bluuebunny/crossref_metadata_2025 huggingface dataset:
Vehicle Collision Avoidance Maneuvers With Limited Lateral Acceleration Using Optimal Trajectory Control
Authors: Soudbakhsh Damoon , Eskandarian Azim , Chichka David
Published: May 2013

In this paper, the possibility of performing severe collision avoidance maneuvers using trajectory optimization is investigated. A two degree of freedom vehicle model was used to represent dynamics of the vehicle. First, a linear tire model was used to calculate the required steering angle to perform the desired evasive maneuver, and a neighboring optimal controller was designed. Second, direct trajectory optimization algorithm was used to find the optimal trajectory with a nonlinear tire model. To evaluate the results, the calculated steering angles were fed to a full vehicle dynamics model. It was shown that the neighboring optimal controller was able to accommodate the introduced disturbances. Comparison of the resultant trajectories with other desired trajectories showed that it results in a lower lateral acceleration profile and a smaller maximum lateral acceleration; thus the time to perform an obstacle avoidance maneuver can be reduced using this method. A simulation case study of a limited lateral acceleration with constrained direct trajectory optimization shows that using the proposed trajectory optimization technique requires less time than that of trapezoidal acceleration profile for a lane change maneuver.
Optimal H∞-Based Linear-Quadratic Regulator Tracking Control for Discrete-Time Takagi–Sugeno Fuzzy Systems With Preview Actions
Authors: Zhang Hui , Shi Yang , Mu Bingxian
Published: May 2013

This paper investigates the optimal tracking control problem for discrete-time Takagi–Sugeno (T–S) systems. The control signal has three components: preview control for the previewable reference signal, integral control for the tracking error, and the state-feedback control for the plant. The optimization objective is a quadratic form of the tracking error and the control signal. By using the augmentation technique, the tracking controller design problem is converted into a design problem of the state-feedback controllers for augmented T–S fuzzy systems. The quadratic optimization objective is equivalent to the two-norm (in fact, the square of the two-norm) of a controlled output. Assuming that the external inputs of the augmented systems are l2 bounded, the H∞ performance index is employed to investigate and optimize the controller design. The controller gains can be obtained by solving a sequence of linear matrix inequalities (LMIs). An example on electromechanical system shows the efficacy of the proposed design method.
Real-Gas Effects in Foil Thrust Bearings Operating in the Turbulent Regime
Authors: Conboy T. M.
Published: May 2013

In this study, an elastohydrodynamic model was created for predicting the pressure field in a compliant thrust bearing assembly lubricated by high pressure CO2. This application is of significance due to ongoing research into the closed-cycle supercritical CO2 turbine as a high-efficiency alternative to steam turbines. Hardware development for this concept has been led by Sandia National Laboratories, where turbomachinery running on gas foil thrust and journal bearings is being tested. The model accounts for the fluid velocity field, hydrodynamic pressure, and frictional losses within the lubrication layer by evaluating the turbulent Reynolds equation coupled with an equation for structural deformation in the bearings, and the fluid properties database RefProp v9.0. The results of numerical simulations have been compared with empirical correlations, with reasonable agreement attained. Of particular interest is the contrast drawn between the performance of high pressure CO2 as a lubricant, and ambient pressure air. Parametric studies covering a range of fluid conditions, operating speeds, and thrust loads were carried out to illustrate the value of this model as a tool for improved understanding and further development of this nascent technology.
Designing Microstructural Architectures With Thermally Actuated Properties Using Freedom, Actuation, and Constraint Topologies
Authors: Hopkins Jonathan B. , Lange Kyle J. , Spadaccini Christopher M.
Published: May 2013

In this paper, we demonstrate how the principles of the freedom, actuation, and constraint topologies (FACT) approach may be applied to the synthesis, analysis, and optimization of microstructural architectures that possess extreme or unusual thermal expansion properties (e.g., zero or large negative-thermal expansion coefficients). FACT provides designers with a comprehensive library of geometric shapes, which may be used to visualize the regions wherein various microstructural elements can be placed for achieving desired bulk material properties. In this way, designers can rapidly consider and compare a multiplicity of microstructural concepts that satisfy the desired design requirements before selecting the final concept. A complementary analytical tool is also provided to help designers rapidly calculate and optimize the desired thermal properties of the microstructural concepts that are generated using FACT. As a case study, this tool is used to calculate the negative-thermal expansion coefficient of a microstructural architecture synthesized using FACT. The result of this calculation is verified using a finite element analysis (FEA) package called ale3d.
Blast Wave Loading Pathways in Heterogeneous Material Systems–Experimental and Numerical Approaches
Authors: Selvan Veera , Ganpule Shailesh , Kleinschmit Nick , Chandra Namas
Published: May 2013

