bluuebunny/crossref_metadata_2025 huggingface dataset:
Equivalent Stochastic Systems
Authors: Lin Y. K. , Cai G. Q.
Published: July 2009

Equivalent stochastic systems are defined as randomly excited dynamical systems whose response vectors in the state space share the same probability distribution. In this paper, the random excitations are restricted to Gaussian white noises; thus, the system responses are Markov vectors, and their probability densities are governed by the associated Fokker-Planck equations. When the associated Fokker-Planck equations are identical, the equivalent stochastic systems must share both the stationary probability distribution and the transient nonstationary probability distribution under identical initial conditions. Such systems are said to be stochastically equivalent in the strict (or strong) sense. A wider class, referred to as the class of equivalent stochastic systems in the wide (or weak) sense, also includes those sharing only the stationary probability distribution but having different Fokker-Planck equations. Given a stochastic system with a known probability distribution, procedures are developed to identify and construct equivalent stochastic systems, both in the strict and in the wide sense.
Trade-Offs Between Identification and Control in Dynamic Systems
Authors: Udwadia Firdaus E. , Flashner Henryk
Published: July 2009

A quantitative study of the trade-offs between the tasks of control law design and plant identification for linear dynamic systems is presented. The problem is formulated in the context of optimal control and optimal identification through the intermediary concept of an optimal input. The duality between identification and control is quantified by optimal inputs, which have a specified amount of energy, and which minimizes the objective function. The optimization problem together with the energy constraint is formulated by using an augmented state vector. This results in a nonlinear two-point boundary value problem and eliminates the need for using a trial and error approach to satisfy the energy constraint. An example of a single-degree-of-freedom oscillator is used to illustrate the basic concepts underlying the proposed approach. Significant trade-offs between identification and control tasks are observed, the trade-offs becoming increasingly important for increasing levels of input energy.
Chaos and Three-Dimensional Horseshoes in Slowly Varying Oscillators
Authors: Wiggins Stephen , Shaw Steven W.
Published: July 2009

We present general results pertaining to chaotic motions in a class of systems termed slowly varying oscillators which consist of weakly perturbed single-degree-of-freedom systems in which parameters vary slowly in time according to an additional equation of motion. Our results include an analytical method for detecting transversal intersections of stable and unstable manifolds (typically a necessary condition for chaotic motions to exist) and a detailed description of the chaotic dynamics that occur when this situation exists.
Comments on Rayleigh’s Quotient and Perturbation Theory for the Eigenvalue Problem
Authors: Pierre Christophe
Published: July 2009

The connection between Rayleigh’s quotient and perturbation theory for the eigenvalue problem is studied. Equivalence of these techniques is proven under certain conditions.
An Historical Note on Finite Rotations
Authors: Cheng Hui , Gupta K. C.
Published: July 2009

It is shown in this paper that Euler was first to derive the finite rotation formula which is often erroneously attributed to Rodrigues, while Rodrigues was responsible for the derivation of the composition formulae for successive finite rotations and the so-called Euler parameters of finite rotation. Therefore, based upon historical facts, the following nomenclature is suggested: Euler’s finite rotation formula, Rodrigues’ composition formulae of finite rotations, and Euler-Rodrigues parameters. The text of the paper contains modern symbols and formula forms, while the Appendices contain brief summaries from relevant historical sources with minor alterations in symbols at the most.
Methods and Gaussian Criterion for Statistical Linearization of Stochastic Parametrically and Externally Excited Nonlinear Systems
Authors: Chang R. J. , Young G. E.
Published: July 2009

The methods of Gaussian linearization along with a new Gaussian Criterion used in the prediction of the stationary output variances of stable nonlinear oscillators subjected to both stochastic parametric and external excitations are presented. The techniques of Gaussian linearization are first derived and the accuracy in the prediction of the stationary output variances is illustrated. The justification of using Gaussian linearization a priori is further investigated by establishing a Gaussian Criterion. The non-Gaussian effects due to system nonlinearities and/or large noise intensities in a Duffing oscillator are also illustrated. The validity of employing the Gaussian Criterion test for assuring accuracy of Gaussian linearization is supported by performing the Chi-square Gaussian goodness-of-fit test.
Boundary Integral Analysis of the Creeping Flow of Long Bubbles in Capillaries
Authors: Martinez M. J. , Udell K. S.
Published: July 2009

A boundary integral analysis of the creeping motion of a long inviscid bubble in a liquid filled tube is presented. The effects of interfacial surface tension are included in the stress balance across the liquid-bubble interface. Velocities, stresses, and the bubble profile are obtained as a function of the capillary number. Computed values of the thickness of the liquid film between the bubble and tube wall are in excellent agreement with published experimental measurements. The results are of interest in exposing the role of surface tension in multiphase flow in capillary tubes and porous materials.
Thermodynamical Inequalities, Reciprocal Relations, and Mixtures
Authors: Green A. E. , Naghdi P. M.
Published: July 2009

A thermodynamical inequality is obtained for mixtures of interacting continua; it represents the analogue of a corresponding inequality for single phase media contained in a paper of Green and Naghdi (1984) and is less restrictive than one proposed earlier (1978b). Also, the use of such inequalities in conjunction with the so-called reciprocal relations is briefly discussed.
An Examination of the Mori-Tanaka Effective Medium Approximation for Multiphase Composites
Authors: Norris A. N.
Published: July 2009

