bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression microarray as a tool to identify differentially expressed genes in horses suffering from inflammatory airway disease
Authors: Ramery Eve , Fraipont Audrey , Richard Eric A. , Art Tatiana , Pirottin Dimitri , van Delm Wouter , Bureau Fabrice , Lekeux Pierre
Published: December 2014

Background

Inflammatory airway disease (IAD) affects performance and well‐being of horses. Diagnosis is primarily reached by bronchoalveolar lavage (BAL) cytology which is invasive and requires sedation.

Objectives

The purpose of this study was to identify differential gene expression in peripheral blood of horses withIADusing species‐specific expression microarrays.

Methods

Equine gene expression microarrays were used to investigate globalmRNAexpression in circulating leukocytes from healthy, IAD‐affected, and low‐performing Standardbred and endurance horses.

Results

Nine genes in Standardbred and 61 genes in endurance horses were significantly differentially regulated (P < .001). These genes were related to inflammation (eg,ALOX15B,PLA2G12B,and PENK), oxidant/antioxidant balance (eg,DUOXA2andGSTO1‐1), and stress (eg,V1aR, GRLF1,Homer‐2, andMAOB). All these genes were up‐regulated, except down‐regulatedHomer‐2andMAOB. DUOXA2,ALOX15B,PLA2G12B, MAOB, andGRLF1expression was further validated by RT‐qPCR. An increase in glutathione peroxidase (GPx) activity in heparinized whole blood of IAD‐affected Standardbred (P = .0025) and endurance horses (P = .0028) also suggests a deregulation of the oxidant/antioxidant balance. There was good correlation (r = .7354) between BAL neutrophil percentage and whole blood GPx activity in all horses.

Conclusions

This study showed that circulating blood cell gene expression reflects inflammatory responses in tissues. Whether any of the genes have potential for diagnostic applications in the future remains to be investigated. Although not specific forIAD, whole bloodGPx activity appears to be correlated withBALneutrophil percentage. This finding should be further assessed by testing a larger number of horses.
Biochemical variables from Holstein‐Friesian calves older than one week are comparable to those obtained from adult animals of stable metabolic status on the same farm
Authors: Pérez‐Santos María , Castillo Cristina , Hernández Joaquín , Abuelo Ángel
Published: December 2014

Background

Age‐related changes in blood variables have previously been reported for cattle. A few studies have investigated differences in biochemistry analytes over time using repeat measures.

Objectives

The purpose of the study was to investigate the variation in select variables during the first 3 months of life of Holstein‐Friesian calves using repeat sampling.

Methods

Twenty healthy calves were sampled on the day of birth (0) and at 6, 13, 21, 30, 60, and 90 days of life. Analyzed variables included concentration of glucose, total protein, albumin, urea and creatinine, and activity of AST, GGT, and CK. Reference intervals (RI) were obtained from 40 adult cows using specific computer software. The variation in each analyte throughout the study period and differences relative to the RI in adult cattle were assessed.

Results

With the exception of glucose, the studied variables were affected by the calf's age. However, for most of the analytes studied, the values obtained from calves from one week of age onwards remained within the RI determined in adult cattle. During the calves' first week of life, some variables outside the RI of adult cattle were due to the changes associated with birth and colostrum intake.

Conclusions

With the exception of AST and GGT activity, RI for standard biochemistry variables determined for adult cattle are likely to be valid for calves older than one week. However, special consideration is necessary for calves within their first week of life.
A Quantitative Structure Tribo-Ability Relationship Model for Ester Lubricant Base Oils
Authors: Gao Xinlei , Wang Zhan , Dai Kang , Wang Tingting
Published: December 2014

Friction tests with point–point contact were carried out using a microtribometer to investigate the tribological characteristics of steel/steel rubbing pair immersed in 57 kinds of esters as lubricant base oils. A set of 57 esters and their wear data were included in the back-propagation neural network (BPNN)-quantitative structure tribo-ability relationship (QSTR) model with two-dimensional (2D) and three-dimensional (3D) QSTR descriptors. The predictive performance of the BPNN-QSTR model is acceptable. The findings of the BPNN-QSTR model show that the extent of polar groups cannot be too large in the molecule to achieve good antiwear performance; and the polar groups with a high degree of relative concentrated charge are favorable for antiwear. A low degree of molecular hydrophobicity of lubricant base oil is beneficial for antiwear behavior. Large molecular dipole moment is disadvantageous for antiwear properties. It is necessary to maintain one large molecular surface in one plane, to have a long and short chain length to be present within the same molecule, and to keep small difference between the long and short chain length to enhance the antiwear performance. Finally, lubricant base oil candidate molecules will have beneficial antiwear properties that they should contain more N groups with three single bonds and more C groups with one double bond and two single bonds; the presence of O atoms with any bonds or CH groups with three single bonds leads to a decrease in the wear resistance performance.
Experimentally Validated Computational Fluid Dynamics Model for a Data Center With Cold Aisle Containment
Authors: Alkharabsheh Sami A. , Sammakia Bahgat G. , Shrivastava Saurabh K.
Published: December 2014