Blast waves generated in the field explosions impinge on the head-brain complex and induce mechanical pressure pulses in the brain resulting in traumatic brain injury. Severity of the brain injury (mild to moderate to severe) is dependent upon the magnitude and duration of the pressure pulse, which in turn depends on the intensity and duration of the oncoming blast wave. A fluid-filled cylinder is idealized to represent the head-brain complex in its simplest form; the cylinder is experimentally subjected to an air blast of Friedlander type, and the temporal variations of cylinder surface pressures and strains and fluid pressures are measured. Based on these measured data and results from computational simulations, the mechanical loading pathways from the external blast to the pressure field in the fluid are identified; it is hypothesized that the net loading at a given material point in the fluid comprises direct transmissive loads and deflection-induced indirect loads. Parametric studies show that the acoustic impedance mismatches between the cylinder and the contained fluid as well as the flexural rigidity of the cylinder determine the shape/intensity of pressure pulses in the fluid.
Considerations for Numerical Modeling of the Pulmonary Circulation—A Review With a Focus on Pulmonary Hypertension
Authors: Kheyfets V. O. , O'Dell W. , Smith T. , Reilly J. J. , Finol E. A.
Published: May 2013

Both in academic research and in clinical settings, virtual simulation of the cardiovascular system can be used to rapidly assess complex multivariable interactions between blood vessels, blood flow, and the heart. Moreover, metrics that can only be predicted with computational simulations (e.g., mechanical wall stress, oscillatory shear index, etc.) can be used to assess disease progression, for presurgical planning, and for interventional outcomes. Because the pulmonary vasculature is susceptible to a wide range of pathologies that directly impact and are affected by the hemodynamics (e.g., pulmonary hypertension), the ability to develop numerical models of pulmonary blood flow can be invaluable to the clinical scientist. Pulmonary hypertension is a devastating disease that can directly benefit from computational hemodynamics when used for diagnosis and basic research. In the present work, we provide a clinical overview of pulmonary hypertension with a focus on the hemodynamics, current treatments, and their limitations. Even with a rich history in computational modeling of the human circulation, hemodynamics in the pulmonary vasculature remains largely unexplored. Thus, we review the tasks involved in developing a computational model of pulmonary blood flow, namely vasculature reconstruction, meshing, and boundary conditions. We also address how inconsistencies between models can result in drastically different flow solutions and suggest avenues for future research opportunities. In its current state, the interpretation of this modeling technology can be subjective in a research environment and impractical for clinical practice. Therefore, considerations must be taken into account to make modeling reliable and reproducible in a laboratory setting and amenable to the vascular clinic. Finally, we discuss relevant existing models and how they have been used to gain insight into cardiopulmonary physiology and pathology.
Three-Dimensional Modeling of Supine Human and Transport System Under Whole-Body Vibration
Authors: Wang Yang , Rahmatalla Salam
Published: May 2013

The development of predictive computer human models in whole-body vibration has shown some success in predicting simple types of motion, mostly for seated positions and in the uniaxial vertical direction. The literature revealed only a handful of papers that tackled supine human modeling in response to vertical vibration. The objective of this work is to develop a predictive, multibody, three-dimensional human model to simulate the supine human and underlying transport system in response to multidirectional whole-body vibration. A three-dimensional dynamic model of a supine human and its underlying transport system is presented in this work to predict supine-human biodynamic response under three-dimensional input random whole-body vibration. The proposed supine-human model consists of three interconnected segments representing the head, torso-arms, and pelvis-legs. The segments are connected via rotational and translational joints that have spring-damper components simulating the three-dimensional muscles and tissuelike connecting elements in the three x, y, and z directions. Two types of transport systems are considered in this work, a rigid support and a long spinal board attached to a standard military litter. The contact surfaces between the supine human and the underlying transport system are modeled using spring-damper components. Eight healthy supine human subjects were tested under combined-axis vibration files with a magnitude of 0.5 m/s2 (rms) and a frequency content of 0.5–16 Hz. The data from seven subjects were used in parameter identification for the dynamic model using optimization schemes in the frequency domain that minimize the differences between the magnitude and phase of the predicted and experimental transmissibility. The predicted accelerations in the time and frequency domains were comparable to those gathered from experiments under different anthropometric, input vibration, and transport conditions under investigation. Based on the results, the proposed dynamic model has the potential to be used to provide motion data to drive a detailed finite element model of a supine human for further investigation of muscle forces and joint dynamics. The predicted kinematics of the supine human and transport system would also benefit patient safety planners and vibration suppression designers in their endeavors.
Integrating the Pressure-Sensitive Nonassociative Plasticity by Exponential-Based Methods
Authors: Rezaiee-Pajand Mohammad , Sharifian Mehrdad , Sharifian Mehrzad
Published: May 2013