The Mori-Tanaka method is considered in the context of both scalar thermal conductivity and anisotropic elasticity of multiphase composites, and some general properties are deduced. Particular attention is given to its relation to known general bounds, and to the differential scheme. It is shown that the moduli predicted by the method always satisfy the Hashin-Shtrikman and Hill-Hashin bounds for two-phase composites. This property does not generalize to multiphase composites. A specific example illustrates that the method can predict moduli in violation of the Hashin-Shtrikman bounds for a three-phase medium. However, if the particle shapes are all spheres, then the prediction for the multiphase composite is coincident with the Hashin-Shtrikman bounds if the matrix material is either the stiffest or the most compliant phase. It is also shown that the generalized differential effective medium method yields the same moduli as the Mori-Tanaka approximation if certain conditions are satisfied in the differential scheme. Thus, it is required that at each stage in the differential process, and for each phase j (j = 1, 2, …, n) of new material, the average field in the incrementally added phase j material must be the same as the average field in the bulk phase j. For two phase media, n = 1, this condition reduces to the less stringent requirement that the ratio of the field in the incrementally added material to the average field in the matrix material is the same as the dilute concentration ratio. The cumulative findings of this paper, particularly those concerning bounds, suggest that the Mori-Tanaka approximation be used with caution in multiphase applications, but is on firmer ground for two-phase composites.
A New Boundary Integral Equation Formulation for Elastodynamic and Elastostatic Crack Analysis
Authors: Zhang Ch. , Achenbach J. D.
Published: July 2009

An elastodynamic conservation integral, the J˜k integral, is employed to derive boundary integral equations for crack configurations in a direct and natural way. These equations immediately have lower-order singularities than the ones obtained in the conventional manner by the use of the Betti-Rayleigh reciprocity relation. This is an important advantage for the development of numerical procedures for solving the BIE’s, and for an accurate calculation of the strains and stresses at internal points close to the crack faces. For curved cracks of arbitrary shape the BIE’s presented here have simple forms, and they do not require integration by parts, as in the conventional formulation. For the dynamic case the unknown quantities are the crack opening displacements and their derivatives (dislocation densities), while for the static case only the dislocation densities appear in the formulation. For plane cracks the boundary integral equations reduce to the ones obtained by other investigators.
End Effects and Time-Harmonic Longitudinal Wave Propagation in a Semi-Infinite Solid Cylinder
Authors: Kim Yoon Young , Steele Charles R.
Published: July 2009

Axisymmetric end problems of longitudinal wave propagation are studied in a semi-infinite isotropic solid circular cylinder which is free of traction on its cylindrical surface. An accurate and computationally efficient method of solution is presented which can exploit the asymptotic behavior for high harmonics in the radial direction. The stresses and displacements are expanded in terms of the eigenfunctions of the case of a lubricated-rigid cylindrical surface condition. The expansions are used to construct a stiffness matrix relating the harmonics of stress and displacement for the traction-free case, which is shown to approach asymptotically that of the case of the mixed condition. Unlike other approaches such as finite element or boundary integral methods, which typically require the solution of large systems of equations for rapidly varying end conditions, the present formulation can lead to a coupled system of equations for lower spatial harmonics and a weakly coupled system for higher spatial harmonics. Due to the small number of equations in the coupled system, the present approach is very effective in handling general boundary conditions, and is particularly efficient for end conditions with rapid spatial variation.
Dynamic Stability of Nonlinear Antisymmetrically-Laminated Cross-Ply Rectangular Plates
Authors: Tylikowski Andrzej
Published: July 2009

The dynamic stability problem is solved for rectangular plates that are laminated antisymmetrically about their middle plane and compressed by time-dependent deterministic or stochastic membrane forces. Moderately large deflection equations taking into account a coupling of in-plane and transverse motions are used. The asymptotic stability and almost-sure asymptotic stability criteria involving a damping coefficient and loading parameters are derived using Liapunov’s direct method. A relation between the stability of nonlinear equations and linearized ones is analyzed. An influence on the number of orthotropic layers, material properties for different classes of parametric excitation on stability domains is shown.
Work-Conjugate Boundary Conditions in the Nonlinear Theory of Thin Shells
Authors: Makowski J. , Pietraszkiewicz W.
Published: July 2009

Work–conjugate boundary conditions for a class of nonlinear theories of thin shells formulated in terms of displacements of the reference surface are discussed. Applying theorems of the theory of differential forms it is shown that many of the sets of static boundary conditions which have been proposed in the literature do not possess work–conjugate geometric counterparts. The general form of four geometric boundary conditions and their work–conjugate static boundary conditions is constructed and three particular cases are analyzed. The boundary conditions given here are valid for unrestricted displacements, rotations, strains and/or changes of curvatures of the reference surface.
Non-Probabilistic Models of Uncertainty in the Nonlinear Buckling of Shells With General Imperfections: Theoretical Estimates of the Knockdown Factor
Authors: Ben-Haim Yakov , Elishakoff Isaac
Published: July 2009

