Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition.

Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible. This opposes the prevailing hypothesis of drug permeation through biological membranes, which integrates the contribution of multiple permeation mechanisms, including both carrier-mediated and passive lipoidal diffusion, depending on the compound's properties, membrane properties, and solution properties. The prevailing hypothesis of drug permeation continues to be successful for application and prediction in drug development. Proponents of the carrier-mediated only concept argue against passive lipoidal diffusion. However, the arguments are not supported by broad pharmaceutics literature. The carrier-mediated only concept lacks substantial supporting evidence and successful applications in drug development.

Brain tissue properties differentiate between motor and limbic basal ganglia circuits.

Despite advances in understanding basic organizational principles of the human basal ganglia, accurate in vivo assessment of their anatomical properties is essential to improve early diagnosis in disorders with corticosubcortical pathology and optimize target planning in deep brain stimulation. Main goal of this study was the detailed topological characterization of limbic, associative, and motor subdivisions of the subthalamic nucleus (STN) in relation to corresponding corticosubcortical circuits. To this aim, we used magnetic resonance imaging and investigated independently anatomical connectivity via white matter tracts next to brain tissue properties. On the basis of probabilistic diffusion tractography we identified STN subregions with predominantly motor, associative, and limbic connectivity. We then computed for each of the nonoverlapping STN subregions the covariance between local brain tissue properties and the rest of the brain using high-resolution maps of magnetization transfer (MT) saturation and longitudinal (R1) and transverse relaxation rate (R2*). The demonstrated spatial distribution pattern of covariance between brain tissue properties linked to myelin (R1 and MT) and iron (R2*) content clearly segregates between motor and limbic basal ganglia circuits. We interpret the demonstrated covariance pattern as evidence for shared tissue properties within a functional circuit, which is closely linked to its function. Our findings open new possibilities for investigation of changes in the established covariance pattern aiming at accurate diagnosis of basal ganglia disorders and prediction of treatment outcome.

Predicting global change impacts on plant species' distributions: Future challenges

Given the rate of projected environmental change for the 21st century, urgent adaptation and mitigation measures are required to slow down the on-going erosion of biodiversity. Even though increasing evidence shows that recent human-induced environmental changes have already triggered species' range shifts, changes in phenology and species' extinctions, accurate projections of species' responses to future environmental changes are more difficult to ascertain. This is problematic, since there is a growing awareness of the need to adopt proactive conservation planning measures using forecasts of species' responses to future environmental changes. There is a substantial body of literature describing and assessing the impacts of various scenarios of climate and land-use change on species' distributions. Model predictions include a wide range of assumptions and limitations that are widely acknowledged but compromise their use for developing reliable adaptation and mitigation strategies for biodiversity. Indeed, amongst the most used models, few, if any, explicitly deal with migration processes, the dynamics of population at the "trailing edge" of shifting populations, species' interactions and the interaction between the effects of climate and land-use. In this review, we propose two main avenues to progress the understanding and prediction of the different processes A occurring on the leading and trailing edge of the species' distribution in response to any global change phenomena. Deliberately focusing on plant species, we first explore the different ways to incorporate species' migration in the existing modelling approaches, given data and knowledge limitations and the dual effects of climate and land-use factors. Secondly, we explore the mechanisms and processes happening at the trailing edge of a shifting species' distribution and how to implement them into a modelling approach. We finally conclude this review with clear guidelines on how such modelling improvements will benefit conservation strategies in a changing world. (c) 2007 Rubel Foundation, ETH Zurich. Published by Elsevier GrnbH. All rights reserved.