A nonassociative plasticity model of Drucker–Prager yield surface coupled with a generalized nonlinear kinematic hardening is considered. Conforming to the plasticity model, two exponential-based methods, called fully explicit and semi-implicit, are recommended for integrating its constitutive equations. These techniques are proposed for the first time to solve nonlinear hardening materials. The integrations are thoroughly investigated by utilizing stress and strain-updating tests along with a boundary value problem in diverse grounds of accuracy, convergence rate, and efficiency. The results indicate that the fully explicit scheme is more accurate and efficient than the Euler's, but the same convergence rate as the classical integrations is also perceived. Having a quadratic convergence, the semi-implicit is noticeably the most accurate and efficient procedure to use for this plasticity model among the algorithms in question. Since the plasticity model is in a great consistency with discontinuously reinforced aluminum (DRA) composites, the suggested formulations can be utilized pragmatically. The tangent moduli of the proposed and Euler's strategies are derived and examined, as well, due to their vital role in achieving the asymptotic quadratic convergence rate of the Newton–Raphson solution in nonlinear finite-element analyses.
Design of Complex Biologically Based Nanoscale Systems Using Multi-Agent Simulations and Structure–Behavior–Function Representations
Authors: Egan Paul F. , Cagan Jonathan , Schunn Christian , LeDuc Philip R.
Published: May 2013

The process of designing integrated biological systems across scales is difficult, with challenges arising from the modeling, understanding, and search of complex system design spaces. This paper explores these challenges through consideration of how stochastic nanoscale phenomenon relate to higher level systems functioning across many scales. A domain-independent methodology is introduced which uses multi-agent simulations to predict emergent system behavior and structure–behavior–function (SBF) representations to facilitate design space navigation. The methodology is validated through a nanoscale design application of synthetic myosin motor systems. In the multi-agent simulation, myosins are independent computational agents with varied structural inputs that enable differently tuned mechanochemical behaviors. Four synthetic myosins were designed and replicated as agent populations, and their simulated behavior was consistent with empirical studies of individual myosins and the macroscopic performance of myosin-powered muscle contractions. However, in order to configure high performance technologies, designers must effectively reason about simulation inputs and outputs; we find that counter-intuitive relations arise when linking system performance to individual myosin structures. For instance, one myosin population had a lower system force even though more myosins contributed to system-level force. This relationship is elucidated with SBF by considering the distribution of structural states and behaviors in agent populations. For the lower system force population, it is found that although more myosins are producing force, a greater percentage of the population produces negative force. The success of employing SBF for understanding system interactions demonstrates how the methodology may aid designers in complex systems embodiment. The methodology's domain-independence promotes its extendibility to similar complex systems, and in the myosin test case the approach enabled the reduction of a complex physical phenomenon to a design space consisting of only a few critical parameters. The methodology is particularly suited for complex systems with many parts operating stochastically across scales, and should prove invaluable for engineers facing the challenges of biological nanoscale design, where designs with unique properties require novel approaches or useful configurations in nature await discovery.
Shaping Patient Specific Surgical Guides for Arthroplasty to Obtain High Docking Robustness
Authors: Mattheijer Joost , Herder Just L. , Tuijthof Gabriëlle J. M. , Nelissen Rob G. H. H. , Dankelman Jenny , Valstar Edward R.
Published: May 2013

Patient specific surgical guides (PSSGs) are used in joint replacement surgery to simplify the surgical process and to increase the accuracy in alignment of implant components with respect to the bone. Each PSSG is fabricated patient specifically and fits only in the planned position on the joint surface by the matching shape. During surgery, the surgeon holds the PSSG in the planned position and the incorporated guidance is used in making the essential cuts to fit the implant components. The shape of the PSSG determines its docking robustness (i.e., the range of forces that the surgeon may apply without losing the planned position). Minimal contact between the PSSG and the joint surface is desired, as this decreases the likelihood of interposition with undetected tissues. No analytical method is known from literature where the PSSG shape can be optimized to have high docking robustness and minimal bone-guide contact. Our objective is to develop and validate such an analytical method. The methods of motion restraint, moment labeling and wrench space—applied in robotic grasping and workpart fixturing—are employed in the creation of this new method. The theoretic approach is utilized in an example by optimizing the PSSG shape for one joint surface step-by-step. The PSSGs that arise from these optimization steps are validated with physical experiments. The following design tools for the analytical method are introduced. The optimal location for bone-guide contact and the application surface where the surgeon may push can be found graphically, respectively, by the use of the wrench space map and the application angle map. A quantitative analysis can be conducted using the complementary wrench space metrics and the robustness metric R. Utilization of the analytical method with an example joint surface shows that the PSSG's shape can be optimized. Experimental validation shows that the standard deviation of the error between the measured and calculated angular limits in the docking force is only 0.7 deg. The analytical method provides valid results and thus can be used for the design of PSSGs.
Approaches for Identifying Consumer Preferences for the Design of Technology Products: A Case Study of Residential Solar Panels
Authors: Chen Heidi Q. , Honda Tomonori , Yang Maria C.
Published: May 2013