A non-probabilistic, set-theoretical treatment of the buckling of shells with uncertain initial geometrical imperfections is presented. The minimum buckling load is determined as a function of the parameters which describe the (generally infinite) range of possible initial imperfection profiles of the shell. The central finding of this paper is a theoretical estimate of the knockdown factor as a function of the characteristics of the uncertainty in the initial imperfections. Two classes of set-theoretical models are employed. The first class represents the range of variation of the most significant N Fourier coefficients by an ellipsoidal set in N-dimensional Euclidean space. The minimum buckling load is then explicitly evaluated in terms of the shape of the ellipsoid. In the second class of models, the uncertainty in the initial imperfection profile is expressed by an envelope of functions. The bounding functions of this envelope can be viewed as a radial tolerance on the shape. It is demonstrated that a non-probabilistic model of uncertainty in the initial imperfections of shells is successful in determining the minimum attainable buckling load of an ensemble of shells and that such an approach is computationally feasible.
An Anisotropic Hardening Rule for Elastoplastic Solids Based on Experimental Observations
Authors: Ellyin Fernand
Published: July 2009

A hardening rule is described based on yield and memory surfaces. A memory surface indicates the extent of loading, and a yield surface is the locus of the elastic region. We define a hardening modulus curve which relates the change in size of the yield and memory surfaces to the tangent modulus of the material at the maximum load. The evolution of the yield surface is described for both the proportional and nonproportional loading paths. Both quasi-static and stable cyclic loading is considered. An attractive feature of this nonlinear hardening law is that the material constants associated with it are limited—three in all—and they can be easily determined from a simple test. The predictions of the proposed hardening law are compared with the experimental data for proportional and nonproportional loading paths, and are found to be in good agreement.
Application of an Internal Variable Constitutive Model to Predict Creep Response of an Aluminum Alloy Under Multiaxial Loading
Authors: Mahmood I. U. , Faruque M. O. , Zaman M. M.
Published: July 2009

This paper discusses the application of an internal variable, creep constitutive model, where the concept of piecewise linearity in the effective stress-creep strain rate relationship is utilized. Since the concept of piecewise linearity is assumed, an explicit functional form for creep strain rate at all levels of stress and temperature is not required. The aforementioned constitutive model is used to predict the creep response of an aluminum alloy (2618-T61) at 200°C and subjected to multiaxial loading. The results are compared with available experimental results. The model shows excellent agreement in the trend of creep response. The quantitative values also agree quite good with the experimental results.
A Green’s Function Formulation of Anticracks and Their Interaction With Load-Induced Singularities
Authors: Dundurs John , Markenscoff Xanthippi
Published: July 2009

This paper provides a Green’s function formulation of anticracks (rigid lamellar inclusions of negligible thickness that are bonded to the surrounding elastic material). Apart from systematizing several previously known solutions, the article gives the pertinent fields for concentrated forces, dislocations, and a concentrated couple applied on the line of the anticrack. There is a reason for working out these results: In contrast to concentrated forces, a concentrated couple approaching the tip of an anticrack makes the elastic fields explode. Finite limits can be achieved, however, by appropriately diminishing the magnitude of the couple, which then leads to fields that are intimately connected with the weight functions for the anticrack. An edge dislocation going to the tip of an anticrack puts a net force on the lamellar inclusion, which is shown to be related to a previously known feature of dislocations near a bimaterial interface.
Thermal Stresses at the Edge of a Bimetallic Thermostat
Authors: Kuo An-Yu
Published: July 2009

The plane stress problem of a semi-infinite, bimetallic thermostat subjected to uniform heating or cooling is treated with the theory of elasticity. Solutions to this problem are expressed as the sum of a basic solution for a bimetallic strip of infinite length and a series of complementary solutions. Interlayer peeling stresses at the free edge of the bimetallic thermostat are shown to be singular or nonsingular (but still higher than the nominal values) depending upon whether the combination of the two Dundurs’ bimaterial constants, α (α−2β), are greater or less than zero. In an example problem, current solutions agree well with finite element results while results predicted by a modified beam theory show a large deviation from the other two solutions near the free edge. Boundary layer effects near the free edges of a bimetallic thermostat are also discussed.
Cantilever Rod in Cross Wind
Authors: Wang C. Y.
Published: July 2009

A thin elastic rod is held at one end in a strong cross wind. The nonlinear large deformation equations are formulated and solved by perturbation and numerical integration. The problem is governed by a nondimensional parameter K representing the relative importance of aerodynamic drag to flexural rigidity. For large K, phenomena such as nonuniqueness, instability, and hysteresis may occur.
Large Deflections of an Elastoplastic Strain-Hardening Cantilever
Authors: Liu J. H. , Stronge W. J. , Yu T. X.
Published: July 2009

This theoretical analysis of an elastoplastic cantilever examines the effects of linear strain-hardening and the development of partial elastic unloading when deflections become large. For a vertical force at the tip, unloading modifies the distribution of curvature in a substantial internal segment after the deflections become very large, but it has a negligible effect on the tip displacement. The analysis uses a bilinear stress-strain constitutive relation that results in slightly better agreement with previous experiments than a corresponding bilinear approximation for the moment-curvature relation.
Wave Propagation Through Elastically-Anisotropic Fluid-Saturated Porous Rocks
Authors: Digby P. J. , Walton K.
Published: July 2009

