Analysis of population pharmacokinetic data using NONMEM and WinBUGS

The aim of this report is to describe the use of WinBUGS for two datasets that arise from typical population pharmacokinetic studies. The first dataset relates to gentamicin concentration-time data that arose as part of routine clinical care of 55 neonates. The second dataset incorporated data from 96 patients receiving enoxaparin. Both datasets were originally analyzed by using NONMEM. In the first instance, although NONMEM provided reasonable estimates of the fixed effects parameters it was unable to provide satisfactory estimates of the between-subject variance. In the second instance, the use of NONMEM resulted in the development of a successful model, albeit with limited available information on the between-subject variability of the pharmacokinetic parameters. WinBUGS was used to develop a model for both of these datasets. Model comparison for the enoxaparin dataset was performed by using the posterior distribution of the log-likelihood and a posterior predictive check. The use of WinBUGS supported the same structural models tried in NONMEM. For the gentamicin dataset a one-compartment model with intravenous infusion was developed, and the population parameters including the full between-subject variance-covariance matrix were available. Analysis of the enoxaparin dataset supported a two compartment model as superior to the one-compartment model, based on the posterior predictive check. Again, the full between-subject variance-covariance matrix parameters were available. Fully Bayesian approaches using MCMC methods, via WinBUGS, can offer added value for analysis of population pharmacokinetic data.

A quantum yield map for synthetic eumelanin

The quantum yield of synthetic eumelanin is known to be extremely low and it has recently been reported to be dependent on excitation wavelength. In this paper, we present quantum yield as a function of excitation wavelength between 250 and 500 nm, showing it to be a factor of 4 higher at 250 nm than at 500 nm. In addition, we present a definitive map of the steady-state fluorescence as a function of excitation and emission wavelengths, and significantly, a three-dimensional map of the specific quantum yield: the fraction of photons absorbed at each wavelength that are subsequently radiated at each emission wavelength. This map contains clear features, which we attribute to certain structural models, and shows that radiative emission and specific quantum yield are negligible at emission wavelengths outside the range of 585 and 385 nm (2.2 and 3.2 eV), regardless of excitation wavelength. This information is important in the context of understanding melanin biofunctionality, and the quantum molecular biophysics therein. (c) 2005 American Institute of Physics.

Mimicking the action of GroEL in molecular dynamics simulations: Application to the refinement of protein structures

Bacterial chaperonin, GroEL, together with its co-chaperonin, GroES, facilitates the folding of a variety of polypeptides. Experiments suggest that GroEL stimulates protein folding by multiple cycles of binding and release. Misfolded proteins first bind to an exposed hydrophobic surface on GroEL. GroES then encapsulates the substrate and triggers its release into the central cavity of the GroEL/ES complex for folding. In this work, we investigate the possibility to facilitate protein folding in molecular dynamics simulations by mimicking the effects of GroEL/ES namely, repeated binding and release, together with spatial confinement. During the binding stage, the (metastable) partially folded proteins are allowed to attach spontaneously to a hydrophobic surface within the simulation box. This destabilizes the structures, which are then transferred into a spatially confined cavity for folding. The approach has been tested by attempting to refine protein structural models generated using the ROSETTA procedure for ab initio structure prediction. Dramatic improvements in regard to the deviation of protein models from the corresponding experimental structures were observed. The results suggest that the primary effects of the GroEL/ES system can be mimicked in a simple coarse-grained manner and be used to facilitate protein folding in molecular dynamics simulations. Furthermore, the results Sur port the assumption that the spatial confinement in GroEL/ES assists the folding of encapsulated proteins.

