We first present a new method for globally optimizing nonlinear models of metabolic pathways that are based on the Generalized Mass Action (GMA) representation. The optimization task is posed as a nonconvex nonlinear programming (NLP) problem that is solved by an outer- approximation algorithm. This method relies on solving iteratively reduced NLP slave subproblems and mixed-integer linear programming (MILP) master problems that provide valid upper and lower bounds, respectively, on the global solution to the original NLP. The capabilities of this method are illustrated through its application to the anaerobic fermentation pathway in Saccharomyces cerevisiae. We next introduce a method to identify the feasibility parametric regions that allow a system to meet a set of physiological constraints that can be represented in mathematical terms through algebraic equations. This technique is based on applying the outer-approximation based algorithm iteratively over a reduced search space in order to identify regions that contain feasible solutions to the problem and discard others in which no feasible solution exists. As an example, we characterize the feasible enzyme activity changes that are compatible with an appropriate adaptive response of yeast Saccharomyces cerevisiae to heat shock Conclusion: Our results show the utility of the suggested approach for investigating the evolution of adaptive responses to environmental changes. The proposed method can be used in other important applications such as the evaluation of parameter changes that are compatible with health and disease states.

Evolution based on domain combinations: the case of glutaredoxins

Background: Protein domains represent the basic units in the evolution of proteins. Domain duplication and shuffling by recombination and fusion, followed by divergence are the most common mechanisms in this process. Such domain fusion and recombination events are predicted to occur only once for a given multidomain architecture. However, other scenarios may be relevant in the evolution of specific proteins, such as convergent evolution of multidomain architectures. With this in mind, we study glutaredoxin (GRX) domains, because these domains of approximately one hundred amino acids are widespread in archaea, bacteria and eukaryotes and participate in fusion proteins. GRXs are responsible for the reduction of protein disulfides or glutathione-protein mixed disulfides and are involved in cellular redox regulation, although their specific roles and targets are often unclear. Results: In this work we analyze the distribution and evolution of GRX proteins in archaea,bacteria and eukaryotes. We study over one thousand GRX proteins, each containing at least one GRX domain, from hundreds of different organisms and trace the origin and evolution of the GRX domain within the tree of life. Conclusion: Our results suggest that single domain GRX proteins of the CGFS and CPYC classes have, each, evolved through duplication and divergence from one initial gene that was present in the last common ancestor of all organisms. Remarkably, we identify a case of convergent evolution in domain architecture that involves the GRX domain. Two independent recombination events of a TRX domain to a GRX domain are likely to have occurred, which is an exception to the dominant mechanism of domain architecture evolution.

In silico pathway reconstruction: Iron-sulfur cluster biogenesis in Saccharomyces cerevisiae

Background: Current advances in genomics, proteomics and other areas of molecular biology make the identification and reconstruction of novel pathways an emerging area of great interest. One such class of pathways is involved in the biogenesis of Iron-Sulfur Clusters (ISC). Results: Our goal is the development of a new approach based on the use and combination of mathematical, theoretical and computational methods to identify the topology of a target network. In this approach, mathematical models play a central role for the evaluation of the alternative network structures that arise from literature data-mining, phylogenetic profiling, structural methods, and human curation. As a test case, we reconstruct the topology of the reaction and regulatory network for the mitochondrial ISC biogenesis pathway in S. cerevisiae. Predictions regarding how proteins act in ISC biogenesis are validated by comparison with published experimental results. For example, the predicted role of Arh1 and Yah1 and some of the interactions we predict for Grx5 both matches experimental evidence. A putative role for frataxin in directly regulating mitochondrial iron import is discarded from our analysis, which agrees with also published experimental results. Additionally, we propose a number of experiments for testing other predictions and further improve the identification of the network structure. Conclusion: We propose and apply an iterative in silico procedure for predictive reconstruction of the network topology of metabolic pathways. The procedure combines structural bioinformatics tools and mathematical modeling techniques that allow the reconstruction of biochemical networks. Using the Iron Sulfur cluster biogenesis in S. cerevisiae as a test case we indicate how this procedure can be used to analyze and validate the network model against experimental results. Critical evaluation of the obtained results through this procedure allows devising new wet lab experiments to confirm its predictions or provide alternative explanations for further improving the models.

Minimization of biosynthetic costs in adaptive gene expression responses of yeast to environmental changes

Yeast successfully adapts to an environmental stress by altering physiology and fine-tuning metabolism. This fine-tuning is achieved through regulation of both gene expression and protein activity, and it is shaped by various physiological requirements. Such requirements impose a sustained evolutionary pressure that ultimately selects a specific gene expression profile, generating a suitable adaptive response to each environmental change. Although some of the requirements are stress specific, it is likely that others are common to various situations. We hypothesize that an evolutionary pressure for minimizing biosynthetic costs might have left signatures in the physicochemical properties of proteins whose gene expression is fine-tuned during adaptive responses. To test this hypothesis we analyze existing yeast transcriptomic data for such responses and investigate how several properties of proteins correlate to changes in gene expression. Our results reveal signatures that are consistent with a selective pressure for economy in protein synthesis during adaptive response of yeast to various types of stress. These signatures differentiate two groups of adaptive responses with respect to how cells manage expenditure in protein biosynthesis. In one group, significant trends towards downregulation of large proteins and upregulation of small ones are observed. In the other group we find no such trends. These results are consistent with resource limitation being important in the evolution of the first group of stress responses.