An elastically-anisotropic sedimentary rock is modeled by a simple cubic packing of identical, contacting spherical particles. The connected pore space is filled with an inviscid, compressible fluid. A set of averaged equations is derived to relate the constitutive and dynamic coupling coefficients, and hence also the effective wave speeds in any given direction explicitly to the microstructural properties of the rock considered. Simple, explicit results are obtained when the propagation of either a purely longitudinal or a purely transverse wave is considered.
Some Axisymmetric Problems for Layered Elastic Media: Part II—Solutions for Annular Indenters and Cracks
Authors: Shield T. W. , Bogy D. B.
Published: July 2009

In Part I, the multiple contact region solutions for an axisymmetric indenter were presented. The solution technique utilized integral transforms and singular integral equations. The emphasis there was the study of the conditions of contact as a function of the physical parameters of the indenter and the layered elastic half space. The method and results were similar to those for the analogous plane-strain problem that was studied in Shield and Bogy (1989). However, several differences in detail were required for the analysis of the axisymmetric geometry. In this Part II, the solution of Part I is used to study some related problems that have been considered previously in the literature for homogeneous half spaces. First we solve the problem of the axisymmetric annular indenter for the layered half space. Multiple contact region solutions are studied and the problem of an axisymmetric punch with internal pressure is solved for the layered half space and also for the special case of a layer with a traction-free lower surface. Finally, the problem of an annular crack in a homogeneous or layered structure is solved.
A First-Order Perturbation Analysis of Crack Trapping by Arrays of Obstacles
Authors: Gao Huajian , Rice James R.
Published: July 2009

A first-order perturbation analysis is presented for the configuration of an initially straight crack front which is trapped against forward advance by contact with an array of obstacles (i.e., regions of higher fracture toughness than their surroundings). The problem is important to the micromechanics of crack advance in brittle, locally heterogeneous solids. The formulation is based on a linear perturbation result for the stress intensity factor distribution along the front of a half-plane crack when the location of that front differs moderately from a straight line. The trapping solutions for a periodic array of blocking rectangular obstacles are given using an analogy to the plane stress Dugdale/BCS elastic-plastic crack model. For a periodic array of obstacles with a given spacing and size in the direction parallel to the crack front, the obstacle shape may affect the limit load at which the crack breaks through the array. When such effects are examined within the range of validity of the linear perturbation theory, it is found that obstacles whose cross-sections fully envelop a critical reference area give the maximum limit load while others are broken through at lower load levels. We also formulate a numerical procedure using the FFT technique and adopting a “viscoplastic” crack growth model which, in an appropriate limit, simulates crack growth at a critical stress intensity factor. This is applied to show how a crack front begins to surround and penetrate into various arrays of round obstacles (with a toughness ratio of 2) as the applied load is gradually increased. The limitations of the first-order analysis restrict its validity to obstacles only slightly tougher than the surrounding elastic medium. Recently, Fares (1988) analyzed the crack trapping problem by a Boundary Element Method (BEM) with results indicating that the first-order linear analysis is acceptable when the fracture of toughness of the obstacles differs by a moderate amount from that of their surroundings (e.g., the toughness ratio can be as large as 2 for circular obstacles spaced by 2 diameters). However, the first-order theory is not only quantitatively inaccurate, but can make qualitatively wrong predictions when applied to very tough obstacles.
Branched Cracks in Anisotropic Elastic Solids
Authors: Obata Makoto , Nemat-Nasser Siavouche , Goto Yoshiaki
Published: July 2009

Branched crack problems are analyzed in two-dimensional, anisotropically elastic homogeneous solids. The method of analysis is based on the complex variable approach of Savin and Lekhnitskii. The Hilbert problem in an anisotropic body is defined, and a pair of singular integral equations are derived for dislocation density functions associated with a branched crack. For both symmetric and nonsymmetric geometries, and under symmetric and antisymmetric loads, the stress intensity factors and the energy release rate are computed numerically by extrapolation for infinitesimally small lengths of branched cracks. The results are compared with those of the isotropic case given in the literature and the effects of anisotropy are discussed.
Dynamic Analysis of Flexible Structures Using Component Mode Synthesis
Authors: De Smet M. , Liefooghe C. , Sas P. , Snoeys R.
Published: July 2009

In this paper a dynamic model of a flexible robot is built out of a finite element model of each of its links. The number of degrees-of-freedom of these models is strongly reduced by applying the Component Mode Synthesis technique which involves the preliminary calculation of a limited number of mode shapes of the separate links. As can be seen from examples, the type of boundary conditions thereby imposed in the nodes in which one link is connected to the others, strongly determines the accuracy of the calculated resonance frequencies of the robot. The method is applied to an industrial manipulator. The reduced finite element model of the robot is changed in order to match the numerically and experimentally (modal analysis) determined resonance data. Further, the influence of the position of the robot on its resonance frequencies is studied using the optimized numerical model.
A Comprehensive Study of the Free Vibration of Rectangular Plates Resting on Symmetrically-Distributed Uniform Elastic Edge Supports
Authors: Gorman D. J.
Published: July 2009