Evolutionary history and its relevance in understanding and conserving southern African biodiversity

Abstract : Understanding how biodiversity is distributed is central to any conservation effort and has traditionally been based on niche modeling and the causal relationship between spatial distribution of organisms and their environment. More recently, the study of species' evolutionary history and relatedness has permeated the fields of ecology and conservation and, coupled with spatial predictions, provides useful insights to the origin of current biodiversity patterns, community structuring and potential vulnerability to extinction. This thesis explores several key ecological questions by combining the fields of niche modeling and phylogenetics and using important components of southern African biodiversity. The aims of this thesis are to provide comparisons of biodiversity measures, to assess how climate change will affect evolutionary history loss, to ask whether there is a clear link between evolutionary history and morphology and to investigate the potential role of relatedness in macro-climatic niche structuring. The first part of my thesis provides a fine scale comparison and spatial overlap quantification of species richness and phylogenetic diversity predictions for one of the most diverse plant families in the Cape Floristic Region (CFR), the Proteaceae. In several of the measures used, patterns do not match sufficiently to argue that species relatedness information is implicit in species richness patterns. The second part of my thesis predicts how climate change may affect threat and potential extinction of southern African animal and plant taxa. I compare present and future niche models to assess whether predicted species extinction will result in higher or lower V phylogenetic diversity survival than what would be experienced under random extinction processes. l find that predicted extinction will result in lower phylogenetic diversity survival but that this non-random pattern will be detected only after a substantial proportion of the taxa in each group has been lost. The third part of my thesis explores the relationship between phylogenetic and morphological distance in southern African bats to assess whether long evolutionary histories correspond to equally high levels of morphological variation, as predicted by a neutral model of character evolution. I find no such evidence; on the contrary weak negative trends are detected for this group, as well as in simulations of both neutral and convergent character evolution. Finally, I ask whether spatial and climatic niche occupancy in southern African bats is influenced by evolutionary history or not. I relate divergence time between species pairs to climatic niche and range overlap and find no evidence for clear phylogenetic structuring. I argue that this may be due to particularly high levels of micro-niche partitioning. Résumé : Comprendre la distribution de la biodiversité représente un enjeu majeur pour la conservation de la nature. Les analyses se basent le plus souvent sur la modélisation de la niche écologique à travers l'étude des relations causales entre la distribution spatiale des organismes et leur environnement. Depuis peu, l'étude de l'histoire évolutive des organismes est également utilisée dans les domaines de l'écologie et de la conservation. En combinaison avec la modélisation de la distribution spatiale des organismes, cette nouvelle approche fournit des informations pertinentes pour mieux comprendre l'origine des patterns de biodiversité actuels, de la structuration des communautés et des risques potentiels d'extinction. Cette thèse explore plusieurs grandes questions écologiques, en combinant les domaines de la modélisation de la niche et de la phylogénétique. Elle s'applique aux composants importants de la biodiversité de l'Afrique australe. Les objectifs de cette thèse ont été l) de comparer différentes mesures de la biodiversité, 2) d'évaluer l'impact des changements climatiques à venir sur la perte de diversité phylogénétique, 3) d'analyser le lien potentiel entre diversité phylogénétique et diversité morphologique et 4) d'étudier le rôle potentiel de la phylogénie sur la structuration des niches macro-climatiques des espèces. La première partie de cette thèse fournit une comparaison spatiale, et une quantification du chevauchement, entre des prévisions de richesse spécifique et des prédictions de la diversité phylogénétique pour l'une des familles de plantes les plus riches en espèces de la région floristique du Cap (CFR), les Proteaceae. Il résulte des analyses que plusieurs mesures de diversité phylogénétique montraient des distributions spatiales différentes de la richesse spécifique, habituellement utilisée pour édicter des mesures de conservation. La deuxième partie évalue les effets potentiels des changements climatiques attendus sur les taux d'extinction d'animaux et de plantes de l'Afrique australe. Pour cela, des modèles de distribution d'espèces actuels et futurs ont permis de déterminer si l'extinction des espèces se traduira par une plus grande ou une plus petite perte de diversité phylogénétique en comparaison à un processus d'extinction aléatoire. Les résultats ont effectivement montré que l'extinction des espèces liées aux changements climatiques pourrait entraîner une perte plus grande de diversité phylogénétique. Cependant, cette perte ne serait plus grande que celle liée à un processus d'extinction aléatoire qu'à partir d'une forte perte de taxons dans chaque groupe. La troisième partie de cette thèse explore la relation entre distances phylogénétiques et morphologiques d'espèces de chauves-souris de l'Afrique australe. ll s'agit plus précisément de déterminer si une longue histoire évolutive correspond également à des variations morphologiques plus grandes dans ce groupe. Cette relation est en fait prédite par un modèle neutre d'évolution de caractères. Aucune évidence de cette relation n'a émergé des analyses. Au contraire, des tendances négatives ont été détectées, ce qui représenterait la conséquence d'une évolution convergente entre clades et des niveaux élevés de cloisonnement pour chaque clade. Enfin, la dernière partie présente une étude sur la répartition de la niche climatique des chauves-souris de l'Afrique australe. Dans cette étude je rapporte temps de divergence évolutive (ou deux espèces ont divergé depuis un ancêtre commun) au niveau de chevauchement de leurs niches climatiques. Les résultats n'ont pas pu mettre en évidence de lien entre ces deux paramètres. Les résultats soutiennent plutôt l'idée que cela pourrait être I dû à des niveaux particulièrement élevés de répartition de la niche à échelle fine.