This paper investigates ways to obtain consumer preferences for technology products to help designers identify the key attributes that contribute to a product's market success. A case study of residential photovoltaic panels is performed in the context of the California, USA, market within the 2007–2011 time span. First, interviews are conducted with solar panel installers to gain a better understanding of the solar industry. Second, a revealed preference method is implemented using actual market data and technical specifications to extract preferences. The approach is explored with three machine learning methods: Artificial neural networks (ANN), Random Forest decision trees, and Gradient Boosted regression. Finally, a stated preference self-explicated survey is conducted, and the results using the two methods compared. Three common critical attributes are identified from a pool of 34 technical attributes: power warranty, panel efficiency, and time on market. From the survey, additional nontechnical attributes are identified: panel manufacturer's reputation, name recognition, and aesthetics. The work shows that a combination of revealed and stated preference methods may be valuable for identifying both technical and nontechnical attributes to guide design priorities.
Uniformity Analysis in Different Flow-Field Configurations of Proton Exchange Membrane Fuel Cell
Authors: Li Yok-Sheung , Han Yi , Zhan Jie-Min
Published: May 2013

Knowledge of the distributions of various properties within a proton exchange membrane (PEM) fuel cell is a prerequisite for the improvement of cell performance, stability, and durability. In this paper, statistical tools are employed to investigate the variations of the current density, membrane water content, and local temperature in six flow-field configurations of PEM fuel cells, utilizing a three-dimensional two-phase multicomponent model. Under the same operating conditions, although the polarizations of the cells are similar, the results show that the extent of the uniformity of different physical properties varies in different flow-field configurations. Due to the proper distributions of reactants, the current density, membrane water content, and temperature in channel-perpendicular flow-fields are distributed more uniformly than in channel-overlapping ones. Furthermore, for all flow-field configurations, the three physical properties showed better uniformity in cases with fewer cathodic serpentine channels than in cases with more channels. These results reveal that a uniformity analysis using statistical tools is useful for a comparison of the merits of different configurations of PEM fuel cells.
Design and Thermodynamic Analysis of an SOFC System for Naval Surface Ship Application
Authors: Ezgi Cüneyt , Turhan Çoban M. , Selvi Özgün
Published: May 2013

Diesel-fueled fuel cell systems can be more clean and efficient energy solutions than internal combustion engines for electric power generation on-board naval surface ships. NATO Navy steam and gas turbine and diesel ships are powered by a naval distillate fuel (NATO symbol F-76). In this study, a 120 kW F-76 diesel-fueled solid oxide fuel cell system (SOFC) as an auxiliary engine on-board a naval surface ship was designed and thermodynamically analyzed. A diesel-fueled SOFC system was compared to diesel-electric generator set in a case naval surface ship.
Development and Diagnosis of a 1-kW Self-Sustainable Proton Exchange Membrane Fuel Cell System With a Methanol Reformer
Authors: Chen Chen-Yu , Hsu Sui-Wei , Yan Wei-Mon , Lai Wei-Hsiang , Huang Keng-Pin , Yang Chen-Cheng , Chen Chun-Chi , Lai Ming-Ping
Published: May 2013

A reformed methanol fuel cell system is one of the most practical of all types of fuel cell systems. It is regarded as one of the best candidates for stationary applications, such as residential power generators, uninterruptible power supply systems, power generators for cell base stations, or power generators in outlying areas. In this research, a 1-kW self-sustainable proton exchange membrane fuel cell system with a methanol reformer is designed and tested. The system performance test and in situ stack monitoring show that the system is stable and reliable. During normal operation, the maximum voltage deviation among the individual cells, which is caused by a nonuniform temperature distribution in the proton exchange membrane fuel cell stack, is 25 mV. The peak power output of the system reaches 1.4 kW. The maximum electrical efficiency is 65.2% at a system power of 1 kW. The system is operated at 1 kW for 4 h, during which the decay rate of the stack power is 0.94%. During the stability test, voltage fluctuation occurs in a certain cell because of a flooding phenomenon. A demonstration is also presented in this paper to show the system’s practicability and commercial potential.
The Use of a Novel Injectable Hydrogel Nucleus Pulposus Replacement in Restoring the Mechanical Properties of Cyclically Fatigued Porcine Intervertebral Discs
Authors: Balkovec Christian , Vernengo Jennifer , McGill Stuart M.
Published: May 2013