Managing performance of organisational units with PIMsoft:a new DEA software

DEA literature continues apace but software has lagged behind. This session uses suitably selected data to present newly developed software which includes many of the most recent DEA models. The software enables the user to address a variety of issues not frequently found in existing DEA software such as: -Assessments under a variety of possible assumptions of returns to scale including NIRS and NDRS; -Scale elasticity computations; -Numerous Input/Output variables and truly unlimited number of assessment units (DMUs) -Panel data analysis -Analysis of categorical data (multiple categories) -Malmquist Index and its decompositions -Computations of Supper efficiency -Automated removal of super-efficient outliers under user-specified criteria; -Graphical presentation of results -Integrated statistical tests

Transitive state alignment for the quantum jensen-shannon kernel

Kernel methods provide a convenient way to apply a wide range of learning techniques to complex and structured data by shifting the representational problem from one of finding an embedding of the data to that of defining a positive semidefinite kernel. One problem with the most widely used kernels is that they neglect the locational information within the structures, resulting in less discrimination. Correspondence-based kernels, on the other hand, are in general more discriminating, at the cost of sacrificing positive-definiteness due to their inability to guarantee transitivity of the correspondences between multiple graphs. In this paper we generalize a recent structural kernel based on the Jensen-Shannon divergence between quantum walks over the structures by introducing a novel alignment step which rather than permuting the nodes of the structures, aligns the quantum states of their walks. This results in a novel kernel that maintains localization within the structures, but still guarantees positive definiteness. Experimental evaluation validates the effectiveness of the kernel for several structural classification tasks. © 2014 Springer-Verlag Berlin Heidelberg.

Mechanisms of Arsenic Detoxification and Resistance

Arsenic is a ubiquitous environmental toxic substance. As a consequence of continual exposure to arsenic, nearly every organism, from Escherichia coli to humans have evolved arsenic detoxification pathways. One of the pathways is extrusion of arsenic from inside the cells, thereby conferring resistance. The R773 arsRDABC operon in E. coli encodes an ArsAB efflux pump that confers resistance to arsenite. ArsA is the catalytic subunit of the pump, while ArsB forms the oxyanion conducting pathway. ArsD is an arsenite metallochaperone that binds arsenite and transfers it to ArsA. The interaction of ArsA and ArsD allows for resistance to As(III) at environmental concentrations. The interaction between ArsA ATPase and ArsD metallochaperone was examined. A quadruple mutant in the arsD gene encoding a K2A/K37A/K62A/K104A ArsD is unable to interact with ArsA. An error-prone mutagenesis approach was used to generate random mutations in the arsA gene that restored interaction with the quadruple arsD mutant in yeast two-hybrid assays. Three such mutants encoding Q56R, F120I and D137V ArsA were able to restore interaction with the quadruple ArsD mutant. Structural models generated by in silico docking suggest that an electrostatic interface favors reversible interaction between ArsA and ArsD. Mutations in ArsA that propagate changes in hydrogen bonding and salt bridges to the ArsA-ArsD interface also affect their interactions. The second objective was to examine the mechanism of arsenite resistance through methylation and subsequent volatilization. Microbial ArsM (As(III) S-adenosylmethyltransferase) catalyzes the formation of trimethylarsine as the volatile end product. The net result is loss of arsenic from cells. The gene for CrArsM from the eukaryotic green alga Chlamydomonas reinhardtii was chemically synthesized and expressed in E. coli. The purified protein catalyzed the methylation of arsenite into methyl-, dimethyl- and trimethyl products. Synthetic purified CrArsM was crystallized in an unliganded form. Biochemical and biophysical studies conducted on CrArsM sheds new light on the pathways of biomethylation. While in microbes ArsM detoxifies arsenic, the human homolog, hAS3MT, converts inorganic arsenic into more toxic and carcinogenic forms. An understanding of the enzymatic mechanism of ArsM will be critical in deciphering its parallel roles in arsenic detoxification and carcinogenesis.

Biogenic opal, carbonat concentrations and stable oxygen isotope ratios of foraminifera from sediment cores of the Southern Ocean

