Center for Nature Interpretation, Lanzarote (2009)

A black plane. The place is an extraordinary landscape, black due to the ash of this volcanic island, the distant horizon and sea in the background to the west. A natural ring of hills surrounds a flat area that reaches to the sea, with a saltwater lake in the center, where the white salt mines were formed in the past century.

Nuances matter: How fossil woody remains changed the interpretation of the vegetation in Iberia

Ejemplos de cómo los macrorrestos ayudan a mejorar la interpretación del paisaje vegetal de la península Ibérica

Improved static analysis and verification of energy consumption and other resources via abstract interpretation

Resource analysis aims at inferring the cost of executing programs for any possible input, in terms of a given resource, such as the traditional execution steps, time ormemory, and, more recently energy consumption or user defined resources (e.g., number of bits sent over a socket, number of database accesses, number of calls to particular procedures, etc.). This is performed statically, i.e., without actually running the programs. Resource usage information is useful for a variety of optimization and verification applications, as well as for guiding software design. For example, programmers can use such information to choose different algorithmic solutions to a problem; program transformation systems can use cost information to choose between alternative transformations; parallelizing compilers can use cost estimates for granularity control, which tries to balance the overheads of task creation and manipulation against the benefits of parallelization. In this thesis we have significatively improved an existing prototype implementation for resource usage analysis based on abstract interpretation, addressing a number of relevant challenges and overcoming many limitations it presented. The goal of that prototype was to show the viability of casting the resource analysis as an abstract domain, and howit could overcome important limitations of the state-of-the-art resource usage analysis tools. For this purpose, it was implemented as an abstract domain in the abstract interpretation framework of the CiaoPP system, PLAI.We have improved both the design and implementation of the prototype, for eventually allowing an evolution of the tool to the industrial application level. The abstract operations of such tool heavily depend on the setting up and finding closed-form solutions of recurrence relations representing the resource usage behavior of program components and the whole program as well. While there exist many tools, such as Computer Algebra Systems (CAS) and libraries able to find closed-form solutions for some types of recurrences, none of them alone is able to handle all the types of recurrences arising during program analysis. In addition, there are some types of recurrences that cannot be solved by any existing tool. This clearly constitutes a bottleneck for this kind of resource usage analysis. Thus, one of the major challenges we have addressed in this thesis is the design and development of a novel modular framework for solving recurrence relations, able to combine and take advantage of the results of existing solvers. Additionally, we have developed and integrated into our novel solver a technique for finding upper-bound closed-form solutions of a special class of recurrence relations that arise during the analysis of programs with accumulating parameters. Finally, we have integrated the improved resource analysis into the CiaoPP general framework for resource usage verification, and specialized the framework for verifying energy consumption specifications of embedded imperative programs in a real application, showing the usefulness and practicality of the resulting tool.---ABSTRACT---El Análisis de recursos tiene como objetivo inferir el coste de la ejecución de programas para cualquier entrada posible, en términos de algún recurso determinado, como pasos de ejecución, tiempo o memoria, y, más recientemente, el consumo de energía o recursos definidos por el usuario (por ejemplo, número de bits enviados a través de un socket, el número de accesos a una base de datos, cantidad de llamadas a determinados procedimientos, etc.). Ello se realiza estáticamente, es decir, sin necesidad de ejecutar los programas. La información sobre el uso de recursos resulta muy útil para una gran variedad de aplicaciones de optimización y verificación de programas, así como para asistir en el diseño de los mismos. Por ejemplo, los programadores pueden utilizar dicha información para elegir diferentes soluciones algorítmicas a un problema; los sistemas de transformación de programas pueden utilizar la información de coste para elegir entre transformaciones alternativas; los compiladores paralelizantes pueden utilizar las estimaciones de coste para realizar control de granularidad, el cual trata de equilibrar el coste debido a la creación y gestión de tareas, con los beneficios de la paralelización. En esta tesis hemos mejorado de manera significativa la implementación de un prototipo existente para el análisis del uso de recursos basado en interpretación abstracta, abordando diversos desafíos relevantes y superando numerosas limitaciones que éste presentaba. El objetivo de dicho prototipo era mostrar la viabilidad de definir el análisis de recursos como un dominio abstracto, y cómo se podían superar las limitaciones de otras herramientas similares que constituyen el estado del arte. Para ello, se implementó como un dominio abstracto en el marco de interpretación abstracta presente en el sistema CiaoPP, PLAI. Hemos mejorado tanto el diseño como la implementación del mencionado prototipo para posibilitar su evolución hacia una herramienta utilizable en el ámbito industrial. Las operaciones abstractas de dicha herramienta dependen en gran medida de la generación, y posterior búsqueda de soluciones en forma cerrada, de relaciones recurrentes, las cuales modelizan el comportamiento, respecto al consumo de recursos, de los componentes del programa y del programa completo. Si bien existen actualmente muchas herramientas capaces de encontrar soluciones en forma cerrada para ciertos tipos de recurrencias, tales como Sistemas de Computación Algebraicos (CAS) y librerías de programación, ninguna de dichas herramientas es capaz de tratar, por sí sola, todos los tipos de recurrencias que surgen durante el análisis de recursos. Existen incluso recurrencias que no las puede resolver ninguna herramienta actual. Esto constituye claramente un cuello de botella para este tipo de análisis del uso de recursos. Por lo tanto, uno de los principales desafíos que hemos abordado en esta tesis es el diseño y desarrollo de un novedoso marco modular para la resolución de relaciones recurrentes, combinando y aprovechando los resultados de resolutores existentes. Además de ello, hemos desarrollado e integrado en nuestro nuevo resolutor una técnica para la obtención de cotas superiores en forma cerrada de una clase característica de relaciones recurrentes que surgen durante el análisis de programas lógicos con parámetros de acumulación. Finalmente, hemos integrado el nuevo análisis de recursos con el marco general para verificación de recursos de CiaoPP, y hemos instanciado dicho marco para la verificación de especificaciones sobre el consumo de energía de programas imperativas embarcados, mostrando la viabilidad y utilidad de la herramienta resultante en una aplicación real.