A protocol describing the genetic correction of somatic human cells and subsequent generation of IPS cell

The generation of patient-specific induced pluripotent stem cells (iPSCPSCPSCs) offers unprecedented opportunities for modeling and treating human disease. In combination with gene therapy, the iPSCPSCPSC technology can be used to generate disease-free progenitor cells of potential interest for autologous cell therapy. We explain a protocol for the reproducible generation of genetically corrected iPSCPSCPSCs starting from the skin biopsies of Fanconi anemia patients using retroviral transduction with OCT4, SOX2 and KLF4. Before reprogramming, the fibroblasts and/or keratinocytes of the patients are genetically corrected with lentiviruses expressing FANCA. The same approach may be used for other diseases susceptible to gene therapy correction. Genetically corrected, characterized lines of patient-specific iPSCPSCPSCs can be obtained in 4–5 months.

U.S. Universities’ Net Returns from Patenting and Licensing: A Quantile Regression Analysis, September 2006

In line with the rights and incentives provided by the Bayh-Dole Act of 1980, U.S. universities have increased their involvement in patenting and licensing activities through their own technology transfer offices. Only a few U.S. universities are obtaining large returns, however, whereas others are continuing with these activities despite negligible or negative returns. We assess the U.S. universities’ potential to generate returns from licensing activities by modeling and estimating quantiles of the distribution of net licensing returns conditional on some of their structural characteristics. We find limited prospects for public universities without a medical school everywhere in their distribution. Other groups of universities (private, and public with a medical school) can expect significant but still fairly modest returns only beyond the 0.9th quantile. These findings call into question the appropriateness of the revenue-generating motive for the aggressive rate of patenting and licensing by U.S. universities.

Computational fluid dynamics of the right ventricular outflow tract and of the pulmonary artery: a bench model of flow dynamics.

OBJECTIVES: The reconstruction of the right ventricular outflow tract (RVOT) with valved conduits remains a challenge. The reoperation rate at 5 years can be as high as 25% and depends on age, type of conduit, conduit diameter and principal heart malformation. The aim of this study is to provide a bench model with computer fluid dynamics to analyse the haemodynamics of the RVOT, pulmonary artery, its bifurcation, and left and right pulmonary arteries that in the future may serve as a tool for analysis and prediction of outcome following RVOT reconstruction. METHODS: Pressure, flow and diameter at the RVOT, pulmonary artery, bifurcation of the pulmonary artery, and left and right pulmonary arteries were measured in five normal pigs with a mean weight of 24.6 ± 0.89 kg. Data obtained were used for a 3D computer fluid-dynamics simulation of flow conditions, focusing on the pressure, flow and shear stress profile of the pulmonary trunk to the level of the left and right pulmonary arteries. RESULTS: Three inlet steady flow profiles were obtained at 0.2, 0.29 and 0.36 m/s that correspond to the flow rates of 1.5, 2.0 and 2.5 l/min flow at the RVOT. The flow velocity profile was constant at the RVOT down to the bifurcation and decreased at the left and right pulmonary arteries. In all three inlet velocity profiles, low sheer stress and low-velocity areas were detected along the left wall of the pulmonary artery, at the pulmonary artery bifurcation and at the ostia of both pulmonary arteries. CONCLUSIONS: This computed fluid real-time model provides us with a realistic picture of fluid dynamics in the pulmonary tract area. Deep shear stress areas correspond to a turbulent flow profile that is a predictive factor for the development of vessel wall arteriosclerosis. We believe that this bench model may be a useful tool for further evaluation of RVOT pathology following surgical reconstructions.