We present records of biogenic opal percentage and burial rate in 12 piston cores from the Atlantic and Indian sectors of the Southern Ocean. These records provide a detailed, quantitative description of changing patterns of opal deposition over the last 450 kyr. The striking regional coherence of these records suggests that dissolution in the deep sea and sediment pore waters does not obscure the surface productivity signal, and therefore these opal time series can be used in combination with other surface water tracers to make inferences about the chemistry and circulation of the Southern Ocean under different global climate conditions. Three broad depositional patterns can be distinguished. Northernmost records (39°-42°S latitude) are characterized by enhanced opal burial during glacial periods and strong 41 kyr periodicity. Records from cores just north of the present Antarctic Polar Front (46°-49°S) show even larger increases in opal burial rate during glacial intervals, but have variance concentrated in the 100 and 23 kyr bands. Southernmost records (51°-55°S) are completely out of phase with those to the north, with greatly reduced opal burial rates during glacial periods. Taken as a whole, the opal records show no evidence for the increased total Antarctic productivity predicted by recent geochemical models of atmospheric CO2 variability. The areal expansion of Southern Ocean sea ice over the present zone of high siliceous productivity provides one plausible explanation for the glacial-interglacial opal patterns. The excess silica not taken up in this zone during glacial periods would contribute to greater nutrient availability and thus higher productivity in the subantarctic region. However, local circulation changes may act to modify this basic signal, possibly accounting for the observed differences in the opal variance spectra.

Model reduction for nonlinear aerodynamics and aeroelasticity using a Discrete Empirical Interpolation Method

A novel surrogate model is proposed in lieu of Computational Fluid Dynamics (CFD) solvers, for fast nonlinear aerodynamic and aeroelastic modeling. A nonlinear function is identified on selected interpolation points by
a discrete empirical interpolation method (DEIM). The flow field is then reconstructed using a least square approximation of the flow modes extracted
by proper orthogonal decomposition (POD). The aeroelastic reduce order
model (ROM) is completed by introducing a nonlinear mapping function
between displacements and the DEIM points. The proposed model is investigated to predict the aerodynamic forces due to forced motions using
a N ACA 0012 airfoil undergoing a prescribed pitching oscillation. To investigate aeroelastic problems at transonic conditions, a pitch/plunge airfoil
and a cropped delta wing aeroelastic models are built using linear structural models. The presence of shock-waves triggers the appearance of limit
cycle oscillations (LCO), which the model is able to predict. For all cases
tested, the new ROM shows the ability to replicate the nonlinear aerodynamic forces, structural displacements and reconstruct the complete flow
field with sufficient accuracy at a fraction of the cost of full order CFD
model.

Projeto de estabilidade de um edifício para uma sala elétrica em betão armado e estrutura metálica

Trabalho de Projeto para obtenção do grau de Mestre em Engenharia Civil na Área de Especialização Estruturas

Analyzing change in medication use - statistical approaches

The objective of this study was to gain an understanding of the effects of population heterogeneity, missing data, and causal relationships on parameter estimates from statistical models when analyzing change in medication use. From a public health perspective, two timely topics were addressed: the use and effects of statins in populations in primary prevention of cardiovascular disease and polypharmacy in older population. Growth mixture models were applied to characterize the accumulation of cardiovascular and diabetes medications among apparently healthy population of statin initiators. The causal effect of statin adherence on the incidence of acute cardiovascular events was estimated using marginal structural models in comparison with discrete-time hazards models. The impact of missing data on the growth estimates of evolution of polypharmacy was examined comparing statistical models under different assumptions for missing data mechanism. The data came from Finnish administrative registers and from the population-based Geriatric Multidisciplinary Strategy for the Good Care of the Elderly study conducted in Kuopio, Finland, during 2004–07. Five distinct patterns of accumulating medications emerged among the population of apparently healthy statin initiators during two years after statin initiation. Proper accounting for time-varying dependencies between adherence to statins and confounders using marginal structural models produced comparable estimation results with those from a discrete-time hazards model. Missing data mechanism was shown to be a key component when estimating the evolution of polypharmacy among older persons. In conclusion, population heterogeneity, missing data and causal relationships are important aspects in longitudinal studies that associate with the study question and should be critically assessed when performing statistical analyses. Analyses should be supplemented with sensitivity analyses towards model assumptions.