Repeated flexion and extension of an intervertebral disc has been shown to affect the angular stiffness of spinal motion segments and is a barometer of the mechanical integrity of the disc. A degenerated disc that loses height causes higher levels of stress on the annulus and facet joints which may increase its level of degeneration; restoring disc height may therefore help to slow this degenerative cascade. Previous research has indicated that nucleus implants have the potential to improve the mechanical characteristics of a disc and an implant that is custom-fit to the intervertebral disc yields the best results with respect to decreasing annular degeneration. Two groups of porcine spinal motion segments were exposed to repeated flexion and extension. One group was then injected with a novel hydrogel while the other group was used as a control. Both groups were then exposed to another round of cyclic flexion and extension to examine the effect that the hydrogel had on restoring the original mechanics to the motion segments. Angular stiffness was restored to the group which received the hydrogel injection in addition to a significant improvement in specimen height. No significant changes were seen in the group which did not receive an injection. It would appear that use of the novel injectable hydrogel is able to restore angular stiffness to cyclically fatigued spinal motion segments. It is also important to note that continued repetition of the event causing specimen fatigue after performing hydrogel injection will result in an eventual return to the same fatigued state.
Elucidating Human Phosphatase-Substrate Networks
Authors: Li Xun , Wilmanns Matthias , Thornton Janet , Köhn Maja
Published: May 2013

An online database provides an analysis of human phosphatases and their substrates.
An Increase in Synaptic NMDA Receptors in the Insular Cortex Contributes to Neuropathic Pain
Authors: Qiu Shuang , Chen Tao , Koga Kohei , Guo Yan-yan , Xu Hui , Song Qian , Wang Jie-jie , Descalzi Giannina , Kaang Bong-Kiun , Luo Jian-hong , Zhuo Min , Zhao Ming-gao
Published: May 2013

Inhibiting NMDA receptor function in the insular cortex may prevent the development of neuropathic pain.
Dendritic Precision Strikes
Authors: Stern Peter R.
Published: May 2013

Inhibitory synapses can control individual dendritic spines independently from their neighbors.
Damaging Thoughts
Authors: Wong Wei
Published: May 2013

Neuronal activity leads to double-stranded DNA breaks through an NMDA receptor–dependent mechanism.
cyp51A
-Based Mechanisms of Aspergillus fumigatus Azole Drug Resistance Present in Clinical Samples from Germany
Authors: Bader Oliver , Weig Michael , Reichard Utz , Lugert Raimond , Kuhns Martin , Christner Martin , Held Jürgen , Peter Silke , Schumacher Ulrike , Buchheidt Dieter , Tintelnot Kathrin , Groß Uwe ,   MykoLabNet-D Partners
Published: May 2013

Since the mid-1990s, a steady increase in the occurrence of itraconazole-resistant
Aspergillus fumigatus
isolates has been observed in clinical contexts, leading to therapeutic failure in the treatment of aspergillosis. This increase has been predominantly linked to a single allele of the
cyp51A
gene, termed TR/L98H, which is thought to have arisen through the use of agricultural azoles. Here, we investigated the current epidemiology of triazole-resistant
A. fumigatus
and underlying
cyp51A
mutations in clinical samples in Germany. From a total of 527 samples, 17 (3.2%) showed elevated MIC
0
values (the lowest concentrations with no visible growth) for at least one of the three substances (itraconazole, voriconazole, and posaconazole) tested. The highest prevalence of resistant isolates was observed in cystic fibrosis patients (5.2%). Among resistant isolates, the TR/L98H mutation in
cyp51A
was the most prevalent, but isolates with the G54W and M220I substitutions and the novel F219C substitution were also found. The isolate with the G54W substitution was highly resistant to both itraconazole and posaconazole, while all others showed high-level resistance only to itraconazole. For the remaining six isolates, no mutations in
cyp51A
were found, indicating the presence of other mechanisms. With the exception of the strains carrying the F219C and M220I substitutions, many itraconazole-resistant strains also showed cross-resistance to voriconazole and posaconazole with moderately increased MIC
0
values. In conclusion, the prevalence of azole-resistant
A. fumigatus
in our clinical test set is lower than that previously reported for other countries. Although the TR/L98H mutation frequently occurs among triazole-resistant strains in Germany, it is not the only resistance mechanism present.
Glyceryl Trinitrate Complements Citrate and Ethanol in a Novel Antimicrobial Catheter Lock Solution To Eradicate Biofilm Organisms
Authors: Rosenblatt Joel , Reitzel Ruth , Dvorak Tanya , Jiang Ying , Hachem Ray Y. , Raad Issam I.
Published: May 2013

