bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of High-Performance Computing to Numerical Simulation of Human Movement
Authors: Anderson F. C. , Ziegler J. M. , Pandy M. G. , Whalen R. T.
Published: February 2008

We have examined the feasibility of using massively-parallel and vector-processing supercomputers to solve large-scale optimization problems for human movement. Specifically, we compared the computational expense of determining the optimal controls for the single support phase of gait using a conventional serial machine (SGI Iris 4D25), a MIMD parallel machine (Intel iPSC/860), and a parallel-vector-processing machine (Cray Y-MP 8/864). With the human body modeled as a 14 degree-of-freedom linkage actuated by 46 musculotendinous units, computation of the optimal controls for gait could take up to 3 months of CPU time on the Iris. Both the Cray and the Intel are able to reduce this time to practical levels. The optimal solution for gait can be found with about 77 hours of CPU on the Cray and with about 88 hours of CPU on the Intel. Although the overall speeds of the Cray and the Intel were found to be similar, the unique capabilities of each machine are better suited to different portions of the computational algorithm used. The Intel was best suited to computing the derivatives of the performance criterion and the constraints whereas the Cray was best suited to parameter optimization of the controls. These results suggest that the ideal computer architecture for solving very large-scale optimal control problems is a hybrid system in which a vector-processing machine is integrated into the communication network of a MIMD parallel machine.
Optimal Control of Non-ballistic Muscular Movements: A Constraint-Based Performance Criterion for Rising From a Chair
Authors: Pandy M. G. , Garner B. A. , Anderson F. C.
Published: February 2008

To understand how humans perform non-ballistic movements, we have developed an optimal control model to simulate rising from a chair. The human body was modeled as a three-segment, articulated, planar linkage, with adjacent links joined together by frictionless revolutes. The skeleton was actuated by eight musculotendinous units with each muscle modeled as a three-element entity in series with tendon. Because rising from a chair presents a relatively ambiguous performance criterion, we chose to evaluate a number of different performance criteria, each based upon a fundamental dynamical property of movement: muscle force. Through a quantitative comparison of model and experiment, we found that neither a minimum-impulse nor a minimum-energy criterion is able to reproduce the major features of standing up. Instead, we introduce a performance criterion based upon an important and previously overlooked dynamical property of muscle: the time derivative of force. Our motivation for incorporating such a quantity into a mathematical description of the goal of a motor task is founded upon the belief that non-ballistic movements are controlled by gradual increases in muscle force rather than by rapid changes in force over time. By computing the optimal control solution for rising from a static squatting position, we show that minimizing the integral of a quantity which depends upon the time derivative of muscle force meets an important physiological requirement: it minimizes the peak forces developed by muscles throughout the movement. Furthermore, by computing the optimal control solution for rising from a chair, we demonstrate that multi-joint coordination is dictated not only by the choice of a performance criterion but by the presence of a motion constraint as well.
Three-Dimensional Recording and Description of Motions of the Shoulder Mechanism
Authors: van der Helm Frans C. T. , Pronk Gijs M.
Published: February 2008

A measurement technique is presented for recording positions of the bones of the shoulder mechanism, i.e., thorax, clavicula, scapula and humerus, in 3-D space, based on palpating and recording positions of bony landmarks. The palpation technique implies that only static positions can be measured. Accuracy of retrieving bony landmarks is checked on-line using rigid body assumptions. The measurement error is calculated afterwards and is comparable with cinegraphic methods. Axial rotation of the clavicula is estimated by minimizing rotations in the acromioclavicular joint. A number of motion definitions is compared by means of interindividual variation and subjective interpretability. Two useful definitions are proposed for describing motions of the shoulder mechanism. Four conditions have been recorded: abduction and anteflexion of the humerus both with and without additional weight in the hand. Abduction and anteflexion result in large differences in scapular and clavicular motions. The effect of additional weight in the hand on the position of the shoulder girdle is negligible.
An Integrated Probe for Magnetic Resonance Imaging Monitored Skin Cryosurgery
Authors: Pease G. R. , Rubinsky B. , Wong S. T. S. , Roos M. S. , Gilbert J. C. , Arav A.
Published: February 2008

Cryosurgery of the skin is a common treatment for both benign and malignant skin cancers. Monitoring the depth of the frozen lesion during cryosurgery, either by estimation based on the lateral spread of freeze at the skin surface or via thermocouples, may be inaccurate because of the heterogeneous nature of tissue. We describe an integrated cryosurgical probe and magnitude resonance imaging probe which we use to obtain high resolution MR images of skin, subcutaneous muscle and the frozen lesion during cryosurgery.
A Model for Heat Transfer From Embedded Blood Vessels in Two-Dimensional Tissue Preparations
Authors: Zhu Liang , Weinbaum Sheldon
Published: February 2008

Two-dimensional microvascular tissue preparations have been extensively used to study blood flow in the microcirculation, and, most recently, the mechanism of thermal equilibration between thermally significant countercurrent artery-vein pairs. In this paper, an approximate three-dimensional solution for the heat transfer from a periodic array of blood vessels in a tissue preparation of uniform thickness with surface convection is constructed using a newly derived fundamental solution for a Green’s function for this flow geometry. This approximate solution is exact when the ratio K′ of the blood to tissue conductivity is unity and a highly accurate approximation when K′ ≠ 1. This basic solution is applied to develop a model for the heat transfer from a countercurrent artery-vein pair in an exteriorized rat cremaster muscle preparation. The numerical results provide important new insight into the design of microvascular experiments in which the axial variation of the thermal equilibration in microvessels can be measured for the first time. The solutions also provide new insight into the design of fluted fins and microchips that are convectively cooled by internal pores.
A Model for Stress-Induced Growth in the Developing Heart
Authors: Lin I-En , Taber L. A.
Published: February 2008