Nucleation and growth of metamorphic minerals in contact aureoles

THESIS ABSTRACT Nucleation and growth of metamorphic minerals are the consequence of changing P-T-X-conditions. The thesis presented here focuses on processes governing nucleation and growth of minerals in contact metamorphic environments using a combination of geochemical analytics (chemical-, isotope-, and trace element composition), statistical treatments of spatial data, and numerical models. It is shown, that a combination of textural modeling and stable isotope analysis allows a distinction between several possible reaction paths for olivine growth in a siliceous dolomite contact aureole. It is suggested that olivine forms directly from dolomite and quartz. The formation of olivine from this metastable reaction implies metamorphic crystallization far from equilibrium. As a major consequence, the spatial distribution of metamorphic mineral assemblages in a contact aureole cannot be interpreted as a proxy for the temporal evolution of a single rock specimen, because each rock undergoes a different reaction path, depending on temperature, heating rate, and fluid-infiltration rate. A detailed calcite-dolomite thermometry study was initiated on multiple scales ranging from aureole scale to the size of individual crystals. Quantitative forward models were developed to evaluate the effect of growth zoning, volume diffusion and the formation of submicroscopic exsolution lamellae (<1 µm) on the measured Mg-distribution in individual calcite crystals and compare the modeling results to field data. This study concludes that Mg-distributions in calcite grains of the Ubehebe Peak contact aureole are the consequence of rapid crystal growth in combination with diffusion and exsolution. The crystallization history of a rock is recorded in the chemical composition, the size and the distribution of its minerals. Near the Cima Uzza summit, located in the southern Adamello massif (Italy), contact metamorphic brucite bearing dolomite marbles are exposed as xenoliths surrounded by mafic intrusive rocks. Brucite is formed retrograde pseudomorphing spherical periclase crystals. Crystal size distributions (CSD's) of brucite pseudomorphs are presented for two profiles and combined with geochemistry data and petrological information. Textural analyses are combined with geochemistry data in a qualitative model that describes the formation periclase. As a major outcome, this expands the potential use of CSD's to systems of mineral formation driven by fluid-infiltration. RESUME DE LA THESE La nucléation et la croissance des minéraux métamorphiques sont la conséquence de changements des conditions de pression, température et composition chimique du système (PT-X). Cette thèse s'intéresse aux processus gouvernant la nucléation et la croissance des minéraux au cours d'un épisode de métamorphisme de contact, en utilisant la géochimie analytique (composition chimique, isotopique et en éléments traces), le traitement statistique des données spatiales et la modélisation numérique. Il est montré que la combinaison d'un modèle textural avec des analyses en isotopes stables permet de distinguer plusieurs chemins de réactions possibles conduisant à la croissance de l'olivine dans une auréole de contact riche en Silice et dolomite. Il est suggéré que l'olivine se forme directement à partir de la dolomie et du quartz. Cette réaction métastable de formation de l'olivine implique une cristallisation métamorphique loin de l'équilibre. La principale conséquence est que la distribution spatiale des assemblages de minéraux métamorphiques dans une auréole de contact ne peut pas être considérée comme un témoin de l'évolution temporelle d'un type de roche donné, puisque chaque type de roche suit différents chemins de réactions, en fonction de la température, la vitesse de réchauffement et le taux d'infiltration du fluide. Une étude thermométrique calcite-dolomite détaillée a été réalisée à diverses échelles, depuis l'échelle de l'auréole de contact jusqu'à l'échelle du cristal. Des modèles numériques quantitatifs ont été développés pour évaluer l'effet des zonations de croissance, de la diffusion volumique et de la formation de