Quichua-Spanish language contact in Salcedo, Ecuador: revisiting media lengua syncretic language practices

The purpose of the current thesis is to develop a better understanding of the interaction between Spanish and Quichua in the Salcedo region and provide more information for the processes that might have given rise to Media Lengua, a ‘mixed’ language comprised of a Quichua grammar and Spanish lexicon. Muysken attributes the formation of Media Lengua to relexification, ruling out any influence from other bilingual phenomena. I argue that the only characteristic that distinguishes Media Lengua from other language contact varieties in central Ecuador is the quantity of the overall Spanish borrowings and not the type of processes that might have been employed by Quichua speakers during the genesis of Media Lengua. The results from the Salcedo data that I have collected show how processes such as adlexification, code-mixing, and structural convergence produce Media Lengua-type sentences, evidence that supports an alternative analysis to Muysken’s relexification hypothesis. Overall, this dissertation is developed around four main objectives: (1) to describe the variation of Spanish loanwords within a bilingual community in Salcedo; (2) to analyze some of the prominent and recent structural changes in Quichua and Spanish; (3) to determine whether Spanish loanword use can be explained by the relationship consultants have with particular social categories; and (4) to analyze the consultants’ language ideologies toward syncretic uses of Spanish and Quichua. Overall, 58% of the content words, 39% of the basic vocabulary, and 50% of the subject pronouns in the Salcedo corpus were derived from Spanish. When compared to Muysken’s description of highlander Quichua in the 1970’s, Spanish loanwords have more than doubled in each category. The overall level of Spanish loanwords in Salcedo Quichua has grown to a level between highlander Quichua in the 1970’s and Media Lengua. Similar to Spanish’s lexical influence in Media Lengua, the increase of Spanish borrowings in today’s rural Quichua can be seen in non-basic and basic vocabularies as well as the subject pronoun system. Significantly, most of the growth has occurred through forms of adlexification i.e., doublets, well-established borrowings, and cultural borrowings, suggesting that ‘ordinary’ lexical borrowing is also capable of producing Media Lengua-type sentences. I approach the second objective by investigating two separate phenomena related to structural convergence. The first examines the complex verbal constructions that have developed in Quichua through Spanish loan translations while the second describes the type of Quichua particles that are attached to Spanish lexemes while speaking Spanish. The calquing of the complex verbal constructions from Spanish were employed when speaking standard Quichua. Since this standard form is typically used by language purists, I argue that their use of calques is a strategy of exploiting the full range of expression from Spanish without incorporating any of the Spanish lexemes which would give the appearance of ‘contamination’. The use of Quichua particles in local varieties of Spanish is a defining characteristic of Quichuacized Spanish, spoken most frequently by women and young children in the community. Although the use of Quichua particles was probably not the main catalyst engendering Media Lengua, I argue that its contribution as a source language to other ‘mixed’ varieties, such as Media Lengua, needs to be accounted for in descriptions of BML genesis. Contrary to Muysken’s representation of relatively ‘unmixed’ Spanish and Quichua as the two source languages of Media Lengua, I propose that local varieties of Spanish might have already been ‘mixed’ to a large degree before Media Lengua was created. The third objective attempts to draw a relationship between particular social variables and the use of Spanish loanwords. Whisker Boxplots and ANOVAs were used to determine which social group, if any, have been introducing new Spanish borrowings into the bilingual communities in Salcedo. Specifically, I controlled for age, education, native language, urban migration, and gender. The results indicate that none of the groups in each of the five social variables indicate higher or lower loanword use. The implication of these results are twofold: (a) when lexical borrowing occurs, it is immediately adopted as the community-wide norm and spoken by members from different backgrounds and generations, or (b) this level of Spanish borrowing (58%) is not a recent phenomenon. The fourth and final objective draws on my ethnographic research that addresses the attitudes of syncretic language use. I observed that Quichuacized Spanish and Hispanicized Quichua are highly stigmatized varieties spoken by the country’s most marginalized populations and families, yet within the community, syncretic ways of speaking are in fact the norm. It was shown that there exists a range of different linguistic definitions for ‘Chaupi Lengua’ and other syncretic language practices as well as many contrasting connotations, most of which were negative. One theme that emerged from the interviews was that speaking syncretic varieties of Quichua weakened the consultant’s claim to an indigenous identity. The linguistic and social data presented in this dissertation supports an alternative view to Muysken’s relexification hypothesis, one that has the advantage of operating with well-precedented linguistic processes and which is actually observable in the present-day Salcedo area. The results from the study on lexical borrowing are significant because they demonstrate how a dynamic bilingual speech community has gradually diversified their Quichua lexicon under intense pressure to shift toward Spanish. They also show that Hispanicized Quichua (Quichua with heavy lexical borrowing) clearly arose from adlexification and prolonged lexical borrowing, and is one of at least six identifiable speech styles found in Salcedo. These results challenge particular interpretations of language contact outcomes, such as, ones that depict sources languages as discrete and ‘unmixed.’ The bilingual continuum presented in this thesis shows on the one hand, the range of speech styles that are accessible to different speakers, and on the other hand, the overlapping, syncretic features that are shared among the different registers and language varieties. It was observed that syncretic speech styles in Salcedo are employed by different consultants in varied interactional contexts, and in turn, produce different evaluations by other fellow community members. In the current dissertation, I challenge the claim that relexification and Media Lengua-type sentences develop in isolation and without the influence of other bilingual phenomena. Based on Muysken's Media Lengua example sentences and the speech styles from the Salcedo corpus, I argue that Media Lengua may have arisen as an institutionalized variant of the highly mixed "middle ground" within the range of the Salcedo bilingual continuum discussed above. Such syncretic forms of Spanish and Quichua strongly resemble Media Lengua sentences in Muysken’s research, and therefore demonstrate how its development could have occurred through several different language contact processes and not only through relexification.