Mechanical loads affect growth and morphogenesis in the developing heart. Using a theoretical model, we studied stress-modulated growth in the embryonic chick ventricle during stages 21–29 (4–6 days of a 21-day incubation period). The model is a thick-walled, compressible, pseudoelastic cylinder, with finite volumetric growth included by letting the rate of change of the local zero-stress configuration depend linearly on the Cauchy stresses. After investigating the fundamental behavior of the model, we used it to study global and local growth in the primitive ventricle due to normal and abnormal cavity pressures. With end-diastolic pressure taken as the growth-modulating stimulus, correlating theoretical and available experimental results yielded the coefficients of the growth law, which was assumed to be independent of time and loading conditions. For both normal and elevated pressures, the predicted changes in radius and wall volume during development were similar to experimental measurements. In addition, the residual stress generated by differential growth agreed with experimental data. These results suggest that wall stress may be a biomechanical factor that regulates growth in the embryonic heart.
Numerical Investigation and Prediction of Atherogenic Sites in Branching Arteries
Authors: Lei M. , Kleinstreuer C. , Truskey G. A.
Published: February 2008

Atherosclerosis, a disease of large- and medium-size arteries, is the chief cause of death in the US and most of the western world. It is widely accepted that the focal nature of the disease in arterial bends, junctions, and bifurcations is directly related to locally abnormal hemodynamics, often labeled “disturbed flows.” Employing the aorto-celiac junction of rabbits as a representative atherosclerotic model and considering other branching blood vessels with their distinctive input wave forms, it is suggested that the local wall shear stress gradient (WSSG) is the single best indicator of nonuniform flow fields leading to atherogenesis. Alternative predictors of susceptible sites are briefly evaluated. The results discussed include transient velocity vector fields, wall shear stress gradient distributions, and a new dimensionless parameter for the prediction of the probable sites of stenotic developments in branching blood vessels. Some of the possible underlying biological aspects of atherogenesis due to locally significant |WSSG|-magnitudes are briefly discussed.
Peristaltic Pumping in a Circular Tube in the Presence of an Eccentric Catheter
Authors: Adabala Ramachandra Rao , Srinivasan Usha
Published: February 2008

The influence of an eccentrically inserted catheter on the peristaltic pumping in a tube is investigated under long wavelength, low Reynolds number assumptions. The radially asymmetric deformation of the wall arising through an eccentrically inserted catheter is taken into consideration by choosing an appropriate bipolar coordinate system. The effect of the position and size of the catheter on pumping characteristics is studied. The best performance of pumping is noticed at a certain position of the catheter. The size of the catheter, when placed eccentrically, alters the pressure signature significantly inside the bolus, unlike the concentric case discussed by Lykoudis and Roos (1971). Further, the maximum pressure rise in one period of the peristaltic wave is observed to decrease with an increase in the eccentricity.
Variations in Rupture Site and Surface Strains at Failure in the Maturing Rabbit Medial Collateral Ligament
Authors: Lam T. C. , Shrive N. G. , Frank C. B.
Published: February 2008

The relationship between the pattern of surface strain and the site of failure in maturing rabbit ligaments was studied in vitro. Bone-medial collateral ligament (MCL)-bone complexes of 24 female New Zealand White rabbits at 3, 6, 9 and 12 months of age (n = 6 rabbits, 12 MCLs per group) were tested in tension to failure. A video dimension analysis (VDA) system was used to map the surface strain at failure across the width and along the length of the medial side of each MCL during testing. Results showed that the highest strains were consistently located at the femoral insertion decreasing towards the midsubstance, with the highest strain occurring in the anterior portion of the MCL immediately adjacent to the femoral insertion. Strains of the complex at failure increased with rabbit maturation. The strain distribution however, did not change dramatically, even though the locations of MCL failure changed from exclusively tibial avulsion in the three month old rabbits to predominantly midsubstance failures in the 12 month old rabbits. In the six month old rabbits, there was a particular dissociation with all MCLs failing near the tibial insertion while femoral strains were apparently the highest. These results suggest two possibilities beyond that of some unknown artifacts of optical strain measurement. First, since failure sites rarely correlated with areas of maximum surface strain in this study, it seems possible that higher strains could exist deeper in the tissue, particularly at the bone-ligament interface of the tibial insertion in immature animals and somewhere within the midsubstance of the MCL in the adult. Secondly, it is possible that the ligament material may be heterogeneous.
Tennis Racket Shock Mitigation Experiments
Authors: Wilson J. F. , Davis J. S.
Published: February 2008

Measured in this study was the effectiveness of two types of retrofits in mitigating shocks in tennis rackets with ideally high grip fixity. The retrofits were a cushioned grip tape and a string implant device. Three types of rackets were investigated: wood, graphite composite, and metal. For low speed ball impact, neither retrofit changed significantly the magnitude and distribution of e, the coefficient of restitution on the racket heads. For moderate ball speeds impacting the rackets along the vertical centerline, three dynamic racket responses were measured: the free vibration damping based on racket head acceleration, the root-mean-square (rms) grip reaction force, and the fast Fourier transform (FFT) of the grip force. These latter experiments showed that the string implant device had a negligible effect on the three dynamic measures of racket response. However, the cushioned grip tape increased racket damping by up to 100 percent, reduced the rms grip force by about 20 percent, and reduced the magnitude of the FFT of this force by about 40 percent.
Reexamination of Steady Solutions of a Collapsible Channel Conveying Fluid
Authors: Matsuzaki Yuji , Fujimura Kyozo
Published: February 2008

