Literature Review: Investigating Drug Transport at the Blood-Brain Barrier and the Effects of P-glycoprotein on the Brain Distribution of Drugs.

The blood-brain barrier (BBB) is a unique barrier that strictly regulates the entry of endogenous substrates and xenobiotics into the brain. This is due to its tight junctions and the array of transporters and metabolic enzymes that are expressed. The determination of brain concentrations in vivo is difficult, laborious and expensive which means that there is interest in developing predictive tools of brain distribution. Predicting brain concentrations is important even in early drug development to ensure efficacy of central nervous system (CNS) targeted drugs and safety of non-CNS drugs. The literature review covers the most common current in vitro, in vivo and in silico methods of studying transport into the brain, concentrating on transporter effects. The consequences of efflux mediated by p-glycoprotein, the most widely characterized transporter expressed at the BBB, is also discussed. The aim of the experimental study was to build a pharmacokinetic (PK) model to describe p-glycoprotein substrate drug concentrations in the brain using commonly measured in vivo parameters of brain distribution. The possibility of replacing in vivo parameter values with their in vitro counterparts was also studied. All data for the study was taken from the literature. A simple 2-compartment PK model was built using the Stella™ software. Brain concentrations of morphine, loperamide and quinidine were simulated and compared with published studies. Correlation of in vitro measured efflux ratio (ER) from different studies was evaluated in addition to studying correlation between in vitro and in vivo measured ER. A Stella™ model was also constructed to simulate an in vitro transcellular monolayer experiment, to study the sensitivity of measured ER to changes in passive permeability and Michaelis-Menten kinetic parameter values. Interspecies differences in rats and mice were investigated with regards to brain permeability and drug binding in brain tissue. Although the PK brain model was able to capture the concentration-time profiles for all 3 compounds in both brain and plasma and performed fairly well for morphine, for quinidine it underestimated and for loperamide it overestimated brain concentrations. Because the ratio of concentrations in brain and blood is dependent on the ER, it is suggested that the variable values cited for this parameter and its inaccuracy could be one explanation for the failure of predictions. Validation of the model with more compounds is needed to draw further conclusions. In vitro ER showed variable correlation between studies, indicating variability due to experimental factors such as test concentration, but overall differences were small. Good correlation between in vitro and in vivo ER at low concentrations supports the possibility of using of in vitro ER in the PK model. The in vitro simulation illustrated that in the simulation setting, efflux is significant only with low passive permeability, which highlights the fact that the cell model used to measure ER must have low enough paracellular permeability to correctly mimic the in vivo situation.

Model-following Neuro-adaptive approach for robust control of high performance aircrafts

Based on dynamic inversion, a relatively straightforward approach is presented in this paper for nonlinear flight control design of high performance aircrafts, which does not require the normal and lateral acceleration commands to be first transferred to body rates before computing the required control inputs. This leads to substantial improvement of the tracking response. Promising results are obtained from six degree-offreedom simulation studies of F-16 aircraft, which are found to be superior as compared to an existing approach (which is also based on dynamic inversion). The new approach has two potential benefits, namely reduced oscillatory response (including elimination of non-minimum phase behavior) and reduced control magnitude. Next, a model-following neuron-adaptive design is augmented the nominal design in order to assure robust performance in the presence of parameter inaccuracies in the model. Note that in the approach the model update takes place adaptively online and hence it is philosophically similar to indirect adaptive control. However, unlike a typical indirect adaptive control approach, there is no need to update the individual parameters explicitly. Instead the inaccuracy in the system output dynamics is captured directly and then used in modifying the control. This leads to faster adaptation, which helps in stabilizing the unstable plant quicker. The robustness study from a large number of simulations shows that the adaptive design has good amount of robustness with respect to the expected parameter inaccuracies in the model.