An analytical-type solution is developed for the free vibration analysis of rectangular plates with uniform elastic edge support symmetrically distributed about the plate central axes. Both linear elastic rotational and translational support are considered to act simultaneously. Rapid convergence is encountered. Because of the symmetry of the problem, the free vibration modes fall into three distinct families. Eigenvalues are tabulated for the first four modes of vibration of a square plate with identical stiffnesses on each edge and with various ratios of translational to rotational stiffnesses. This represents, to the author’s knowledge, the first comprehensive treatment of this problem.
Stability of a Semi-Active Impact Damper: Part I—Global Behavior
Authors: Karyeaclis M. P. , Caughey T. K.
Published: July 2009

A study is made of the general behavior of a semi-active impact damper. The system consists of an undamped forced torsional oscillator, and a flywheel which can be locked to the oscillator through a clutch. The impact which results during clutch engagement is effective in reducing the vibration amplitude level of the oscillator when it is subjected to bounded excitation. All solutions of the system are shown to be bounded when the input is bounded. Periodic solutions are discussed in the following paper, Part II.
Novel Genetic Environment of the Carbapenem-Hydrolyzing β-Lactamase KPC-2 among
Enterobacteriaceae
in China
Authors: Shen Ping , Wei Zeqing , Jiang Yan , Du Xiaoxing , Ji Shujuan , Yu Yunsong , Li Lanjuan
Published: July 2009

Thirty-nine
bla
KPC
-producing isolates of the family
Enterobacteriaceae
with carbapenem resistance or reduced carbapenem susceptibility were obtained from inpatients from eight hospitals in six cities of three provinces in eastern China. The pulsed-field gel electrophoresis analysis of all 36
Klebsiella pneumoniae
isolates revealed six major patterns. The resistant plasmids of most isolates were successfully transferred by conjugation and evaluated experimentally to be 40 to 180 kb in size. A 20.2-kb
bla
KPC
-surrounding nucleotide sequence from plasmid pKP048 has been obtained and contains an integration structure of a Tn
3
-based transposon and partial Tn
4401
segment, with the gene order Tn
3
-transposase, Tn
3
-resolvase, IS
Kpn8
, the
bla
KPC-2
gene, and the IS
Kpn6
-like element. The chimera of several transposon-associated elements indicated a novel genetic environment of the
K. pneumoniae
carbapenemase β-lactamase gene in isolates from China.
Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women
Authors: Karunajeewa Harin A. , Salman Sam , Mueller Ivo , Baiwog Francisca , Gomorrai Servina , Law Irwin , Page-Sharp Madhu , Rogerson Stephen , Siba Peter , Ilett Kenneth F. , Davis Timothy M. E.
Published: July 2009

To determine the pharmacokinetic disposition of sulfadoxine (SDOX) and pyrimethamine (PYR) when administered as intermittent presumptive treatment during pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were given a single dose of 1,500 mg of SDOX plus 75 mg of pyrimethamine PYR. Blood was taken at baseline and 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h and at 7, 10, 14, 28, and 42 days posttreatment in all women. Plasma samples were assayed for SDOX,
N
-acetylsulfadoxine (NASDOX), and PYR by high-performance liquid chromatography. Population pharmacokinetic modeling was performed using NONMEM v6.2.0. Separate user-defined mamillary models were fitted to SDOX/NASDOX and PYR. When the covariate pregnancy was applied to clearance, there was a significant improvement in the base model for both treatments. Pregnancy was associated with a significantly lower area under the concentration-time curve from 0 to ∞ for SDOX (22,315 versus 33,284 mg·h/liter), NASDOX (801 versus 1,590 mg·h/liter), and PYR (72,115 versus 106,065 μg·h/liter;
P
< 0.001 in each case). Because lower plasma concentrations of SDOX and PYR could compromise both curative efficacy and posttreatment prophylaxis in pregnant patients, IPTp regimens incorporating higher mg/kg doses than those recommended for nonpregnant patients should be considered.
Imidocarb Dipropionate Clears PersistentBabesia caballiInfection with Elimination of Transmission Potential
Authors: Schwint O. Nicolas , Ueti Massaro W. , Palmer Guy H. , Kappmeyer Lowell S. , Hines Melissa T. , Cordes R. Timothy , Knowles Donald P. , Scoles Glen A.
Published: July 2009

Antimicrobial treatment of persistent infection to eliminate transmission risk represents a specific challenge requiring compelling evidence of complete pathogen clearance. The limited repertoire of antimicrobial agents targeted at protozoal parasites magnifies this challenge. UsingBabesia caballias both a model and a specific apicomplexan pathogen for which evidence of the elimination of transmission risk is required for international animal movement, we tested whether a high-dose regimen of imidocarb dipropionate cleared infection from persistently infected asymptomatic horses and/or eliminated transmission risk. Clearance with elimination of transmission risk was supported by the following four specific lines of evidence: (i) inability to detect parasites by quantitative PCR and nested PCR amplification, (ii) conversion from seropositive to seronegative status, (iii) inability to transmit infection by direct inoculation of blood into susceptible recipient horses, and (iv) inability to transmit infection by ticks acquisition fed on the treated horses and subsequently transmission fed on susceptible horses. In contrast, untreated horses remained infected and capable of transmittingB. caballiusing the same criteria. These findings establish that imidocarb dipropionate treatment clearsB. caballiinfection with confirmation of lack of transmission risk either by direct blood transfer or a high tick burden. Importantly, the treated horses revert to seronegative status according to the international standard for serologic testing and would be permitted to move between countries where the pathogen is endemic and countries that are free of the pathogen.
Pharmacokinetic Assessment of Nevirapine and Metabolites in Human Immunodeficiency Virus Type 1-Infected Patients with Hepatic Fibrosis
Authors: Cammett Anna Maria , MacGregor Thomas R. , Wruck Jan M. , Felizarta Franco , Miailhes Patrick , Mallolas Josep , Piliero Peter J.
Published: July 2009