lamelles d'exsolution submicroscopiques (<1µm) sur la distribution du magnésium mesuré dans des cristaux de calcite individuels. Les résultats de ce modèle ont été comparés ä des échantillons naturels. Cette étude montre que la distribution du Mg dans les grains de calcite de l'auréole de contact de l'Ubehebe Peak (USA) résulte d'une croissance cristalline rapide, associée aux processus de diffusion et d'exsolution. L'histoire de cristallisation d'une roche est enregistrée dans la composition chimique, la taille et la distribution de ses minéraux. Près du sommet Cima Uzza situé au sud du massif d'Adamello (Italie), des marbres dolomitiques à brucite du métamorphisme de contact forment des xénolithes dans une intrusion mafique. La brucite constitue des pseudomorphes rétrogrades du périclase. Les distributions de taille des cristaux (CSD) des pseudomorphes de brucite sont présentées pour deux profiles et sont combinées aux données géochimiques et pétrologiques. Les analyses textorales sont combinées aux données géochimiques dans un modèle qualitatif qui décrit la formation du périclase. Ceci élargit l'utilisation potentielle de la C5D aux systèmes de formation de minéraux controlés par les infiltrations fluides. THESIS ABSTRACT (GENERAL PUBLIC) Rock textures are essentially the result of a complex interaction of nucleation, growth and deformation as a function of changing physical conditions such as pressure and temperature. Igneous and metamorphic textures are especially attractive to study the different mechanisms of texture formation since most of the parameters like pressure-temperature-paths are quite well known for a variety of geological settings. The fact that textures are supposed to record the crystallization history of a rock traditionally allowed them to be used for geothermobarometry or dating. During the last decades the focus of metamorphic petrology changed from a static point of view, i.e. the representation of a texture as one single point in the petrogenetic grid towards a more dynamic view, where multiple metamorphic processes govern the texture formation, including non-equilibrium processes. This thesis tries to advance our understanding on the processes governing nucleation and growth of minerals in contact metamorphic environments and their dynamic interplay by using a combination of geochemical analyses (chemical-, isotope-, and trace element composition), statistical treatments of spatial data and numerical models. In a first part the thesis describes the formation of metamorphic olivine porphyroblast in the Ubehebe Peak contact aureole (USA). It is shown that not the commonly assumed succession of equilibrium reactions along a T-t-path formed the textures present in the rocks today, but rather the presence of a meta-stable reaction is responsible for forming the olivine porphyroblast. Consequently, the spatial distribution of metamorphic minerals within a contact aureole can no longer be regarded as a proxy for the temporal evolution of a single rock sample. Metamorphic peak temperatures for samples of the Ubehebe Peak contact aureole were determined using calcite-dolomite. This geothermometer is based on the temperature-dependent exchange of Mg between calcite and dolomite. The purpose of the second part of this thesis was to explain the interfering systematic scatter of measured Mg-content on different scales and thus to clarify the interpretation of metamorphic temperatures recorded in carbonates. Numerical quantitative forward models are used to evaluate the effect of several processes on the distribution of magnesium in individual calcite crystals and the modeling results were then compared to measured field. Information about the crystallization history is not only recorded in the chemical composition of grains, like isotope composition or mineral zoning. Crystal size distributions (CSD's) provide essential information about the complex interaction of nucleation and growth of minerals. CSD's of brucite pseudomorphs formed retrograde after periclase of the southern Adamello massif (Italy) are presented. A combination of the textural 3D-information with geochemistry data is then used to evaluate reaction kinetics and to