A High‐Gain Audiofrequency Amplifier

The design of a three‐stage high‐gain amplifier for laboratory use in audiofrequency investigations is described. Four‐electrode tubes are used as screen‐grid amplifiers and an amplification of the order of 200 per stage is obtained. The inaccuracy of McDonald's formula for calculation of stage‐gain has been pointed out. The gain‐frequency characteristics are given for power as well as voltage amplification. It is shown that extreme care is necessary in the design of shielding to obtain high‐voltage amplification of the order of 120 decibels as obtained in this three‐stage amplifier.

Adaptive Flight-Control Design Using Neural-Network-Aided Optimal Nonlinear Dynamic Inversion

A neural-network-aided nonlinear dynamic inversion-based hybrid technique of model reference adaptive control flight-control system design is presented in this paper. Here, the gains of the nonlinear dynamic inversion-based flight-control system are dynamically selected in such a manner that the resulting controller mimics a single network, adaptive control, optimal nonlinear controller for state regulation. Traditional model reference adaptive control methods use a linearized reference model, and the presented control design method employs a nonlinear reference model to compute the nonlinear dynamic inversion gains. This innovation of designing the gain elements after synthesizing the single network adaptive controller maintains the advantages that an optimal controller offers, yet it retains a simple closed-form control expression in state feedback form, which can easily be modified for tracking problems without demanding any a priori knowledge of the reference signals. The strength of the technique is demonstrated by considering the longitudinal motion of a nonlinear aircraft system. An extended single network adaptive control/nonlinear dynamic inversion adaptive control design architecture is also presented, which adapts online to three failure conditions, namely, a thrust failure, an elevator failure, and an inaccuracy in the estimation of C-M alpha. Simulation results demonstrate that the presented adaptive flight controller generates a near-optimal response when compared to a traditional nonlinear dynamic inversion controller.

A Smooth Discretization Bridging Finite Element and Mesh-free Methods Using Polynomial Reproducing Simplex Splines

This work sets forth a `hybrid' discretization scheme utilizing bivariate simplex splines as kernels in a polynomial reproducing scheme constructed over a conventional Finite Element Method (FEM)-like domain discretization based on Delaunay triangulation. Careful construction of the simplex spline knotset ensures the success of the polynomial reproduction procedure at all points in the domain of interest, a significant advancement over its precursor, the DMS-FEM. The shape functions in the proposed method inherit the global continuity (Cp-1) and local supports of the simplex splines of degree p. In the proposed scheme, the triangles comprising the domain discretization also serve as background cells for numerical integration which here are near-aligned to the supports of the shape functions (and their intersections), thus considerably ameliorating an oft-cited source of inaccuracy in the numerical integration of mesh-free (MF) schemes. Numerical experiments show the proposed method requires lower order quadrature rules for accurate evaluation of integrals in the Galerkin weak form. Numerical demonstrations of optimal convergence rates for a few test cases are given and the method is also implemented to compute crack-tip fields in a gradient-enhanced elasticity model.

Experimental and finite element studies of a large arch dam

Forced vibration field tests and finite element studies have been conducted on Morrow Point (arch) Dam in order to investigate dynamic dam-water interaction and water compressibility. Design of the data acquisition system incorporates several special features to retrieve both amplitude and phase of the response in a low signal to noise environment. These features contributed to the success of the experimental program which, for the first time, produced field evidence of water compressibility; this effect seems to play a significant role only in the symmetric response of Morrow Point Dam in the frequency range examined. In the accompanying analysis, frequency response curves for measured accelerations and water pressures as well as their resonating shapes are compared to predictions from the current state-of-the-art finite element model for which water compressibility is both included and neglected. Calibration of the numerical model employs the antisymmetric response data since they are only slightly affected by water compressibility, and, after calibration, good agreement to the data is obtained whether or not water compressibility is included. In the effort to reproduce the symmetric response data, on which water compressibility has a significant influence, the calibrated model shows better correlation when water compressibility is included, but the agreement is still inadequate. Similar results occur using data obtained previously by others at a low water level. A successful isolation of the fundamental water resonance from the experimental data shows significantly different features from those of the numerical water model, indicating possible inaccuracy in the assumed geometry and/or boundary conditions for the reservoir. However, the investigation does suggest possible directions in which the numerical model can be improved.