The living plant; a description and interpretation of its functions and structure, by William F. Ganong.

1913

Uncertainty in Structural Interpretation : Lessons to be learnt

Peer reviewed

Increasing the quality of seismic interpretation

Euan Macrae was funded by a NERC Open CASE PhD award (NE/F013728/1) with Midland Valley Exploration Ltd. as the industry partner. We thank the 763 geoscientists for their participation, and in particular, the reference experts who gave their time freely to the project. Marian Scott (University of Glasgow, UK) is thanked for assisting with the statistical analysis. Four reviewers are thanked for their constructive comments which improved the manuscript.

Inhibition of the electrostatic interaction between β-amyloid peptide and membranes prevents β-amyloid-induced toxicity

The accumulation of β-amyloid peptides (Aβ) into senile plaques is one of the hallmarks of Alzheimer disease. Aggregated Aβ is toxic to cells in culture and this has been considered to be the cause of neurodegeneration that occurs in the Alzheimer disease brain. The discovery of compounds that prevent Aβ toxicity may lead to a better understanding of the processes involved and ultimately to possible therapeutic drugs. Low nanomolar concentrations of Aβ1-42 and the toxic fragment Aβ25-35 have been demonstrated to render cells more sensitive to subsequent insults as manifested by an increased sensitivity to formazan crystals following MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction. Formation of the toxic β-sheet conformation by Aβ peptides is increased by negatively charged membranes. Here we demonstrate that phloretin and exifone, dipolar compounds that decrease the effective negative charge of membranes, prevent association of Aβ1-40 and Aβ25-35 to negatively charged lipid vesicles and Aβ induced cell toxicity. These results suggest that Aβ toxicity is mediated through a nonspecific physicochemical interaction with cell membranes.

Direct molecular level measurements of the electrostatic properties of a protein surface

In this work, we used direct measurements with the surface force apparatus to determine the pH-dependent electrostatic charge density of a single binding face of streptavidin. Mean field calculations have been used with considerable success to model electrostatic potential fields near protein surfaces, but these models and their inherent assumptions have not been tested directly at the molecular level. Using the force apparatus and immobilized, oriented monolayers of streptavidin, we measured a pI of 5–5.5 for the biotin-binding face of the protein. This differs from the pI of 6.3 for the soluble protein and confirms that we probed the local electrostatic features of the macromolecule. With finite difference solutions of the linearized Poisson–Boltzmann equation, we then calculated the pH-dependent charge densities adjacent to the same face of the protein. These calculated values agreed quantitatively with those obtained by direct force measurements. Although our study focuses on the pH-dependence of surface electrostatics, this direct approach to probing the electrostatic features of proteins is applicable to investigations of any perturbations that alter the charge distribution of the surfaces of immobilized molecules.

Novel dimeric interface and electrostatic recognition in bacterial Cu,Zn superoxide dismutase

Eukaryotic Cu,Zn superoxide dismutases (CuZnSODs) are antioxidant enzymes remarkable for their unusually stable β-barrel fold and dimer assembly, diffusion-limited catalysis, and electrostatic guidance of their free radical substrate. Point mutations of CuZnSOD cause the fatal human neurodegenerative disease amyotrophic lateral sclerosis. We determined and analyzed the first crystallographic structure (to our knowledge) for CuZnSOD from a prokaryote, Photobacterium leiognathi, a luminescent symbiont of Leiognathid fish. This structure, exemplifying prokaryotic CuZnSODs, shares the active-site ligand geometry and the topology of the Greek key β-barrel common to the eukaryotic CuZnSODs. However, the β-barrel elements recruited to form the dimer interface, the strategy used to forge the channel for electrostatic recognition of superoxide radical, and the connectivity of the intrasubunit disulfide bond in P. leiognathi CuZnSOD are discrete and strikingly dissimilar from those highly conserved in eukaryotic CuZnSODs. This new CuZnSOD structure broadens our understanding of structural features necessary and sufficient for CuZnSOD activity, highlights a hitherto unrecognized adaptability of the Greek key β-barrel building block in evolution, and reveals that prokaryotic and eukaryotic enzymes diverged from one primordial CuZnSOD and then converged to distinct dimeric enzymes with electrostatic substrate guidance.