The objective of this note is to reexamine the static behavior of a 2-D channel conveying fluid, when the wall tension becomes small or zero at some point along the channel. In addition to the shear stress exerted by the fluid flow, we take into account restoring forces acting on the wall, such as the bending moment, the transverse shearing force, etc., which have often been neglected in the equation of equilibrium of the tube wall. Numerical results show that zero wall tension does not mean nonexistence of steady solutions. When the wall tension becomes small, it is important to derive the equation of equilibrium by taking into account those terms which have been neglected in comparison with strong effect of the wall tension in physiological vessels.
The Fibroblast-Populated Collagen Microsphere Assay of Cell Traction Force—Part 2: Measurement of the Cell Traction Parameter
Authors: Barocas V. H. , Moon A. G. , Tranquillo R. T.
Published: February 2008

In Part 1 of this work, we formulated and analyzed a mathematical model for our fibroblast-populated collagen microsphere (FPCM) assay of cell traction forces (Moon and Tranquillo, 1993). In this assay, the FPCM diameter decreases with time as the cells compact the gel by exerting traction on collagen fibrils. In Part I we demonstrated that the diameter reduction profiles for varied initial cell concentration and varied initial FPCM diameter are qualitatively consistent with the model predictions. We show here in Part 2 how predictions of a model similar to that of Part 1, along with the determination of the growth parameters of the cells and the viscoelastic parameters of the gel, allow us to estimate the magnitude of a cell traction parameter, the desired objective index of cell traction forces. The model is based on a monophasic continuum-mechanical theory of cell-extracellular matrix (ECM) mechanical interactions, with a species conservation equation for cells (1), a mass conservation equation for ECM (2), and a mechanical force balance for the cell/ECM composite (3). Using a constant-stress rheometer and a fluids spectrometer in creep and oscillatory shear modes, respectively, we establish and characterize the linear viscoelastic regime for the reconstituted type 1 collagen gel used in our FPCM traction assay and in other assays of cell-collagen mechanical interactions. Creep tests are performed on collagen gel specimens in a state resembling that in our FPCM traction assay (initially uncompacted, and therefore nearly isotropic and at a relatively low collagen concentration of 2.1 mg/ml), yielding measurements of the zero shear viscosity, μ0 (7.4 × 106 Poise), and the steady-state creep compliance, Je0. The shear modulus, G (155 dynes/cm2), is then determined from the inverse of Je0 in the linear viscoelastic regime. Oscillatory shear tests are performed in strain sweep mode, indicating linear viscoelastic behavior up to shear strains of approximately 10 percent. We discuss the estimation of Poisson’s ratio, v, which along with G and μ0 specifies the assumed isotropic, linear viscoelastic stress tensor for the cell/collagen gel composite which appears in (3). The proliferation rate of fibroblasts in free floating collagen gel (appearing in (1)) is characterized by direct cell counting, yielding an estimate of the first-order growth rate constant, k (5.3 × 10-6 s-1). These independently measured and estimated parameter values allow us to estimate that the cell traction parameter, τ0, defined in the active stress tensor which also appears in (3), is in the range of 0.00007–0.0002 dyne · cm4/mg collagen · cell. This value is in agreement with a reported measure of traction obtained directly via isometric force measurement across a slab of fibroblast-containing collagen gel.
Characterization of a Sudden Expansion Flow Chamber to Study the Response of Endothelium to Flow Recirculation
Authors: Truskey George A. , Barber Kevin M. , Robey Thomas C. , Olivier Lauri A. , Combs Marty P.
Published: February 2008

In order to simulate regions of flow separation observed in vivo, a conventional parallel plate flow chamber was modified to produce an asymmetric sudden expansion. The flow field was visualized using light reflecting particles and the size of the recirculation zone was measured by image analysis of the particles. Finite element numerical solutions of the two and three-dimensional forms of the Navier-Stokes equation were used to determine the wall shear stress distribution and predict the location of reattachment. For two different size expansions, numerical estimates of the reattachment point along the centerline of the flow chamber agreed well with experimental values for Reynolds numbers below 473. Even at a Reynolds number of 473, the flow could be approximated as two-dimensional for 80 percent of the chamber width. Peak shear stresses in the recirculation zone as high as 80 dyne/cm2 and shear stress gradients of 2500 (dyne/cm2)/cm were produced. As an application of this flow chamber, subconfluent bovine aortic endothelial cell shape and orientation were examined in the zone of recirculation during a 24 h exposure to flow at a Reynolds number of 267. After 24 h, gradients in cell orientation and shape were observed within the recirculation zone. At the location of reattachment, where the wall shear stress was zero but the shear stress gradients were large, cells plated at low density were still aligned with the direction of flow. No preferred orientation was observed at the gasket edge where the wall shear stress and shear stress gradients were zero. At higher cell densities, no alignment was observed at the separation point. The results suggest that endothelial cells can respond to spatial gradients of wall shear stress.
An Automated Three-Dimensional Particle Tracking Technique for the Study of Modeled Arterial Flow Fields
Authors: Tsao R. , Jones S. A. , Giddens D. P. , Zarins C. K. , Glagov S.
Published: February 2008