Nevirapine is a nonnucleoside reverse transcriptase inhibitor used as part of combination therapy for human immunodeficiency virus (HIV) infection. Nevirapine may be prescribed for patients with hepatic fibrosis and cirrhosis. Significant autoinduction of cytochrome P450 3A4 and 2B6 following multiple dosing prompted an assessment of the metabolic profiles in patients with liver disease receiving chronic nevirapine therapy. HIV-infected patients with hepatic fibrosis who were receiving a stable antiretroviral regimen containing nevirapine for ≥6 weeks had liver biopsy specimens assessed by Ishak histologic scoring and were grouped by severity (group 1, Ishak scores of 1 and 2; group 2, Ishak scores of 3 and 4; group 3, Ishak scores of 5 and 6). Steady-state trough nevirapine levels were determined for all patients, and additional measurements were obtained at 1, 2, and 4 h following nevirapine dosing for a subset of patients. The pharmacokinetics of nevirapine and its five metabolites were characterized, and a comparison of the results for the different Ishak groups was performed. Among 51 patients with hepatic fibrosis, the majority of whom were coinfected with hepatitis C virus or hepatitis B virus, differences between the maximum and the minimum observed plasma concentrations demonstrated a statistically significant flattening of the systemic exposure curves with progression from Ishak group 1 to Ishak group 2 or 3, suggesting a decrease in systemic clearance with the progression of liver disease. However, there were no significant differences in the trough and the maximum nevirapine concentrations between the Ishak groups. The metabolite profiles were also comparable across the Ishak groups. In HIV-infected patients who were chronically treated with nevirapine and who had various degrees of hepatic fibrosis, including cirrhosis, trough plasma nevirapine concentrations were not significantly increased, and thus, no dose adjustment is warranted.
Development of a Cell-Based Hepatitis C Virus Infection Fluorescent Resonance Energy Transfer Assay for High-Throughput Antiviral Compound Screening
Authors: Yu Xuemei , Sainz Bruno , Uprichard Susan L.
Published: July 2009

A major obstacle in the treatment of chronic hepatitis C virus (HCV) infection has been the lack of effective, well-tolerated therapeutics. Notably, the recent development of the HCV cell culture infection system now allows not only for the study of the entire viral life cycle, but also for the screening of inhibitors against all aspects of HCV infection. However, in order to screen libraries of potential antiviral compounds, it is necessary to develop a highly reproducible, accurate assay for HCV infection adaptable for high-throughput screening (HTS) automation. Using an internally quenched 5-FAM/QXL 520 fluorescence resonance energy transfer (FRET) substrate containing the HCV NS3 peptide cleavage sequence, we report the development of a simple, mix-and-measure, homogenous, cell-based HCV infection assay amendable for HTS. This assay makes use of synchronized, nondividing human hepatoma-derived Huh7 cells, which support more-reproducible long-term HCV infection and can be readily scaled down to a 96-well-plate format. We demonstrate that this stable cell culture method eliminates common problems associated with standard cell-based HTS, such as cell culture variability, poor reproducibility, and low signal intensity. Importantly, this HCV FRET assay not only can identify inhibitors that act throughout the viral life cycle as effectively as more-standard HCV assays, such as real-time quantitative PCR and Western blot analysis, but also exhibits a high degree of accuracy with limited signal variation (i.e.,
Z
′ ≥ 0.6), providing the basis for a robust HTS campaign for screening compound libraries and identifying novel HCV antivirals.
In Vitro Antibacterial Activity of Acyl-Lysyl Oligomers againstHelicobacter pylori
Authors: Makobongo Morris O. , Kovachi Tchelet , Gancz Hanan , Mor Amram , Merrell D. Scott
Published: July 2009