The accuracy of Kirchhoff's approximation in describing the far field speckles produced by random self-affine fractal surfaces

Based on the rigorous formulation of integral equations for the propagations of light waves at the medium interface, we carry out the numerical solutions of the random light field scattered from self-affine fractal surface samples. The light intensities produced by the same surface samples are also calculated in Kirchhoff's approximation, and their comparisons with the corresponding rigorous results show directly the degree of the accuracy of the approximation. It is indicated that Kirchhoff's approximation is of good accuracy for random surfaces with small roughness value w and large roughness exponent alpha. For random surfaces with larger w and smaller alpha, the approximation results in considerable errors, and detailed calculations show that the inaccuracy comes from the simplification that the transmitted light field is proportional to the incident field and from the neglect of light field derivative at the interface.

Soberania e acumulação de capital: uma análise crítica de Hugo Grotius, Pasquale Mancini e Hans Kelsen

A soberania já foi conceituada de diversos modos ao longo da história. Apesar disso, não deixou de ser a categoria mais elementar do direito internacional; expressando o fundamento de atuação dos Estados, foi através da soberania que o direito internacional se desenvolveu do Século XVII até os dias de hoje. Isso evidencia uma distinção entre o conteúdo da soberania, quer dizer, o seu modo de manifestação, o seu conceito, que se altera em cada período histórico, de um lado, e, do outro, a forma jurídica internacional expressa pela soberania, que se mantém intacta e que existe independentemente do conteúdo que lhe é dado, quer dizer, o lugar que ela ocupa no direito internacional. Através da análise do conceito de soberania fornecido por três autores clássicos de diferentes períodos históricos Hugo Grotius, Pasquale Mancini e Hans Kelsen o presente trabalho tem por objetivo demonstrar o caráter ideológico de cada teoria e, conseqüentemente, sua inexatidão. Para fazê-lo, foi adotado o método materialista dialético, através do qual a produção de idéias por parte do homem deve ser observada nos limites das suas condições de existência e as idéias produzidas como um reflexo consciente do mundo real. Cuida-se, assim, de observar o direito de superioridade afirmado por Grotius nos limites das condições de existência humana que se alteravam com a transição do feudalismo para capitalismo, e extrai-se o seu sentido da luta entre a Igreja e os monarcas que iam centralizando sob si o poder. Da mesma forma, observa-se o direito de nacionalidade de Mancini sob as condições de existência propiciadas pelo amadurecimento das classes sociais do capitalismo na Europa Ocidental como fruto da Revolução Industrial, extraindo-se seu sentido das lutas revolucionárias por libertação nacional que ali se desenrolavam. O caráter essencialmente limitado da soberania de Kelsen, enfim, será observado no contexto da passagem do capitalismo para sua época imperialista, como um reflexo consciente dos desenvolvimentos experimentados pelo direito internacional no fim do Século XIX e início do Século XX, após a Primeira Guerra Mundial. Assim, além de demonstrar o caráter ideológico e a inexatidão dos conceitos mencionados, busca-se demonstrar que o conteúdo da soberania em cada período histórico analisado encontra sua razão de ser na correspondente fase de desenvolvimento do capitalismo e que a forma jurídica soberania, isto é, o lugar que ela ocupa no direito internacional, é determinado pela necessidade do capitalismo de um instrumento de força que assegure a acumulação de capital, o Estado soberano.