An automated three-dimensional particle tracking technique has been developed to study particle motion in modeled flow fields. A high speed video recording system, Kodak Ektapro 1000, with two cameras airanged relatively orthogonally is used for this technique. The particle tracking data are compared to theoretical Poiseuille flow and to laser Doppler data from an axisymmetric stenosis model. The particle tracking data are in good agreement with both theoretical and laser Doppler data, and at least 79 percent of the particle paths were determined successfully. Fluid dynamic properties derived by this technique are: 3-D particle paths, velocity, and particle residence time.
Three Thioesterases Are Involved in the Biosynthesis of Phosphinothricin Tripeptide in
Streptomyces viridochromogenes
Tü494
Authors: Eys S. , Schwartz D. , Wohlleben W. , Schinko E.
Published: February 2008

Phosphinothricin tripeptide (PTT) is a peptide antibiotic produced by
Streptomyces viridochromogenes
Tü494, and it is synthesized by nonribosomal peptide synthetases. The PTT biosynthetic gene cluster contains three peptide synthetase genes:
phsA
,
phsB
, and
phsC
. Each of these peptide synthetases comprises only one module. In neither PhsB nor PhsC is a typical C-terminal thioesterase domain present. In contrast, a single thioesterase GXSXG motif has been identified in the N terminus of the first peptide synthetase, PhsA. In addition, two external thioesterase genes,
theA
and
theB
, are located within the PTT biosynthetic gene cluster. To analyze the thioesterase function as well as the assembly of the peptide synthetases within PTT biosynthesis, several mutants were generated and analyzed. A
phsA
deletion mutant (MphsA) was complemented with two different
phsA
constructs that were carrying mutations in the thioesterase motif. In one construct, the thioesterase motif comprising 45 amino acids of
phsA
were deleted. In the second construct, the conserved serine residue of the GXSXG motif was replaced by an alanine. In both cases, the complementation of MphsA did not restore PTT biosynthesis, revealing that the thioesterase motif in the N terminus of PhsA is required for PTT production. In contrast, TheA and TheB might have editing functions, as an interruption of the
theA
and
theB
genes led to reduced PTT production, whereas an overexpression of both genes in the wild type enhanced the PTT yield. The presence of an active single thioesterase motif in the N terminus of PhsA points to a novel mechanism of product release.
Plasmid-Mediated
qepA
Gene among
Escherichia coli
Clinical Isolates from Japan
Authors: Yamane Kunikazu , Wachino Jun-ichi , Suzuki Satowa , Arakawa Yoshichika
Published: February 2008

Seven hundred fifty-one
Escherichia coli
clinical isolates collected from 140 Japanese hospitals between 2002 and 2006 were screened for the
qepA
and
qnr
genes. Two
E. coli
isolates (0.3%) harbored
qepA
, but no
qnr
was identified. The results suggested a low prevalence of
E. coli
harboring
qepA
or
qnr
in Japan.
Activity of Daptomycin against
Listeria monocytogenes
Isolates from Cerebrospinal Fluid
Authors: Spanjaard Lodewijk , Vandenbroucke-Grauls Christina M. J. E.
Published: February 2008

We tested the activity of daptomycin against 76
Listeria monocytogenes
isolates from cerebrospinal fluid by broth dilution and Etest methods. For the broth dilution method, the MIC range was 1.0 to 8.0 and the MIC at which 90% of the isolates tested were inhibited (MIC
90
) was 4.0 mg/liter. For the Etest method, the MIC range was 1.0 to 4.0 and the MIC
90
was 4.0 mg/liter. Presently, daptomycin cannot be recommended for the treatment of
L. monocytogenes
meningitis.
Predictive Values of the Human Immunodeficiency Virus Phenotype and Genotype and of Amprenavir and Lopinavir Inhibitory Quotients in Heavily Pretreated Patients on a Ritonavir-Boosted Dual-Protease-Inhibitor Regimen
Authors: Barrail-Tran Aurélie , Morand-Joubert Laurence , Poizat Gwendoline , Raguin Gilles , Le Tiec Clotilde , Clavel François , Dam Elisabeth , Chêne Geneviève , Girard Pierre-Marie , Taburet Anne-Marie
Published: February 2008

The inhibitory quotient (IQ) of human immunodeficiency virus (HIV) protease inhibitors (PIs), which is the ratio of drug concentration to viral susceptibility, is considered to be predictive of the virological response. We used several approaches to calculate the IQs of amprenavir and lopinavir in a subset of heavily pretreated patients participating in the French National Agency for AIDS Research (ANRS) 104 trial and then compared their potentials for predicting changes in the plasma HIV RNA level. Thirty-seven patients were randomly assigned to receive either amprenavir (600 mg twice a day [BID]) or lopinavir (400 mg BID) plus ritonavir (100 or 200 mg BID) for 2 weeks before combining the two PIs. The 90% inhibitory concentration (IC90) was measured using a recombinant assay without or with additional human serum (IC90+serum). Total and unbound PI concentrations in plasma were measured. Univariate linear regression was used to estimate the relation between the change in viral load and the IC90or IQ values. The amprenavir phenotypic IQ values were very similar when measured with the standard and protein binding-adjusted IC90s. No relationship was found between the viral load decline and the lopinavir IQ. During combination therapy, the amprenavir and lopinavir genotypic IQ values were predictive of the viral response at week 6 (P= 0.03). The number of protease mutations (<5 or ≥5) was related to the virological response throughout the study. These findings suggest that the combined genotypic IQ and the number of protease mutations are the best predictors of virological response. High amprenavir and lopinavir concentrations in these patients might explain why plasma concentrations and the phenotypic IQ have poor predictive value.
The Hepatitis C Virus Replicon Presents a Higher Barrier to Resistance to Nucleoside Analogs than to Nonnucleoside Polymerase or Protease Inhibitors
Authors: McCown Matthew F. , Rajyaguru Sonal , Le Pogam Sophie , Ali Samir , Jiang Wen-Rong , Kang Hyunsoon , Symons Julian , Cammack Nick , Najera Isabel
Published: February 2008