The gastric pathogenHelicobacter pylorihas developed resistance to virtually all current antibiotics; thus, there is a pressing need to develop new anti-H. pyloritherapies. The goal of this work was to evaluate the antibacterial effect of oligo-acyl-lysyl (OAK) antimicrobial peptidomimetics to determine if they might represent alternatives to conventional antibiotic treatment ofH. pyloriinfection. A total of five OAK sequences were screened for growth-inhibitory and/or bactericidal effects againstH. pyloristrain G27; four of these sequences had growth-inhibitory and bactericidal effects. The peptide with the highest efficacy against strain G27, C12K-2β12, was selected for further characterization against five additionalH. pyloristrains (26695, J99, 7.13, SS1, and HPAG1). C12K-2β12displayed MIC and minimum bactericidal concentration (MBC) ranges of 6.5 to 26 μM and 14.5 to 90 μM, respectively, across the six strains after 24 h of exposure. G27 was the most sensitiveH. pyloristrain (MIC = 6.5 to 7 μM; MBC = 15 to 20 μM), whereas 26695 was the least susceptible strain (MIC = 25 to 26 μM; MBC = 70 to 90 μM).H. pyloriwas completely killed after 6 to 8 h of incubation in liquid cultures containing two times the MBC of C12K-2β12. The OAK demonstrated strong in vitro stability, since efficacy was maintained after incubation at extreme temperatures (4°C, 37°C, 42°C, 50°C, 55°C, 60°C, and 95°C) and at low pH, although reduced killing kinetics were observed at pH 4.5. Additionally, upon transient exposure to the bacteria, C12K-2β12showed irreversible and significant antibacterial effects and was also nonhemolytic. Our results show a significant in vitro effect of C12K-2β12againstH. pyloriand suggest that OAKs may be a valuable resource for the treatment ofH. pyloriinfection.
Investigation of New Dominant-Negative Inhibitors of Anthrax Protective Antigen Mutants for Use in Therapy and Vaccination
Authors: Cao Sha , Guo Aizhen , Liu Ziduo , Tan Yadi , Wu Gaobing , Zhang Chengcai , Zhao Yaxing , Chen Huanchun
Published: July 2009

The lethal toxin (LeTx) of
Bacillus anthracis
plays a key role in the pathogenesis of anthrax. The protective antigen (PA) is a primary part of the anthrax toxin and forms LeTx by combination with lethal factor (LF). Phenylalanine-427 (F427) is crucial for PA function. This study was designed to discover potential novel therapeutic agents and vaccines for anthrax. This was done by screening PA mutants that were mutated at the F427 residue for a dominant-negative inhibitory (DNI) phenotype which was nontoxic but inhibited the toxicity of the wild-type LeTx. For this, PA residue F427 was first mutated to each of the other 19 naturally occurring amino acids. The cytotoxicity and DNI phenotypes of the mutated PA proteins were tested in the presence of 1 μg/ml LF in RAW264.7 cells and were shown to be dependent on the individual amino acid replacements. A total of 16 nontoxic mutants with various levels of DNI activity were identified in vitro. Among them, F427D and F427N mutants had the highest DNI activities in RAW264.7 cells. Both mutants inhibited LeTx intoxication in mice in a dose-dependent way. Furthermore, they induced a Th2-predominant immune response and protected mice against a challenge with five 50% lethal doses of LeTx. The protection was correlated mainly with a low level of interleukin-1β (IL-1β) and with high levels of PA-specific immunoglobulin G1, IL-6, and tumor necrosis factor alpha. Thus, PA DNI mutants, such as F427D and F427N mutants, may serve in the development of novel therapeutic agents and vaccines to fight
B. anthracis
infections.
Indoleamine 2,3-Dioxygenase Is Involved in Defense againstNeospora caninumin Human and Bovine Cells
Authors: Spekker Katrin , Czesla Markus , Ince Vanessa , Heseler Kathrin , Schmidt Silvia K. , Schares Gereon , Däubener Walter
Published: July 2009

Neospora caninumis an apicomplexan parasite closely related toToxoplasma gondii. In nature this parasite is found especially in dogs and cattle, but it may also infect other livestock. The growth ofN. caninum, which is an obligate intracellular parasite, is controlled mainly by the cell-mediated immune response. During infection the cytokine gamma interferon (IFN-γ) plays a prominent role in regulating the growth ofN. caninumin natural and experimental disease. The present study showed that induction of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) is responsible for the inhibition of parasite growth that is mediated by IFN-γ-activated bovine fibroblasts and endothelial cells. This antiparasite effect could be abrogated by addition of tryptophan, as well as by the IDO-specific inhibitor 1-l-methyltryptophan. In conclusion, our data show that human and bovine cells use the same effector mechanism to control the growth ofN. caninum.
Comparative Analysis of the Properties and Ligand Binding Characteristics of CspZ, a Factor H Binding Protein, Derived fromBorrelia burgdorferiIsolates of Human Origin
Authors: Rogers Elizabeth A. , Abdunnur Shane V. , McDowell John V. , Marconi Richard T.
Published: July 2009

Borrelia burgdorferiCspZ (BBH06/BbCRASP-2) binds the complement regulatory protein factor H (FH) and additional unidentified serum proteins. The goals of this study were to assess the ligand binding capability of CspZ orthologs derived from an extensive panel of human Lyme disease isolates and to further define the molecular basis of the interaction between FH and CspZ. While mostB. burgdorferiCspZ orthologs analyzed bound FH, specific, naturally occurring polymorphisms, most of which clustered in a specific loop domain of CspZ, prevented FH binding in some orthologs. Sequence analyses also revealed the existence of CspZ phyletic groups that correlate with FH binding and with the relationships inferred from ribosomal spacer types (RSTs). CspZ type 1 (RST1) and type 3 (RST3) strains bind FH, while CspZ type 2 (RST2) strains do not. Antibody responses to CspZ were also assessed. Anti-CspZ antibodies were detected in mice by week 2 of infection, indicating that there was expression during early-stage infection. Analyses of sera collected from infected mice suggested that CspZ production continued over the course of long-term infection as the antibody titer increased over time. While antibody to CspZ was detected in several human Lyme disease serum samples, the response was not universal, and the titers were generally low. Vaccination studies with mice demonstrated that while CspZ is immunogenic, it does not elicit an antibody that is protective or that inhibits dissemination. The data presented here provide significant new insight into the interaction between CspZ and FH and suggest that there is a correlation between CspZ production and dissemination. However, in spite of its possible contributory role in pathogenesis, the immunological analyses indicated that CspZ is likely to have limited potential as a diagnostic marker and vaccine candidate for Lyme disease.
Role of Nod1 in Mucosal Dendritic Cells during
Salmonella
Pathogenicity Island 1-Independent
Salmonella enterica
Serovar Typhimurium Infection
Authors: Le Bourhis Lionel , Magalhaes Joao Gamelas , Selvanantham Thirumahal , Travassos Leonardo H. , Geddes Kaoru , Fritz Jörg H. , Viala Jérôme , Tedin Karsten , Girardin Stephen E. , Philpott Dana J.
Published: July 2009