Use of physiological constraints to identify quantitative design principles for gene expression in yeast adaptation to heat shock

Background: Understanding the relationship between gene expression changes, enzyme activity shifts, and the corresponding physiological adaptive response of organisms to environmental cues is crucial in explaining how cells cope with stress. For example, adaptation of yeast to heat shock involves a characteristic profile of changes to the expression levels of genes coding for enzymes of the glycolytic pathway and some of its branches. The experimental determination of changes in gene expression profiles provides a descriptive picture of the adaptive response to stress. However, it does not explain why a particular profile is selected for any given response. Results: We used mathematical models and analysis of in silico gene expression profiles (GEPs) to understand how changes in gene expression correlate to an efficient response of yeast cells to heat shock. An exhaustive set of GEPs, matched with the corresponding set of enzyme activities, was simulated and analyzed. The effectiveness of each profile in the response to heat shock was evaluated according to relevant physiological and functional criteria. The small subset of GEPs that lead to effective physiological responses after heat shock was identified as the result of the tuning of several evolutionary criteria. The experimentally observed transcriptional changes in response to heat shock belong to this set and can be explained by quantitative design principles at the physiological level that ultimately constrain changes in gene expression. Conclusion: Our theoretical approach suggests a method for understanding the combined effect of changes in the expression of multiple genes on the activity of metabolic pathways, and consequently on the adaptation of cellular metabolism to heat shock. This method identifies quantitative design principles that facilitate understating the response of the cell to stress.

The Francoist repression in the Catalan Countries

This article offers an overview of Francoist repression in the Catalan Countries from the outbreak of the Civil War to the first decade after the establishment of the dictatorship. It covers both physical violence and measures such as economic repression, imprisonment, professional purges and the social and moral control to which the population as a whole was subjected. First the type of violence and domination exercised by the insurgents in the territories occupied is briefly examined. Then the author offers an account of the events: she commences in the summer of 1936 in Majorca, the only Catalan-speaking territory to remain in rebel hands, then proceeds to the Lleida region, which was occupied in the spring of 1938, and concludes with the final offensive against Catalonia and Valencia, launched in the winter of that same year. Special stress is laid on the repercussions of the 1939 Law of Political Responsibilities and the meaning attached by the occupiers to the pacification and reconstruction of the conquered territories.

Las monedas con nombres de étnicos del s. II a.C. en el nordeste peninsular: ¿Reflejo de posibles circunscripciones? ¿Civitates con doble nombre?

En el s. II a.C. se emiten en el nordeste de Hispania monedas con el nombre de étnicos conocidos por las fuentes escritas. Se plantea el problema de si responden a una organización territorial en circunscripciones que, curiosamente, correponden con las regiones principales populi que cita Plinio. Por otro lado estas cecas podrían corresponder a localidades que pudieran tener otro nombre.

Un trípode de tipo chipriotra procedente de La Clota (Calaceite, Teruel)

El objetivo de este breve artículo es presentar dos pequeños fragmentos de bronce procedentes de un sepulcro de La Clota (Calaceite, Teruel) que han sido identificados recientemente como pertenecientes a un trípode de tipo chipriota. Pasamos revista sucintamente a las principales cuestiones que plantea el hallazgo: cronología, orígenes, contexto social e influencia en el artesanado local.

Primeros datos arqueométricos sobre la metalurgia del poblado y necrópolis de Calvari del Molar (Priorat, Tarragona)

La presencia de materiales fenicios en el curso del río Ebro se ha relacionado con su interés hacia los recursos mineros de nordeste peninsular en general y del área Molar-Bellmunt-Falset en particular, pero hasta la fecha esta propuesta no había sido adecuadamente contratada. En este artículo presentamos las primeras evidencias de actividad metalúrgica procedente del poblado de Calvari del Molar (Priorat, Tarragona) (campañas 2002-2003), que consisten en una tobera de tipología desconocida hasta la fecha en Cataluña, un molino empleado para triturar el mineral y una punta de flecha orientalizante que puede interpretarse como una imitación local de modelos foráneos. Damos a conocer también el estudio arqueometalúrgico de otros cuatro bronces procedentes de las excavaciones de S. Vilaseca (1930). La publicación de los resultados arqueológicos y arqueométricos nos sirve para presentar las perspectivas de futuro de nuestra investigación acerca del poblado, de su área minero-metalúrgica y de su relación con los intereses comerciales fenicios. Se presta especial atención a la plata, obtenida a partir de minerales de este metal, plata nativa y galena argentífera, como un subproducto de la explotación de plomo.