Core-level photoemission investigations of the CDTE(100) and INSB(100) surface and interfacial structures

Photoemission techniques, utilizing a synchrotron light source, were used to analyze the clean (100) surfaces of the zinc-blende semiconductor materials CdTe and InSb. Several interfacial systems involving the surfaces of these materials were also studied, including the CdTe(lOO)-Ag interface, the CdTe(lOO)-Sb system, and the InSb(lOO)-Sn interface. High-energy electron diffraction was also employed to acquire information about of surface structure. A one-domain (2xl) structure was observed for the CdTe(lOO) surface. Analysis of photoemission spectra of the Cd 4d core level for this surface structure revealed two components resulting from Cd surface atoms. The total intensity of these components accounts for a full monolayer of Cd atoms on the surface. A structural model is discussed commensurate with these results. Photoemission spectra of the Cd and Te 4d core levels indicate that Ag or Sb deposited on the CdTe(l00)-(2xl) surface at room temperature do not bound strongly to the surface Cd atoms. The room temperature growth characteristics for these two elements on the CdTe(lOO)-(2xl) are discussed. The growth at elevated substrate temperatures was also studied for Sb deposition. The InSb(lOO) surface differed from the CdTe(lOO) surface. Using molecular beam epitaxy, several structures could be generated for the InSb(lOO) surface, including a c(8x2), a c(4x4), an asymmetric (lx3), a symmetric (lx3), and a (lxl). Analysis of photoemission intensities and line shapes indicates that the c(4x4) surface is terminated with 1-3/4 monolayers of Sb atoms. The c(8x2) surface is found to be terminated with 3/4 monolayer of In atoms. Structural models for both of these surfaces are proposed based upon the photoemission results and upon models of the similar GaAs(lOO) structures. The room temperature growth characteristics of grey Sn on the lnSb(lOO)-c(4x4) and InSb(l00)-c(8x2) surfaces were studied with photoemission. The discontinuity in the valence band maximum for this semiconductor heterojunction system is measured to be 0.40 eV, independent of the starting surface structure and stoichiometry. This result is reconciled with theoretical predictions for heterostructure behavior.