Prosomal-width-to-weight relationships in American horseshoe crabs (Limulus polyphemus): examining conversion factors used to estimate landings

Horseshoe crabs (Limulus polyphemus) are valued by many stakeholders, including the commercial fishing industry, biomedical companies, and environmental interest groups. We designed a study to test the accuracy of the conversion factors that were used by NOAA Fisheries and state agencies to estimate horseshoe crab landings before mandatory reporting that began in 1998. Our results indicate that the NOAA Fisheries conversion factor consistently overestimates the weight of male horseshoe crabs, particularly those from New England populations. Because of the inaccuracy of this and other conversion factors, states are now mandated to report the number (not biomass) and sex of landed horseshoe crabs. However, accurate estimates of biomass are still necessary for use in prediction models that are being developed to better manage the horseshoe crab fishery. We recommend that managers use the conversion factors presented in this study to convert current landing data from numbers to biomass of harvested horseshoe crabs for future assessments.

Degeneration of postovulatory follicles in the Iberian sardine Sardina pilchardus: structural changes and factors affecting resorption

Inaccuracy in the aging of postovulatory follicles (POFs) and in estimating the effect of temperature on the resorption rate of POFs may introduce bias in the determination of the daily spawning age classes with the daily egg production method (DEPM). To explore the above two bias problems with f ield-collected European pilchard (Sardina pilchardus, known regionally as the Iberian sardine), a method was developed in which the time elapsed from spawning (POF age) was estimated from the size of POFs (i.e., from the cross-sectional area in histological sections). The potential effect of the preservative type and embedding material on POF size and the effect of ambient water temperature on POF resorption rate are taken into account with this method. A highly significant loglinear relationship was found between POF area and age; POF area shrank by approximately 50% per day. POFs were also shown to shrink faster at higher temperatures (approximately 3% per degree), but this temperature effect is unlikely to be an important source of bias in the assignment of females to daily spawning classes. The embedding material was also shown to influence the size of POFs, the latter being significantly larger in resin than in paraffin sections. In conclusion, the size of POFs provides an indirect, reliable estimation of the time elapsed from spawning and may thus be used to test both the validity of POF staging criteria for identifying daily classes of spawners and the effect of other factors (such as temperature and laboratory processing) in applications of the DEPM to S. pilchardus and other fish species.

Collection of fish lengths for stock assessment in developing countries

A review of the data (handling) requirements for length-based stock assessment is presented, with emphasis on the relationship between the expected outputs and the key features of the samples required, and on biases and other sources of inaccuracy.

Localização de Terminais Móveis utilizando Correlação de Assinaturas de Rádio-Frequência.

Nesta dissertação são analisados métodos de localização baseados na rede, com destaque para os métodos de correlação de assinaturas de rádio-frequência (DCM - Database Correlation Methods). Métodos baseados na rede não requerem modificações nos terminais móveis (MS - Mobile Stations), sendo portanto capazes de estimar a localização de MS legados, i.e., sem suporte específico a posicionamento. Esta característica, associada a alta disponibilidade e precisão dos métodos DCM, torna-os candidatos viáveis para diversas aplicações baseadas em posição, e em particular para a localização de chamadas para números de emergência - polícia, defesa civil, corpo de bombeiros, etc. - originadas de telefones móveis celulares. Duas técnicas para diminuição do tempo médio para produção de uma estimativa de posição são formuladas: a filtragem determinística e a busca otimizada utilizando algoritmos genéticos. Uma modificação é realizada nas funções de avaliação utilizadas em métodos DCM, inserindo um fator representando a inacurácia intrínseca às medidas de nível de sinal realizadas pelos MS. As modificações propostas são avaliadas experimentalmente em redes de telefonia móvel celular de segunda e terceira gerações em ambientes urbanos e suburbanos, assim como em redes locais sem fio em ambiente indoor. A viabilidade da utilização de bancos de dados de correlação (CDB - Correlation Database) construídos a partir de modelagem de propagação é analisada, bem como o efeito da calibração de modelos de propagação empíricos na precisão de métodos DCM. Um dos métodos DCM propostos, utilizando um CDB calibrado, teve um desempenho superior ao de vários outros métodos DCM publicados na literatura, atingindo em área urbana a precisão exigida dos métodos baseados na rede pela regulamentação FCC (Federal Communications Commission) para o serviço E911 (Enhanced 911 ).