Colonic perianastomotic carcinogenesis in an experimental model

Background To examine the effect of anastomosis on experimental carcinogenesis in the colon of rats. Methods Forty-three 10-week-old male and female Sprague-Dawley rats were operated on by performing an end-to-side ileorectostomy. Group A:16 rats received no treatment. Group B: 27 rats received 18 subcutaneous injections weekly at a dose of 21 mg/kg wt of 1–2 dimethylhydrazine (DMH), from the eighth day after the intervention. Animals were sacrificed between 25–27 weeks. The number of tumours, their localization, size and microscopic characteristics were recorded. A paired chi-squared analysis was performed comparing tumoral induction in the perianastomotic zone with the rest of colon with faeces. Results No tumours appeared in the dimethylhydrazine-free group. The percentage tumoral area was greater in the perianastomotic zone compared to tumours which had developed in the rest of colon with faeces (p = 0.014). Conclusion We found a cocarcinogenic effect due to the creation of an anastomosis, when using an experimental model of colonic carcinogenesis induced by DMH in rats.

Caracterización de las almazaras cooperativas catalanas, análisis interno de la fase industrial o de transformación

En el presente artículo hemos tratado de analizar las características de las almazaras cooperativas catalanas con la finalidad de destacar no solamente sus elementos más importantes de gestión sino también sus principales debilidades.Las cooperativas se consideran instrumentos útiles para acometer políticas de desarrollo económico y bienestar social. A pesar de ello hay un gran debate abierto acerca de la eficiencia de estas organizaciones, que plantean el interrogante de si están en condiciones de competir con éxito en una economía cada vez más abierta, liberalizada y global. A través de las encuestas que hemos realizado al conjunto de las cooperativas oleícolas de Catalunya, hemos podido averiguar sus características distintivas, así como las principales desventajas y problemas a los que se enfrentan. Creemos puede ser de interés analizar las características de estas organizaciones, que tanto desde el punto de vista organizativo como de recursos humanos, como financiero, las hace diferentes de otro tipo de organizaciones pero que sin embargo, han de hacer frente a un mercado cada día más exigente y competitivo.

La nueva política criminal de la seguridad vial. Reflexiones a propósito de la LO 15/2007, de 30 de noviembre, y del Proyecto de Reforma del Código Penal

La reforma de los delitos contra la seguridad en el tráfico operada por LO 15/2007, de 30 de noviembre, constituye la expresión de un programa político-criminal de más amplio alcance, presente en el Proyecto de Reforma del Código Penal de 2007. En este trabajo se exponen las causas de la emergencia del nuevo derecho penal de la seguridad vial a la luz del paradi gma explicativo que ofrece el derecho penal postmoderno del riesgo -sometido aquí a necesarios ajustes- y se ofrece un análisis crítico de dos de los nuevos tipos: la conducción a velocidad por encima de determinados límites (art. 379.1) y la conducción con concentraciones de alcohol en aire espirado o en sangre superiores a determinadas tasas (0.6 mgr. o 1,2 gr. respectivamente) –art. 379.2-. Igualmente se analiza la propuesta del Proyecto de Reforma del Código de elevar a la categoría de delito las imprudencias leves con resultado de muerte. Tres piezas clave de un programa que trasluce una gran desconfianza hacia el estamento judicial y un optimismo infundado en las posibilidades del derecho penal para reducir eficazmente la siniestralidad vial.

Real-time tree-foliage surface estimation using a ground laser scanner

The optimization of most pesticide and fertilizer applications is based on overall grove conditions. In this work we measurements. Recently, Wei [9, 10] used a terrestrial propose a measurement system based on a ground laser scanner to LIDAR to measure tree height, width and volume developing estimate the volume of the trees and then extrapolate their foliage a set of experiments to evaluate the repeatability and surface in real-time. Tests with pear trees demonstrated that the accuracy of the measurements, obtaining a coefficient of relation between the volume and the foliage can be interpreted as variation of 5.4% and a relative error of 4.4% in the linear with a coefficient of correlation (R) of 0.81 and the foliar estimation of the volume but without real-time capabilities. surface can be estimated with an average error less than 5 %.

Sistema de sanciones y política criminal: un estudio de Derecho comparado europeo

El trabajo aborda una comparación de los diversos sistemas de penas estatales en Europa, con el objetivo de sistematizar los diversos modelos político-criminales y de calibrar la aflictividad de los mismos. A través de determinados indicadores se pone de relieve que los sistemas jurídicos que abren un mayor espacio a la discrecionalidad judicial en la selección y la determinación de la pena muestran una mayor moderación del rigor punitivo y están en mejores condiciones de dar respuesta a una fenomenología criminal cada vez más diversa.

Comisiones de la verdad y justicia penal en contextos de transición

Una de las cuestiones más controvertidas en la problemática de la justicia de transición es la relativa a las Comisiones de la Verdad. En este artículo se analizan estos órganos de investigación desde el prisma de la obligación de proveer justicia ante las graves violaciones de derechos humanos y se plantea en qué condiciones una fórmula basada en la verdad y la reparación puede servir a los fines de la justicia penal.