Antimicrobial catheter lock therapy is practiced to prevent lumenal-sourced infections of central venous catheters. Citrate has been used clinically as an anticoagulant in heparin-free catheter locks. Ethanol has also been widely studied as an antimicrobial lock solution component. This study reports on the synergy of glyceryl trinitrate (GTN) with citrate and ethanol in rapidly eradicating methicillin-resistant
Staphylococcus aureus
, methicillin-resistant
Staphylococcus epidermidis
,
Pseudomonas aeruginosa
, and
Candida albicans
biofilms in an
in vitro
model for catheter biofilm colonization. GTN has a long history of intravenous use as a hypotensive agent. It is potentially attractive as a component of a catheter lock solution because its physiologic half-life is quite short and its metabolic pathways are known. A lock containing 7% citrate and 20% ethanol required 0.01% GTN to fully eradicate biofilms of all test organisms within 2 h in the model. This GTN concentration is below the levels where clinically significant hypotensive effects are expected.
Metabolism, Excretion, and Mass Balance of the HIV-1 Integrase Inhibitor Dolutegravir in Humans
Authors: Castellino Stephen , Moss Lee , Wagner David , Borland Julie , Song Ivy , Chen Shuguang , Lou Yu , Min Sherene S. , Goljer Igor , Culp Amanda , Piscitelli Stephen C. , Savina Paul M.
Published: May 2013

The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [
14
C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (
t
1/2
) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.
Population-Based Survey of Filamentous Fungi and Antifungal Resistance in Spain (FILPOP Study)
Authors: Alastruey-Izquierdo A. , Mellado E. , Peláez T. , Pemán J. , Zapico S. , Alvarez M. , Rodríguez-Tudela J. L. , Cuenca-Estrella M. ,   FILPOP Study Group
Published: May 2013

A population-based survey was conducted to investigate the epidemiology of and antifungal resistance in Spanish clinical strains of filamentous fungi isolated from deep tissue samples, blood cultures, and respiratory samples. The study was conducted in two different periods (October 2010 and May 2011) to analyze seasonal variations. A total of 325 strains were isolated in 29 different hospitals. The average prevalence was 0.0016/1,000 inhabitants. Strains were identified by sequencing of DNA targets and susceptibility testing by the European Committee for Antimicrobial Susceptibility Testing reference procedure. The most frequently isolated genus was
Aspergillus
, accounting for 86.3% of the isolates, followed by
Scedosporium
at 4.7%; the order Mucorales at 2.5%;
Penicillium
at 2.2%, and
Fusarium
at 1.2%. The most frequent species was
Aspergillus fumigatus
(48.5%), followed by
A. flavus
(8.4%),
A. terreus
(8.1%),
A. tubingensis
(6.8%), and
A. niger
(6.5%). Cryptic/sibling
Aspergillus
species accounted for 12% of the cases. Resistance to amphotericin B was found in 10.8% of the isolates tested, while extended-spectrum triazole resistance ranged from 10 to 12.7%, depending on the azole tested. Antifungal resistance was more common among emerging species such as those of
Scedosporium
and Mucorales and also among cryptic species of
Aspergillus
, with 40% of these isolates showing resistance to all of the antifungal compounds tested. Cryptic
Aspergillus
species seem to be underestimated, and their correct classification could be clinically relevant. The performance of antifungal susceptibility testing of the strains implicated in deep infections and multicentric studies is recommended to evaluate the incidence of these cryptic species in other geographic areas.
Synthesis and Antiviral Activities of Methylenecyclopropane Analogs with 6-Alkoxy and 6-Alkylthio Substitutions That Exhibit Broad-Spectrum Antiviral Activity against Human Herpesviruses
Authors: Prichard Mark N. , Williams John D. , Komazin-Meredith Gloria , Khan Atiyya R. , Price Nathan B. , Jefferson Geraldine M. , Harden Emma A. , Hartline Caroll B. , Peet Norton P. , Bowlin Terry L.
Published: May 2013