Specific inhibitors of hepatitis C virus (HCV) replication that target the NS3/4A protease (e.g., VX-950) or the NS5B polymerase (e.g., R1479/R1626, PSI-6130/R7128, NM107/NM283, and HCV-796) have advanced into clinical development. Treatment of patients with VX-950 or HCV-796 rapidly selected for drug-resistant variants after a 14-day monotherapy treatment period. However, no viral resistance was identified after monotherapy with R1626 (prodrug of R1479) or NM283 (prodrug of NM107) after 14 days of monotherapy. Based upon the rapid selection of resistance to the protease and nonnucleoside inhibitors during clinical trials and the lack of selection of resistance to the nucleoside inhibitors, we used the replicon system to determine whether nucleoside inhibitors demonstrate a higher genetic barrier to resistance than protease and nonnucleoside inhibitors. Treatment of replicon cells with nucleoside inhibitors at 10 and 15 times the 50% effective concentration resulted in clearance of the replicon, while treatment with a nonnucleoside or protease inhibitor selected resistant colonies. In combination, the presence of a nucleoside inhibitor reduced the frequency of colonies resistant to the other classes of inhibitors. These results indicate that the HCV replicon presents a higher barrier to the selection of resistance to nucleoside inhibitors than to nonnucleoside or protease inhibitors. Furthermore, the combination of a nonnucleoside or protease inhibitor with a nucleoside polymerase inhibitor could have a clear clinical benefit through the delay of resistance emergence.
A Peptide with a ProGln C Terminus in the Human Saliva Peptidome Exerts Bactericidal Activity against
Propionibacterium acnes
Authors: Huang Chun-Ming , Torpey Justin W. , Liu Yu-Tseung , Chen Yun-Ru , Williams Katherine E. , Komives Elizabeth A. , Gallo Richard L.
Published: February 2008

Nine proline-rich peptides ending with a proline-glutamine C terminus in a salivary peptidome were sequenced by matrix-assisted laser desorption ionization time of flight time of flight tandem mass spectrometry. A GPPPQGGRPQ peptide binds gram-positive
Propionibacterium acnes
and considerably inhibits bacterial growth. The peptide exhibiting innate immunity may be applied for treatment of various
P. acnes
-associated human diseases.
Genetic Susceptibility to Chronic Hepatitis Is Inherited Codominantly in
Helicobacter hepaticus
-Infected AB6F1 and B6AF1 Hybrid Male Mice, and Progression to Hepatocellular Carcinoma Is Linked to Hepatic Expression of Lipogenic Genes and Immune Function-Associated Networks
Authors: García Alexis , Ihrig Melanie M. , Fry Rebecca C. , Feng Yan , Xu Sandy , Boutin Samuel R. , Rogers Arlin B. , Muthupalani Suresh , Samson Leona D. , Fox James G.
Published: February 2008

Helicobacter hepaticus
causes hepatitis in susceptible strains of mice. Previous studies indicated that A/JCr mice are susceptible and C57BL/6NCr mice are resistant to
H. hepaticus
-induced hepatitis. We used F1 hybrid mice derived from A/J and C57BL/6 matings to investigate their phenotype and determine their hepatic gene expression profile in response to
H. hepaticus
infection. F1 hybrid mice, as well as parental A/J and C57BL/6 mice, were divided equally into control and
H. hepaticus
-infected groups and euthanized at 18 months postinoculation. Hepatic lesions were evaluated histologically and the differential hepatic gene expression in F1 mice was determined by microarray-based global gene expression profiling analysis.
H. hepaticus
-infected parental strains including A/J and C57BL/6 mice, as well as F1 mice, developed significant hepatitis. Overall, hepatocellular carcinomas or dysplastic liver lesions were observed in 69% of
H. hepaticus
-infected F1 male mice and
H. hepaticus
was isolated from hepatic tissues of all F1 mice with liver tumors. Liver tumors, characterized by hepatic steatosis, developed in livers with high hepatitis scores. To identify gene expression specific to
H. hepaticus
-induced hepatitis and progression to hepatocellular carcinoma in F1 mice, a method using comparative group transcriptome analysis was utilized. The canonical pathway most significantly enriched was immunological disease. Fatty acid synthase and steaoryl-coenzyme A desaturase, the two rate-limiting enzymes in lipogenesis, were upregulated in neoplastic relative to dysplastic livers. This study suggests a synergistic interaction between hepatic steatosis and infectious hepatitis leading to hepatocellular carcinoma. The use of AB6F1 and B6AF1 mice, as well as genetically engineered mice, on a C57BL/6 background will allow studies investigating the role of chronic microbial hepatitis and steatohepatitis in the pathogenesis of liver cancer.
Human Dendritic Cell-Specific Intercellular Adhesion Molecule-Grabbing Nonintegrin (CD209) Is a Receptor forYersinia pestisThat Promotes Phagocytosis by Dendritic Cells
Authors: Zhang Pei , Skurnik Mikael , Zhang Shu-Sheng , Schwartz Olivier , Kalyanasundaram Ramaswamy , Bulgheresi Silvia , He Johnny J. , Klena John D. , Hinnebusch B. Joseph , Chen Tie
Published: February 2008