constrain the actual reaction mechanism for the formation of periclase. The reaction is shown to be the consequence of the infiltration of a limited amount of a fluid phase at high temperatures. The composition of this fluid phase is in large disequilibrium with the rest of the rock resulting in very fast reaction rates. RESUME DE LA THESE POUR LE GRAND PUBLIC: La texture d'une roche résulte de l'interaction complexe entre les processus de nucléation, croissance et déformation, en fonction des variations de conditions physiques telles que la pression et la température. Les textures ignées et métamorphiques présentent un intérêt particulier pour l'étude des différents mécanismes à l'origine de ces textures, puisque la plupart des paramètres comme les chemin pression-température sont relativement bien contraints dans la plupart des environnements géologiques. Le fait que les textures soient supposées enregistrer l'histoire de cristallisation des roches permet leur utilisation pour la datation et la géothermobarométrie. Durant les dernières décennies, la recherche en pétrologie métamorphique a évolué depuis une visualisation statique, c'est-à-dire qu'une texture donnée correspondait à un point unique de la grille pétrogénétique, jusqu'à une visualisation plus dynamique, où les multiples processus métamorphiques qui gouvernent 1a formation d'une texture incluent des processus hors équilibre. Cette thèse a pour but d'améliorer les connaissances actuelles sur les processus gouvernant la nucléation et la croissance des minéraux lors d'épisodes de métamorphisme de contact et l'interaction dynamique existant entre nucléation et croissance. Pour cela, les analyses géochimiques (compositions chimiques en éléments majeurs et traces et composition isotopique), le traitement statistique des données spatiales et la modélisation numérique ont été combinés. Dans la première partie, cette thèse décrit la formation de porphyroblastes d'olivine métamorphique dans l'auréole de contact de l'Ubehebe Peak (USA). Il est montré que la succession généralement admise des réactions d'équilibre le long d'un chemin T-t ne peut pas expliquer les textures présentes dans les roches aujourd'hui. Cette thèse montre qu'il s'agirait plutôt d'une réaction métastable qui soit responsable de la formation des porphyroblastes d'olivine. En conséquence, la distribution spatiale des minéraux métamorphiques dans l'auréole de contact ne peut plus être interprétée comme le témoin de l'évolution temporelle d'un échantillon unique de roche. Les pics de température des échantillons de l'auréole de contact de l'Ubehebe Peak ont été déterminés grâce au géothermomètre calcite-dolomite. Celui-ci est basé sur l'échange du magnésium entre la calcite et la dolomite, qui est fonction de la température. Le but de la deuxième partie de cette thèse est d'expliquer la dispersion systématique de la composition en magnésium à différentes échelles, et ainsi d'améliorer l'interprétation des températures du métamorphisme enregistrées dans les carbonates. Des modèles numériques quantitatifs ont permis d'évaluer le rôle de différents processus sur la distribution du magnésium dans des cristaux de calcite individuels. Les résultats des modèles ont été comparés aux échantillons naturels. La composition chimique des grains, comme la composition isotopique ou la zonation minérale, n'est pas le seul témoin de l'histoire de la cristallisation. La distribution de la taille des cristaux (CSD) fournit des informations essentielles sur les interactions entre nucléation et croissance des minéraux. La CSD des pseudomorphes de brucite retrograde formés après le périclase dans le sud du massif Adamello (Italie) est présentée dans la troisième partie. La combinaison entre les données textorales en trois dimensions et les données géochimiques a permis d'évaluer les cinétiques de réaction et de contraindre les mécanismes conduisant à la formation du périclase. Cette réaction est présentée comme étant la conséquence de l'infiltration d'une quantité limitée d'une phase fluide à haute température. La composition de cette phase fluide est en grand déséquilibre avec le reste de la roche, ce qui permet des cinétiques de réactions très rapides.