Methylenecyclopropane nucleosides have been reported to be active against many of the human herpesviruses. The most active compound of this class is cyclopropavir (CPV), which exhibits good antiviral activity against human cytomegalovirus (HCMV), Epstein-Barr virus, both variants of human herpesvirus 6, and human herpesvirus 8. CPV has two hydroxymethyl groups on the methylenecyclopropane ring, but analogs with a single hydroxymethyl group, such as the prototypical (
S
)-synguanol, are also active and exhibit a broader spectrum of antiviral activity that also includes hepatitis B virus and human immunodeficiency virus. Here, a large set of monohydroxymethyl compounds with ether and thioether substituents at the 6 position of the purine was synthesized and evaluated for antiviral activity against a range of human herpesviruses. Some of these analogs had a broader spectrum of antiviral activity than CPV, in that they also inhibited the replication of herpes simplex viruses 1 and 2 and varicella-zoster virus. Interestingly, the antiviral activity of these compounds appeared to be dependent on the activity of the HCMV UL97 kinase but was relatively unaffected by the absence of thymidine kinase activity in HSV. These data taken together indicate that the mechanism of action of these analogs is distinct from that of CPV. They also suggest that they might be useful as broad-spectrum antiherpesvirus agents and may be effective in the treatment of resistant virus infections.
Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics
Authors: Kamal Mohamed A. , Van Wart Scott A. , Rayner Craig R. , Subramoney Vishak , Reynolds Daniel K. , Bulik Catharine C. , Smith Patrick F. , Bhavnani Sujata M. , Ambrose Paul G. , Forrest Alan
Published: May 2013

Oseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F, while Vcm/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individualpost hocpredictions of maximum concentration of drug at steady state (Cmax) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC0–24) was high (r2= 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.
Pharmacokinetic-Pharmacodynamic Determinants of Oseltamivir Efficacy Using Data from Phase 2 Inoculation Studies
Authors: Rayner C. R. , Bulik C. C. , Kamal M. A. , Reynolds D. K. , Toovey S. , Hammel J. P. , Smith P. F. , Bhavnani S. M. , Van Wart S. A. , Ambrose P. G. , Forrest A.
Published: May 2013

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC50] = 0.18 nM) or B/Yamagata (IC50= 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC0–24), minimum concentration of OC in plasma (Cmin), and maximum concentration of OC in plasma (Cmax). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC0–24evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC0–24threshold (∼14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.
Interaction of Mycobacterium leprae with Human Airway Epithelial Cells: Adherence, Entry, Survival, and Identification of Potential Adhesins by Surface Proteome Analysis
Authors: Silva Carlos A. M. , Danelishvili Lia , McNamara Michael , Berredo-Pinho Márcia , Bildfell Robert , Biet Franck , Rodrigues Luciana S. , Oliveira Albanita V. , Bermudez Luiz E. , Pessolani Maria C. V.
Published: May 2013

This study examined the
in vitro
interaction between
Mycobacterium leprae
, the causative agent of leprosy, and human alveolar and nasal epithelial cells, demonstrating that
M. leprae
can enter both cell types and that both are capable of sustaining bacterial survival. Moreover, delivery of
M. leprae
to the nasal septum of mice resulted in macrophage and epithelial cell infection in the lung tissue, sustaining the idea that the airways constitute an important
M. leprae
entry route into the human body. Since critical aspects in understanding the mechanisms of infection are the identification and characterization of the adhesins involved in pathogen-host cell interaction, the nude mouse-derived
M. leprae
cell surface-exposed proteome was studied to uncover potentially relevant adhesin candidates. A total of 279 cell surface-exposed proteins were identified based on selective biotinylation, streptavidin-affinity purification, and shotgun mass spectrometry; 11 of those proteins have been previously described as potential adhesins.
In vitro
assays with the recombinant forms of the histone-like protein (Hlp) and the heparin-binding hemagglutinin (HBHA), considered to be major mycobacterial adhesins, confirmed their capacity to promote bacterial attachment to epithelial cells. Taking our data together, they suggest that the airway epithelium may act as a reservoir and/or portal of entry for
M. leprae
in humans. Moreover, our report sheds light on the potentially critical adhesins involved in
M. leprae
-epithelial cell interaction that may be useful in designing more effective tools for leprosy control.
Protective Role of Murine β-Defensins 3 and 4 and Cathelin-Related Antimicrobial Peptide in Fusarium solani Keratitis
Authors: Kolar Satya Sree N. , Baidouri Hasna , Hanlon Samuel , McDermott Alison M.
Published: May 2013