Yersinia pestisis the etiologic agent of bubonic and pneumonic plagues. It is speculated thatY. pestishijacks antigen-presenting cells (APCs), such as dendritic cells (DCs) and alveolar macrophages, in order to be delivered to lymph nodes. However, how APCs initially capture the bacterium remains uncharacterized. It is well known that HIV-1 uses human DC-specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN) (CD209) receptor, expressed by APCs, to be captured and delivered to target cell, such as CD4+lymphocytes. Several gram-negative bacteria utilize their core lipopolysaccharides (LPS) as ligands to interact with the human DC-SIGN. Therefore, it is possible thatY. pestis, whose core LPS is naturally exposed, might exploit DC-SIGN to invade APCs. We demonstrate in this study thatY. pestisdirectly interacts with DC-SIGN and invades both DCs and alveolar macrophages. In contrast, when engineered to cover the core LPS,Y. pestisloses its ability to invade DCs, alveolar macrophages, and DC-SIGN-expressing transfectants. The interaction betweenY. pestisand human DCs can be reduced by a combination treatment with anti-CD209 and anti-CD207 antibodies. This study shows that human DC-SIGN is a receptor forY. pestisthat promotes phagocytosis by DCs in vitro.
Intracellular Neutralization of Shiga Toxin 2 by an A Subunit-Specific Human Monoclonal Antibody
Authors: Krautz-Peterson Greice , Chapman-Bonofiglio Susan , Boisvert Karen , Feng Hanping , Herman Ira M. , Tzipori Saul , Sheoran Abhineet S.
Published: February 2008

Infection of children with Shiga toxin (Stx)-producing
Escherichia coli
(STEC) is the leading cause of hemolytic-uremic syndrome (HUS). Stx2, one of two toxins liberated by the bacteria, is directly linked with HUS. We have previously shown that Stx2-specific human monoclonal antibodies (HuMAbs) protect mice and piglets from fatal systemic complications of Stx2. The present study investigates the mechanisms by which our most efficacious A- and B-subunit-specific HuMAbs neutralize the cytotoxic effects of Stx2 in vitro. Whereas the B-subunit-specific HuMAb 5H8 blocked binding of Stx2 to its receptor on the cell surface, the A-subunit-specific HuMAb 5C12 did not interfere with the toxin-receptor binding. Further investigations revealed that 5C12 did not block endocytosis of Stx2 by HeLa cells as both Stx2 and 5C12 colocalized with early endosomes. However, 5C12 blocked the retrograde transport of the toxin into the Golgi and the endoplasmic reticulum, preventing the toxin from entering the cytosol where the toxin exerts its cytotoxic effect. The endocytosed 5C12/Stx2 complexes appear to be rapidly transported to the plasma membrane and/or to the slow recycling perinuclear compartments, followed by their slow recycling to the plasma membrane, and release into the extracellular environment.
Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge
Authors: Thirumalapura Nagaraja R. , Stevenson Heather L. , Walker David H. , Ismail Nahed
Published: February 2008

The roles of antibodies and memory T cells in protection against virulentEhrlichiahave not been completely investigated. In this study, we addressed these issues by using murine models of mild and fatal ehrlichiosis caused by related monocytotropicEhrlichiastrains. Mice were primed with eitherEhrlichia murisor closely related virulent ehrlichiae transmitted byIxodes ovatus(IOE) ticks given intraperitoneally or intradermally. All groups were reinfected intraperitoneally, 30 days later, with a lethal high dose of IOE. Priming withE. muris, but not IOE, induced strong CD4+and CD8+memory type 1 T-cell responses,Ehrlichia-specific immunoglobulin G (IgG) antibodies, and persistent infection. Compared to IOE-primed mice, subsequent lethal IOE challenge ofE. muris-primed mice, resulted in (i) 100% protection against lethal infection, (ii) strongEhrlichia-specific secondary gamma interferon (IFN-γ)-producing effector/effector memory CD4+and CD8+T-cell responses, (iii) enhanced secondary anti-ehrlichial antibody response, (iv) accelerated bacterial clearance, and (v) the formation of granulomas in the liver and lung.E. muris-primed mice challenged with IOE had lower levels of serum interleukin-1α (IL-1α), IL-6, and IL-10 compared to unprimed mice challenged with IOE. Interestingly, the fatal secondary response in IOE-primed mice correlated with (i) decline in theEhrlichia-specific CD4+and CD8+type 1 responses, (ii) marked hepatic apoptosis and necrosis, and (iii) substantial bacterial clearance, suggesting that fatal secondary response is due to immune-mediated tissue damage. In conclusion, protection against fatal ehrlichial infection correlates with strong expansion of IFN-γ-producing CD4+and CD8+effector memory type 1 T cells, which appear to be maintained in the presence of IgG antibodies and persistent infection.
The EtpA Exoprotein of Enterotoxigenic
Escherichia coli
Promotes Intestinal Colonization and Is a Protective Antigen in an Experimental Model of Murine Infection
Authors: Roy Koushik , Hamilton David , Allen Kenneth P. , Randolph Mildred P. , Fleckenstein James M.
Published: February 2008