Estudo do genoma do vírus causador da mionecrose infecciosa em camarões e desenvolvimento de métodos para detecção de polimorfismos

Shrimp farming is one of the activities that contribute most to the growth of global aquaculture. However, this business has undergone significant economic losses due to the onset of viral diseases such as Infectious Myonecrosis (IMN). The IMN is already widespread throughout Northeastern Brazil and affects other countries such as Indonesia, Thailand and China. The main symptom of disease is myonecrosis, which consists of necrosis of striated muscles of the abdomen and cephalothorax of shrimp. The IMN is caused by infectious myonecrosis virus (IMNV), a non-enveloped virus which has protrusions along its capsid. The viral genome consists of a single molecule of double-stranded RNA and has two Open Reading Frames (ORFs). The ORF1 encodes the major capsid protein (MCP) and a potential RNA binding protein (RBP). ORF2 encodes a probable RNA-dependent RNA polymerase (RdRp) and classifies IMNV in Totiviridae family. Thus, the objective of this research was study the IMNV complete genome and encoded proteins in order to develop a system differentiate virus isolates based on polymorphisms presence. The phylogenetic relationship among some totivirus was investigated and showed a new group to IMNV within Totiviridae family. Two new genomes were sequenced, analyzed and compared to two other genomes already deposited in GenBank. The new genomes were more similar to each other than those already described. Conserved and variable regions of the genome were identified through similarity graphs and alignments using the four IMNV sequences. This analyze allowed mapping of polymorphic sites and revealed that the most variable region of the genome is in the first half of ORF1, which coincides with the regions that possibly encode the viral protrusion, while the most stable regions of the genome were found in conserved domains of proteins that interact with RNA. Moreover, secondary structures were predicted for all proteins using various softwares and protein structural models were calculated using threading and ab initio modeling approaches. From these analyses was possible to observe that the IMNV proteins have motifs and shapes similar to proteins of other totiviruses and new possible protein functions have been proposed. The genome and proteins study was essential for development of a PCR-based detection system able to discriminate the four IMNV isolates based on the presence of polymorphic sites

Design gráfico para televisão

Dissertação para obtenção do grau de Mestre em Design de Comunicação apresentada na Universidade de Lisboa - Faculdade de Arquitetura.

E-handel- Konkurrent eller komplement för mikroföretag? : En studie om lokala mikroföretag

I dagens samhälle har det skett en strukturomvandling på marknaden gällande detaljhandeln.Strukturomvandlingen har inneburit utveckling av bland annat omnikanaler och e-handelvilket har förändrat företagens affärsmodellsval för att kunna överleva på marknaden. Ehandelnhar i många år setts som en konkurrent för mikroföretag, men det börjar även blimöjligt för mikroföretag att införa ett integrerat system som innebär att den fysiska butikensamverkar med e-handeln. Resultatet av de ökade möjligheterna för mikroföretag är att de kanvälja mellan tre olika affärsmodellsval gällande sin marknadsplats och tillgänglighet avföretaget och sedan utifrån omnikanaler kan företagen välja hur de vill nå ut tillkonsumenterna.I denna studie vill vi få en ökad förståelse för hur lokala mikroföretag arbetar med att behållasin marknadsplats i den ökade konkurrensen som blir i och med e-handelns tillväxt. För attkunna undersöka mikroföretagen har vi tillämpat en kvalitativ metod med djupgåendehalvstrukturerade intervjuer. För att få reda på hur lokala handlare uppfattar marknaden,konkurrensen och handelsutvecklingen, intervjuades fem stycken strategiskt valdadetaljhandelsföretag.Av undersökningen framgick det att en gemensam syn kring marknaden föreligger vilketinnebar att oavsett företagens val så har företagen sitt fokus på konsumenten. Det framgickäven att en av de viktigaste framgångsfaktorerna är att tillgodose konsumenten med högservicegrad och på så sätt skapa en relation. Relationer bidrar till återkommande och lojalakonsumenter vilket i sin tur bidrar till lönsamhet för företaget. Samtliga informanter var enigaom att relationer upprättas i den fysiska butiken och har således valt att fokusera på denenskilda butiken i internets ständiga utveckling. För att attrahera konsumenter till butiken harde valt att tillhandahålla ett unikt sortiment. Sammanfattningsvis har internet och handelnsutveckling och den konkurrens det medför på lokala handlarna blivit tvungna ta ställning tilldet och anpassa en affärsmodell utefter sin egen verksamhet.