Antimicrobial peptides (AMPs), such as β-defensins and cathelicidins, are essential components of innate and adaptive immunity owing to their extensive multifunctional activities. However, their role in fungal infectionin vivoremains elusive. In this study, we investigated the protective effect of murine β-defensin 3 (mBD3), mBD4, and the cathelicidin cathelin-related antimicrobial peptide (CRAMP) in a murine model ofFusarium solanikeratitis. C57BL/6 mice showed significant corneal disease 1 and 3 days after infection, which was accompanied by enhanced expression of β-defensins and CRAMP. Disease severity was significantly improved 7 days after infection, at which time AMP expression was returning to baseline. Mice deficient in mBD3 (genetic knockout), mBD4 (short interfering RNA knockdown), or CRAMP (genetic knockout) exhibited enhanced disease severity and progression, increased neutrophil recruitment, and delayed pathogen elimination compared to controls. Taken together, these data suggest a vital role for AMPs in defense againstF. solanikeratitis, a potentially blinding corneal disease.
A UNIFIED FRAMEWORK FOR BI(TRI)CONNECTIVITY AND CHORDAL AUGMENTATION
Authors: NARAYANASWAMY N. S. , SADAGOPAN N.
Published: May 2013

For a connected non-complete graph, a vertex separator is a subset of vertices whose deletion increases the number of connected components and the vertex connectivity of the graph refers to the size of a minimum vertex separator. A graph with the vertex connectivity k is said to be k-vertex connected. Given a k-vertex connected graph G, vertex connectivity augmentation determines a smallest set of edges whose augmentation to G makes it (k + 1)-vertex connected. In this paper, we report our study on connectivity augmentation in 1-connected graphs, 2-connected graphs, and k-connected chordal graphs. We first represent the graph under consideration using a "tree-like" graph. This tree is unique and explicitly captures the connectivity information of the graph. Using this tree, our proposed data structure maintains the set of equivalence classes based on an equivalence relation on the set of leaves of the tree. This partition determines a set of edges to be augmented to increase the connectivity of the graph by one. Based on our data structure, we present a new combinatorial analysis and an elegant proof of correctness of our linear-time algorithm for an optimum connectivity augmentation. The novelty is in the data structure which is a unified framework for all three augmentations. As far as the run-time analysis is concerned, given the associated tree, our approach yields an augmentation set in linear time.
DECIDABILITY OF UNIFORM RECURRENCE OF MORPHIC SEQUENCES
Authors: DURAND FABIEN
Published: May 2013

We prove that the uniform recurrence of morphic sequences is decidable. For this we show that the number of derived sequences of uniformly recurrent morphic sequences is bounded. As a corollary we obtain that uniformly recurrent morphic sequences are primitive substitutive sequences.
Electrochemical characterization of dilithium phthalocyanine carbonaceous electrodes
Authors: Apetrei Constantin , Medina-Plaza Cristina , de Saja José Antonio , Rodriguez-Mendez Maria Luz
Published: May 2013

Carbonaceous electrodes of dilithium phthalocyanine were prepared using graphite, carbon microspheres and multiwall carbon nanotubes. The electrochemical behavior of the dilithium bisphthalocyanine electrodes was found to be dependent on the nature of the carbonaceous material and on the nature of the electrolytic solution. The electrocatalytic properties of the dilithium phthalocyanine electrodes for oxidation of ascorbic acid were evidenced by the enhancement of the oxidation peak current, (~10 fold compared to the bare carbon electrodes) and the decrease of the oxidation potential at which oxidation of ascorbic acid takes place. The combined use of multiwall carbon nanotubes and dilithium phthalocyanine produces a synergistic effect that improves the electrocatalytic effect towards ascorbic acid.
Identity verification based on handwritten signatures with haptic information using genetic programming
Authors: Alsulaiman Fawaz A. , Sakr Nizar , Valdés Julio J. , El Saddik Abdulmotaleb
Published: May 2013

In this article, haptic-based handwritten signature verification using Genetic Programming (GP) classification is presented. A comparison of GP-based classification with classical classifiers including support vector machine,
k
-nearest neighbors, naïve Bayes, and random forest is conducted. In addition, the use of GP in discovering small knowledge-preserving subsets of features in high-dimensional datasets of haptic-based signatures is investigated and several approaches are explored. Subsets of features extracted from GP-generated models (analytic functions) are also exploited to determine the importance and relevance of different haptic data types (e.g., force, position, torque, and orientation) in user identity verification. The results revealed that GP classifiers compare favorably with the classical methods and use a much fewer number of attributes (with simple function sets).
Better estimation of small sobol' sensitivity indices
Authors: Owen Art B.
Published: May 2013

A new method for estimating Sobol' indices is proposed. The new method makes use of 3 independent input vectors rather than the usual 2. It attains much greater accuracy on problems where the target Sobol' index is small, even outperforming some oracles that adjust using the true but unknown mean of the function. The new estimator attains a better rate of convergence than the old one in a small effects limit. When the target Sobol' index is quite large, the oracles do better than the new method.