Recent advances in immunology have highlighted the critical function of pattern-recognition molecules (PRMs) in generating the innate immune response to effectively target pathogens. Nod1 and Nod2 are intracellular PRMs that detect peptidoglycan motifs from the cell walls of bacteria once they gain access to the cytosol.
Salmonella enterica
serovar Typhimurium is an enteric intracellular pathogen that causes a severe disease in the mouse model. This pathogen resides within vacuoles inside the cell, but the question of whether cytosolic PRMs such as Nod1 and Nod2 could have an impact on the course of
S
. Typhimurium infection in vivo has not been addressed. Here, we show that deficiency in the PRM Nod1, but not Nod2, resulted in increased susceptibility toward a mutant strain of
S
. Typhimurium that targets directly lamina propria dendritic cells (DCs) for its entry into the host. Using this bacterium and bone marrow chimeras, we uncovered a surprising role for Nod1 in myeloid cells controlling bacterial infection at the level of the intestinal lamina propria. Indeed, DCs deficient for Nod1 exhibited impaired clearance of the bacteria, both in vitro and in vivo, leading to increased organ colonization and decreased host survival after oral infection. Taken together, these findings demonstrate a key role for Nod1 in the host response to an enteric bacterial pathogen through the modulation of intestinal lamina propria DCs.
Phagocytosis Inhibits F-Actin-Enriched Membrane Protrusions Stimulated by Fractalkine (CX3CL1) and Colony-Stimulating Factor 1
Authors: Luo Yong , Isaac Beth M. , Casadevall Arturo , Cox Dianne
Published: July 2009

Cryptococcus neoformansis the only encapsulated human-pathogenic fungus and a facultative intracellular pathogen that can reside in macrophages without host cell lysis. In the present study, we investigated how phagocytosis ofC. neoformansaffected the macrophage response to chemoattractants such as fractalkine (FKN) (CX3CL1) and colony-stimulating factor 1 (CSF-1). Phagocytosis of immunoglobulin G (IgG)-opsonizedC. neoformansand IgG- or C3bi-opsonized sheep erythrocytes was performed using a RAW 264.7 subline (LR5 cells) and bone marrow-derived macrophages (BMM). The chemotactic response to FKN or CSF-1 was quantitated by measurement of the formation of F-actin-enriched membrane protrusions (ruffles), which showed that FKN or CSF-1 stimulated strong transient ruffling in both LR5 cells and BMM. This stimulated cell ruffling was inhibited by phagocytosis in an intracellular-pathogen-number-dependent manner. The inhibition of ruffling was not simply a result of reduced membrane availability since membrane sequestration by sucrose treatment did not inhibit the ruffling response. The phagocytosis process was required to inhibit ruffling as BMM from FcγR−/−mice that boundC. neoformansbut did not ingest it retained the ability to ruffle in response to chemoattractants. These results imply that the inhibition of FKN- or CSF-1-stimulated cell ruffling was a direct consequence of the phagocytosis process. Since cell ruffling is a prelude to chemotaxis, this observation links two functions of macrophages that are critical to host defense, chemotaxis and phagocytosis. Phagocytosis-induced chemotactic suppression may enhance host defense by keeping these antimicrobial effector cells at infected sites and reduce the likelihood of microbial spread by wandering macrophages containing infectious cargo.
ESTIMATION OF POWER-LAW EXPONENT OF DEGREE DISTRIBUTION USING MEAN VERTEX DEGREE
Authors: IKEDA NOBUTOSHI
Published: July 2009

The power-law exponent γ describing the form of the degree distribution of networks is related to the mean degree of the networks. This relation provides a useful method to estimate this exponent because mean degrees can easily be obtained by the number of vertices and edges in the networks. We improved the relation obtained only by ordinary integral approximation, and examined its availability for number of vertices, minimum degree considered, and range of γ, taking also into consideration the number of vertices with minimum degree. As a result, we were able to estimate slight deviations of γ from 3, which are usually observed in numerical simulations of growing networks with linear preferential attachment. Furthermore, using this method, we were also able to predict to what extent γ changed by joining pre-existing vertices in growing networks or by imposing restrictions to prevent the gaining of new edges for certain vertices. For cases where γ < 2, we estimated the power-law exponent of degree distributions of networks formed by traces of random walkers from the increased rate of vertices with created edges.