The effect of a twin tunnel on the propagation of ground-borne vibration from an underground railway

Accurate predictions of ground-borne vibration levels in the vicinity of an underground railway are greatly sought after in modern urban centres. Yet the complexity involved in simulating the underground environment means that it is necessary to make simplifying assumptions about this system. One such commonly made assumption is to ignore the effects of neighbouring tunnels, despite the fact that many underground railway lines consist of twin-bored tunnels, one for the outbound direction and one for the inbound direction. This paper presents a unique model for two tunnels embedded in a homogeneous, elastic fullspace. Each of these tunnels is subject to both known, dynamic train forces and dynamic cavity forces. The net forces acting on the tunnels are written as the sum of those tractions acting on the invert of a single tunnel, and those tractions that represent the motion induced by the neighbouring tunnel. By apportioning the tractions in this way, the vibration response of a two-tunnel system is written as a linear combination of displacement fields produced by a single-tunnel system. Using Fourier decomposition, forces are partitioned into symmetric and antisymmetric modenumber components to minimise computation times. The significance of the interactions between two tunnels is quantified by calculating the insertion gains, in both the vertical and horizontal directions, that result from the existence of a second tunnel. The insertion-gain results are shown to be localised and highly dependent on frequency, tunnel orientation and tunnel thickness. At some locations, the magnitude of these insertion gains is greater than 20 dB. This demonstrates that a high degree of inaccuracy exists in any surface vibration prediction model that includes only one of the two tunnels. This novel two-tunnel solution represents a significant contribution to the existing body of research into vibration from underground railways, as it shows that the second tunnel has a significant influence on the accuracy of vibration predictions for underground railways. © 2011 Elsevier Ltd. All rights reserved.

The effects of a second tunnel on the propagation of ground-borne vibration from an underground railway

Accurate predictions of ground-borne vibration levels in the vicinity of an underground railway are greatly sought in modern urban centers. Yet the complexity involved in simulating the underground environment means that it is necessary to make simplifying assumptions about this environment. One such commonly-made assumption is to model the railway as a single tunnel, despite many underground railway lines consisting of twin-bored tunnels. A unique model for two tunnels embedded in a homogeneous, elastic full space is developed. The vibration response of this two-tunnel system is calculated using the superposition of two displacement fields: one resulting from the forces acting on the invert of a single tunnel, and the other resulting from the interaction between the tunnels. By partitioning of the stresses into symmetric and anti-symmetric mode number components using Fourier decomposition, these two displacement fields can by calculated with minimal computational requirements. The significance of the interactions between twin-tunnels is quantified by calculating the insertion gains that result from the existence of a second tunnel. The insertion-gain results are shown to be localized and highly dependent on frequency, tunnel orientation and tunnel thickness. At some locations, the magnitude of these insertion gains is greater than 20dB. This demonstrates that a high degree of inaccuracy exists in any surface vibration-prediction model that includes only one of the two tunnels. © 2012 Springer.

Low-temperature heat capacities and derived thermodynamic functions of cyclohexane

The low-temperature heat capacities of cyclohexane were measured in the temperature range from 78 to 350 K by means of an automatic adiabatic calorimeter equipped with a new sample container adapted to measure heat capacities of liquids. The sample container was described in detail. The performance of this calorimetric apparatus was evaluated by heat capacity measurements on water. The deviations of experimental heat capacities from the corresponding smoothed values lie within +/-0.3%, while the inaccuracy is within +/-0.4%, compared with the reference data in the whole experimental temperature range. Two kinds of phase transitions were found at 186.065 and 279.684 K corresponding solid-solid and solid-liquid phase transitions, respectively. The entropy and enthalpy of the phase transition, as well as the thermodynamic functions {H-(T)- H-298.15 K} and {S-(T)-S-298.15 K}, were derived from the heat capacity data. The mass fraction purity of cyclohexane sample used in the present calorimetric study was determined to be 99.9965% by fraction melting approach.