Differential Recognition of Old World and New World Arenavirus Envelope Glycoproteins by Subtilisin Kexin Isozyme 1 (SKI-1)/Site 1 Protease (S1P).

The arenaviruses are an important family of emerging viruses that includes several causative agents of severe hemorrhagic fevers in humans that represent serious public health problems. A crucial step of the arenavirus life cycle is maturation of the envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). Comparison of the currently known sequences of arenavirus GPCs revealed the presence of a highly conserved aromatic residue at position P7 relative to the SKI-1/S1P cleavage side in Old World and clade C New World arenaviruses but not in New World viruses of clades A and B or cellular substrates of SKI-1/S1P. Using a combination of molecular modeling and structure-function analysis, we found that residueY285 of SKI-1/S1P, distal from the catalytic triad, is implicated in the molecular recognition of the aromatic "signature residue" at P7 in the GPC of Old World Lassa virus. Using a quantitative biochemical approach, we show that Y285 of SKI-1/S1P is crucial for the efficient processing of peptides derived from Old World and clade C New World arenavirus GPCs but not of those from clade A and B New World arenavirus GPCs. The data suggest that during coevolution with their mammalian hosts, GPCs of Old World and clade C New World viruses expanded the molecular contacts with SKI-1/S1P beyond the classical four-amino-acid recognition sequences and currently occupy an extended binding pocket.

Prediction of the bulking phenomenon in wastewater treatment plants

The control and prediction of wastewater treatment plants poses an important goal: to avoid breaking the environmental balance by always keeping the system in stable operating conditions. It is known that qualitative information — coming from microscopic examinations and subjective remarks — has a deep influence on the activated sludge process. In particular, on the total amount of effluent suspended solids, one of the measures of overall plant performance. The search for an input–output model of this variable and the prediction of sudden increases (bulking episodes) is thus a central concern to ensure the fulfillment of current discharge limitations. Unfortunately, the strong interrelationbetween variables, their heterogeneity and the very high amount of missing information makes the use of traditional techniques difficult, or even impossible. Through the combined use of several methods — rough set theory and artificial neural networks, mainly — reasonable prediction models are found, which also serve to show the different importance of variables and provide insight into the process dynamics

Local influence for spatial analysis of soil physical properties and soybean yield using student's t-distribution

The modeling and estimation of the parameters that define the spatial dependence structure of a regionalized variable by geostatistical methods are fundamental, since these parameters, underlying the kriging of unsampled points, allow the construction of thematic maps. One or more atypical observations in the sample data can affect the estimation of these parameters. Thus, the assessment of the combined influence of these observations by the analysis of Local Influence is essential. The purpose of this paper was to propose local influence analysis methods for the regionalized variable, given that it has n-variate Student's t-distribution, and compare it with the analysis of local influence when the same regionalized variable has n-variate normal distribution. These local influence analysis methods were applied to soil physical properties and soybean yield data of an experiment carried out in a 56.68 ha commercial field in western Paraná, Brazil. Results showed that influential values are efficiently determined with n-variate Student's t-distribution.

Lack of Enantioselectivity in the SULT1A3-catalyzed Sulfoconjugation of Normetanephrine Enantiomers: An In Vitro and Computational Study.

(1R)-Normetanephrine is the natural stereoisomeric substrate for sulfotransferase 1A3 (SULT1A3)-catalyzed sulfonation. Nothing appears known on the enantioselectivity of the reaction despite its potential significance in the metabolism of adrenergic amines and in clinical biochemistry. We confronted the kinetic parameters of the sulfoconjugation of synthetic (1R)-normetanephrine and (1S)-normetanephrine by recombinant human SULT1A3 to a docking model of each normetanephrine enantiomer with SULT1A3 and the 3'-phosphoadenosine-5'-phosphosulfate cofactor on the basis of molecular modeling and molecular dynamics simulations of the stability of the complexes. The K(M) , V(max) , and k(cat) values for the sulfonation of (1R)-normetanephrine, (1S)-normetanephrine, and racemic normetanephrine were similar. In silico models were consistent with these findings as they showed that the binding modes of the two enantiomers were almost identical. In conclusion, SULT1A3 is not substrate-enantioselective toward normetanephrine, an unexpected finding explainable by a mutual adaptability between the ligands and SULT1A3 through an "induced-fit model" in the catalytic pocket. Chirality, 00:000-000, 2012.© 2012 Wiley Periodicals, Inc.

Integrating species distribution models (SDMs) and phylogeography for two species of Alpine Primula.