The enterotoxigenic
Escherichia coli
(ETEC) strains are major causes of morbidity and mortality due to diarrheal illness in developing countries. At present, there is no broadly protective vaccine for this diverse group of pathogens. The EtpA protein, identified in ETEC H10407 in a recent search for candidate immunogens, is a large glycosylated exoprotein secreted via two-partner secretion (TPS). Similar to structurally related molecules, EtpA functions in vitro as an adhesin. The studies reported here use a recently developed murine model of ETEC intestinal colonization to examine the immunogenicity and protective efficacy of EtpA. We report that mice repeatedly exposed to ETEC are protected from subsequent colonization and that they mount immune responses to both EtpA and its presumed two-partner secretion transporter (EtpB) during the course of experimental infection. Furthermore, isogenic
etpA
deletion mutants were impaired in the colonization of mice, and intranasal immunization of mice with recombinant EtpA conferred protection against ETEC H10407 in this model. Together, these data suggest that EtpA is required for optimal colonization of the intestine, findings paralleling those of previous in vitro studies demonstrating its role in adherence. EtpA and other TPS proteins may be viable targets for ETEC vaccine development.
O Antigen Protects
Bordetella parapertussis
from Complement
Authors: Goebel Elizabeth M. , Wolfe Daniel N. , Elder Kelly , Stibitz Scott , Harvill Eric T.
Published: February 2008

Bordetella pertussis
, a causative agent of whooping cough, expresses BrkA, which confers serum resistance, but the closely related human pathogen that also causes whooping cough,
Bordetella parapertussis
, does not. Interestingly,
B. parapertussis
, but not
B. pertussis
, produces an O antigen, a factor shown in other models to confer serum resistance. Using a murine model of infection, we determined that O antigen contributes to the ability of
B. parapertussis
to colonize the respiratory tract during the first week of infection, but not thereafter. Interestingly, an O antigen-deficient strain of
B. parapertussis
was not defective in colonizing mice lacking the complement cascade. O antigen prevented both complement component C3 deposition on the surface and complement-mediated killing of
B. parapertussis
. In addition, O antigen was required for
B. parapertussis
to systemically spread in complement-sufficient mice, but not complement-deficient mice. These data indicate that O antigen enables
B. parapertussis
to efficiently colonize the lower respiratory tract by protecting against complement-mediated control and clearance.
Youth exposure to smoking in the home and in cars: how often does it happen and what do youth think about it?
Authors: Leatherdale S T , Smith P , Ahmed R
Published: February 2008

Aim:

Little is known about what youth think about restricting smoking in their homes or in cars. The present study characterises the frequency of youth being exposed to smoking in their homes and cars, and the beliefs that youth have about restricting people from smoking around youth in those locations.

Methods:

Data from the 2004 Youth Smoking Survey (YSS) were used to examine youth exposure to smoking and beliefs about smoking in the home and car among 29 243 Canadian youth in grades 5–9. Logistic regression models were conducted to examine if being exposed to smoking at home or in the car were associated with the beliefs youth have about either smoking around children at home or smoking around children in cars.

Results:

In 2004, 23.1% of youth in grades 5–9 were exposed to smoking in their home on a daily or almost daily basis, 26.3% were exposed to smoking while travelling in a car at least once in the previous week. The majority of youth reported that they do not think smoking should be allowed around children at home (90.6%) or in cars (90.2%). Males were more likely than females to report that smoking should not be allowed around children at home (OR 1.38) or in cars (OR 1.39). Youth living in a house where someone smokes inside daily were more likely to report that smoking should not be allowed around children at home (OR 1.20) or in cars (OR 1.21). Youth living in a house where the rules do not prevent people from smoking inside were also more likely to report that smoking should not be allowed around children at home (OR 2.07) or in cars (OR 1.76). Youth who have ridden in a car with someone who was smoking cigarettes in the past 7 days were more likely to report that smoking should not be allowed around children in cars (OR 1.73).

Conclusions:

It is common for Canadian youth to be exposed to SHS in their homes or while in cars on a frequent basis even though the vast majority of youth do not think smoking should be allowed around children in those locations. This new evidence suggests that programs and policies designed to prevent individuals from smoking around youth in these locations should be a public health priority.
Association of snuff use with chronic bronchitis among South African women: implications for tobacco harm reduction
Authors: Ayo-Yusuf O A , Reddy P S , van den Borne B W
Published: February 2008

Objective:

Nasal use of snuff is the predominant form of tobacco use among black South African women. This study examines the association between snuff use and chronic bronchitis (CB) among black South African women.

Design:

The study investigated a nationally representative sample of 4464 black South African women ⩾25 years old who participated in the 1998 South African Demographic and Health Survey. Data on participants’ tobacco use patterns, medical history and other relevant factors were obtained through an interviewer-administered questionnaire. Peak expiratory flow rates (PEFR) were also measured. Data analysis included χ2statistics, Student t tests and multiple logistic regression analysis.

Outcome measure:

CB, defined as reporting a productive cough for ⩾3 months/year for at least 2 successive years.