Sources of selection bias in evaluating social programs: An interpretation of conventional measures and evidence on the effectiveness of matching as a program evaluation method

This paper decomposes the conventional measure of selection bias in observational studies into three components. The first two components are due to differences in the distributions of characteristics between participant and nonparticipant (comparison) group members: the first arises from differences in the supports, and the second from differences in densities over the region of common support. The third component arises from selection bias precisely defined. Using data from a recent social experiment, we find that the component due to selection bias, precisely defined, is smaller than the first two components. However, selection bias still represents a substantial fraction of the experimental impact estimate. The empirical performance of matching methods of program evaluation is also examined. We find that matching based on the propensity score eliminates some but not all of the measured selection bias, with the remaining bias still a substantial fraction of the estimated impact. We find that the support of the distribution of propensity scores for the comparison group is typically only a small portion of the support for the participant group. For values outside the common support, it is impossible to reliably estimate the effect of program participation using matching methods. If the impact of participation depends on the propensity score, as we find in our data, the failure of the common support condition severely limits matching compared with random assignment as an evaluation estimator.

A local electrostatic change is the cause of the large-scale protein conformation shift in bacteriorhodopsin

During light-driven proton transport bacteriorhodopsin shuttles between two protein conformations. A large-scale structural change similar to that in the photochemical cycle is produced in the D85N mutant upon raising the pH, even without illumination. We report here that (i) the pKa values for the change in crystallographic parameters and for deprotonation of the retinal Schiff base are the same, (ii) the retinal isomeric configuration is nearly unaffected by the protein conformation, and (iii) preventing rotation of the C13—C14 double bond by replacing the retinal with an all-trans locked analogue makes little difference to the Schiff base pKa. We conclude that the direct cause of the conformational shift is destabilization of the structure upon loss of interaction of the positively charged Schiff base with anionic residues that form its counter-ion.

Electrostatic interaction between helical macromolecules in dense aggregates: An impetus for DNA poly- and meso-morphism

DNA exhibits a surprising multiplicity of structures when it is packed into dense aggregates. It undergoes various polymorphous transitions (e.g., from the B to A form) and mesomorphous transformations (from hexagonal to orthorhombic or monoclinic packing, changes in the mutual alignment of nearest neighbors, etc). In this report we show that such phenomena may have their origin in the specific helical symmetry of the charge distribution on DNA surface. Electrostatic interaction between neighboring DNA molecules exhibits strong dependence on the patterns of molecular surface groups and adsorbed counter-ions. As a result, it is affected by such structural parameters as the helical pitch, groove width, the number of base pairs per helical turn, etc. We derive expressions which relate the energy of electrostatic interaction with these parameters and with the packing variables characterizing the axial and azimuthal alignment between neighboring macromolecules. We show, in particular, that the structural changes upon the B-to-A transition reduce the electrostatic energy by ≈kcal/mol per base pair, at a random adsorption of counter ions. Ion binding into the narrow groove weakens or inverts this effect, stabilizing B-DNA, as it is presumably the case in Li+-DNA assemblies. The packing symmetry and molecular alignment in DNA aggregates are shown to be affected by the patterns of ion binding.

Electrostatic interactions between rotor and stator in the bacterial flagellar motor

Bacterial flagellar motors rotate, obtaining power from the membrane gradient of protons or, in some species, sodium ions. Torque generation in the flagellar motor must involve interactions between components of the rotor and components of the stator. Sites of interaction between the rotor and stator have not been identified. Mutational studies of the rotor protein FliG and the stator protein MotA showed that both proteins contain charged residues essential for motor rotation. This suggests that functionally important electrostatic interactions might occur between the rotor and stator. To test this proposal, we examined double mutants with charged-residue substitutions in both the rotor protein FliG and the stator protein MotA. Several combinations of FliG mutations with MotA mutations exhibited strong synergism, whereas others showed strong suppression, in a pattern that indicates that the functionally important charged residues of FliG interact with those of MotA. These results identify a functionally important site of interaction between the rotor and stator and suggest a hypothesis for electrostatic interactions at the rotor–stator interface.

Analysis and interpretation of cost data in randomised controlled trials: review of published studies

Objective To review critically the statistical methods used for health economic evaluations in randomised controlled trials where an estimate of cost is available for each patient in the study.