The major intention of the present study was to investigate whether an approach combining the use of niche-based palaeodistribution modeling and phylo-geography would support or modify hypotheses about the Quaternary distributional history derived from phylogeographic methods alone. Our study system comprised two closely related species of Alpine Primula. We used species distribution models based on the extant distribution of the species and last glacial maximum (LGM) climate models to predict the distribution of the two species during the LGM. Phylogeographic data were generated using amplified fragment length polymorphisms (AFLPs). In Primula hirsuta, models of past distribution and phylogeographic data are partly congruent and support the hypothesis of widespread nunatak survival in the Central Alps. Species distribution models (SDMs) allowed us to differentiate between alpine regions that harbor potential nunatak areas and regions that have been colonized from other areas. SDMs revealed that diversity is a good indicator for nunataks, while rarity is a good indicator for peripheral relict populations that were not source for the recolonization of the inner Alps. In P. daonensis, palaeo-distribution models and phylogeographic data are incongruent. Besides the uncertainty inherent to this type of modeling approach (e.g., relatively coarse 1-km grain size), disagreement of models and data may partly be caused by shifts of ecological niche in both species. Nevertheless, we demonstrate that the combination of palaeo-distribution modeling with phylogeographical approaches provides a more differentiated picture of the distributional history of species and partly supports (P. hirsuta) and partly modifies (P. daonensis and P. hirsuta) hypotheses of Quaternary distributional history. Some of the refugial area indicated by palaeodistribution models could not have been identified with phylogeographic data.

Statistical modeling of bowing control applied to violin sound synthesis

Excitation-continuous music instrument control patterns are often not explicitly represented in current sound synthesis techniques when applied to automatic performance. Both physical model-based and sample-based synthesis paradigmswould benefit from a flexible and accurate instrument control model, enabling the improvement of naturalness and realism. Wepresent a framework for modeling bowing control parameters inviolin performance. Nearly non-intrusive sensing techniques allow for accurate acquisition of relevant timbre-related bowing control parameter signals.We model the temporal contour of bow velocity, bow pressing force, and bow-bridge distance as sequences of short Bézier cubic curve segments. Considering different articulations, dynamics, and performance contexts, a number of note classes are defined. Contours of bowing parameters in a performance database are analyzed at note-level by following a predefined grammar that dictates characteristics of curve segment sequences for each of the classes in consideration. As a result, contour analysis of bowing parameters of each note yields an optimal representation vector that is sufficient for reconstructing original contours with significant fidelity. From the resulting representation vectors, we construct a statistical model based on Gaussian mixtures suitable for both the analysis and synthesis of bowing parameter contours. By using the estimated models, synthetic contours can be generated through a bow planning algorithm able to reproduce possible constraints caused by the finite length of the bow. Rendered contours are successfully used in two preliminary synthesis frameworks: digital waveguide-based bowed stringphysical modeling and sample-based spectral-domain synthesis.

Calibration of Highway Safety Manual Work Zone Crash Modification Factors, TPF-5(081), 2014

The Highway Safety Manual is the national safety manual that provides quantitative methods for analyzing highway safety. The HSM presents crash modification factors related to work zone characteristics such as work zone duration and length. These crash modification factors were based on high-impact work zones in California. Therefore there was a need to use work zone and safety data from the Midwest to calibrate these crash modification factors for use in the Midwest. Almost 11,000 Missouri freeway work zones were analyzed to derive a representative and stratified sample of 162 work zones. The 162 work zones was more than four times the number of work zones used in the HSM. This dataset was used for modeling and testing crash modification factors applicable to the Midwest. The dataset contained work zones ranging from 0.76 mile to 9.24 miles and with durations from 16 days to 590 days. A combined fatal/injury/non-injury model produced a R2 fit of 0.9079 and a prediction slope of 0.963. The resulting crash modification factors of 1.01 for duration and 0.58 for length were smaller than the values in the HSM. Two practical application examples illustrate the use of the crash modification factors for comparing alternate work zone setups.