Results:

The prevalence of current snuff use was 16.1% (n = 719). Compared to non-users of snuff, snuff users were not only more likely to present with a history of tuberculosis (TB) (23.3% vs 15.9%; p = 0.06), but they were also more likely to present with CB (5.3% vs 2.8%; p<0.01) and a lower PEFR (275 litres/min vs 293 litres/min; p<0.01). Significant determinants of CB included snuff use >8 times/day (odds ratio (OR) 2.86, 95% CI 1.17 to 7.02), a history of TB (OR 7.23, 95% CI 4.02 to 13.03), current smoking (OR 2.84, 95% CI 1.60 to 5.04) and exposure to smoky cooking fuels (OR 1.98, 95% CI 1.32 to 2.96).

Conclusions:

These data suggest that snuff use, in the form predominantly used in South Africa, increases the risk of CB. This challenges the idea that snuff may be a much less harmful alternative to smoking in South Africa.
FLIPPING LETTERS TO MINIMIZE THE SUPPORT OF A STRING
Authors: LANCIA GIUSEPPE , RINALDI FRANCA , RIZZI ROMEO
Published: February 2008

Given a string s on an alphabet Σ, a word-length k and a budget D, we want to determine the smallest number of distinct k-mers that can be left in s, if we are allowed to replace up to D letters of s. This problem has several parameters, and we discuss its complexity under all sorts of restrictions on the parameters values. We prove that some versions of the problem are polynomial, while others are NP-hard. We also introduce some Integer Programming formulations to model the NP-hard cases.
A MARKOVIAN APPROACH FOR THE ANALYSIS OF THE GENE STRUCTURE
Authors: MELODELIMA CHRISTELLE , GUEGUEN LAURENT , GAUTIER CHRISTIAN , PIAU DIDIER
Published: February 2008

Hidden Markov models (HMMs) are effective tools to detect series of statistically homogeneous structures, but they are not well suited to analyse complex structures. Numerous methodological difficulties are encountered when using HMMs to segregate genes from transposons or retroviruses, or to determine the isochore classes of genes. The aim of this paper is to analyse these methodological difficulties, and to suggest new tools for the exploration of genome data. We show that HMMs can be used to analyse complex genes structures with bell-shaped distributed lengths, modelling them by macro-states. Our data processing method, based on discrimination between macro-states, allows to reveal several specific characteristics of intronless genes, and a break in the homogeneity of the initial coding exons. This potential use of markovian models to help in data exploration seems to have been underestimated until now, and one aim of our paper is to promote this use of Markov modelling.
IDENTIFYING RHYTHMS IN MUSICAL TEXTS
Authors: CHRISTODOULAKIS MANOLIS , ILIOPOULOS COSTAS S. , RAHMAN M. SOHEL , SMYTH WILLIAM F.
Published: February 2008

A fundamental problem in music is to classify songs according to their rhythm. A rhythm is represented by a sequence of “Quick” (Q) and “Slow” (S) symbols, which correspond to the (relative) duration of notes, such that S = 2Q. In this paper, we present an efficient algorithm for locating the maximum-length substring of a music text t that can be covered by a given rhythm r.
INDEXING GAPPED-FACTORS USING A TREE
Authors: PETERLONGO PIERRE , ALLALI JULIEN , SAGOT MARIE-FRANCE
Published: February 2008

We present a data structure to index a specific kind of factors, that is of substrings, called gapped-factors. A gapped-factor is a factor containing a gap that is ignored during the indexation. The data structure presented is based on the suffix tree and indexes all the gapped-factors of a text with a fixed size of gap, and only those. The construction of this data structure is done online in linear time and space. Such a data structure may play an important role in various pattern matching and motif inference problems, for instance in text filtration.
USING ALIGNMENT FOR MULTILINGUAL TEXT COMPRESSION
Authors: CONLEY EHUD S. , KLEIN SHMUEL T.
Published: February 2008

Multilingual text compression exploits the existence of the same text in several languages to compress the second and subsequent copies by reference to the first. We explore the details of this framework and present experimental results for parallel English and French texts.
ON SOME COMBINATORIAL PROBLEMS CONCERNING THE HARMONIC STRUCTURE OF MUSICAL CHORD SEQUENCES
Authors: CANTONE DOMENICO , CRISTOFARO SALVATORE , FARO SIMONE
Published: February 2008

We present some combinatorial problems which arise in the fields of music representation and music processing, in particular in the context of analysis of the harmonic structure of chord sequences. We are mainly concerned with problems related to chord sequences which exhibit a certain kind of regular harmonic structure, and provide also algorithms to solve some of them. In particular, we present an [Formula: see text]-time algorithm, based on bit-parallelism, to check whether a given chord progression of length n is regular, where m is the size of the chords in the progression.
REACHABILITY ON SUFFIX TREE GRAPHS
Authors: HIGA YASUTO , BANNAI HIDEO , INENAGA SHUNSUKE , TAKEDA MASAYUKI
Published: February 2008

We analyze the complexity of graph reachability queries on ST-graphs, defined as directed acyclic graphs (DAGs) obtained by merging the suffix tree of a given string and its suffix links. Using a simplified reachability labeling algorithm presented by Agrawal et al. (1989), we show that for a random string of length n, its ST-graph can be preprocessed in O(n log n) expected time and space to answer reachability queries in O( log n) time. Furthermore, we present a series of strings that require [Formula: see text] time and space to answer reachability queries in O( log n) time for the same algorithm. Exhaustive computational calculations for strings of length n ≤ 33 have revealed that the same strings are also the worst case instances of the algorithm. We therefore conjecture that reachability queries can be answered in O( log n) time with a worst case time and space preprocessing complexity of [Formula: see text].