This paper presents the results of an experimentally validated computational fluid dynamics (CFD) model for a data center with fully implemented fan curves on both the servers and the computer room air conditioner (CRAC). Both open and contained cold aisle systems are considered in this study. This work is divided into sections for the baseline system (prior to installing containment) calibration and the fully contained cold aisle system calibration and leakage characterization. In the open system, the fan curve of the CRAC unit is extracted from the manufacturer data, while the fan curve of the load banks is obtained through experimental measurements. The experimental results are found to be in good agreement with the average model predictions. In the fully contained cold aisle system, a detailed containment CFD model is developed based on experimental measurements. The model is validated by comparing the flow rate through the perforated floor tiles and the rack inlet temperatures with the experimental measurements. The CFD results are found to be in good agreement with the experimental data with an average relative error between the measured and computed flow rate of approximately 6.7%. Temperature measurements are used to calibrate the sources of leakage in the containment and rack mounting rails. The temperature measurements and the CFD results agree well with an average difference of less than 1 °C. This study provides important modeling guidelines for data centers. In order to predict the performance of contained cold aisle systems flow distribution, it is crucial that physics based models of fan curves, server internal resistances, detailed rack models, and other design details are all accurate and experimentally verified.
Test Uncertainty and Failure Mode Discovery
Authors: Foster Chad R.
Published: December 2014

An uncertainty metric is used to prioritize testing for initial product development. Similar metrics are used in signal processing, cryptography, and digital communication. The greatest benefit of this metric is to maximize testing value to discover failures. A major drawback is a reduction in the accuracy of launch reliability estimates. A preferred approach uses two separate testing processes, the first will increase the initial issue discovery using the uncertainty metric while the second increases the accuracy of the reliability estimation. Engine development data is presented to highlight the application of this metric for both engine and vehicle testing.
An Investigation on Sensitivity of Ignition Delay and Activation Energy in Diesel Combustion
Authors: Joshi Umashankar , Zheng Ziliang , Shrestha Amit , Henein Naeim , Sattler Eric
Published: December 2014

The auto-ignition process plays a major role in the combustion, performance, fuel economy and emission in diesel engines. The auto-ignition quality of different fuels has been rated by its cetane number (CN) determined in the CFR engine, according to ASTM D613. More recently, the Ignition Quality Tester (IQT), a constant volume vessel, has been used to determine the derived cetane number (DCN) to avoid the elaborate, time consuming and costly engine tests, according to ASTM D6890. The ignition delay period in these two standard tests and many investigations has been considered to be the time period between start of injection (SOI) and start of combustion (SOC). The ignition delay (ID) values determined in different investigations can vary due to differences in instrumentation and definitions. This paper examines the different definitions and the parameters that effect ID period. In addition the activation energy dependence on the ID definition is investigated. Furthermore, results of an experimental investigation in a single-cylinder research diesel engine will be presented while the charge density is kept constant during the ID period. The global activation energy is determined and its sensitivity to the charge temperature is examined.
Effect of Cetane Improver on Combustion and Emission Characteristics of Coal-Derived Sasol IPK in a Single Cylinder Diesel Engine
Authors: Zheng Ziliang , Joshi Umashankar , Henein Naeim , Sattler Eric
Published: December 2014

Sasol IPK is a coal-derived synthetic fuel under consideration as a blending stock with JP-8 for use in military ground vehicles. Since Sasol IPK is a low ignition quality fuel with Derived Cetane Number (DCN) of 31, there is a need to improve its ignition quality. This paper investigates the effect of adding different amounts of Lubrizol 8090 cetane improver to Sasol IPK on increasing its DCN. The experimental investigation was conducted in a single-cylinder research type diesel engine. The engine is equipped with a common rail injection system and an open Engine Control Unit (ECU). Experiments covered different injection pressures and intake air temperatures. Analysis of test results was made to determine the effect of cetane improver percentage in the coal-derived Sasol IPK blend on autoignition, combustion and emissions of carbon monoxide (CO), total unburned hydrocarbon (HC), oxides of nitrogen (NOx), and particulate matter (PM). In addition, the effect of cetane improver on the apparent activation energy of the global autoignition reactions was determined.
Performance and Emissions of Acetone-Butanol-Ethanol (ABE) and Gasoline Blends in a Port Fuel Injected Spark Ignition Engine
Authors: Nithyanandan Karthik , Lee Chia-fon F. , Wu Han , Zhang Jiaxiang
Published: December 2014

Acetone-Butanol-Ethanol (ABE), an intermediate product in the ABE fermentation process for producing bio-butanol, is considered a promising alternative fuel because it not only preserves the advantages of oxygenated fuels which typically emit fewer pollutants, but also lowers the cost of fuel recovery for each individual component during fermentation. An experiment was conducted using a Ford single-cylinder spark-ignition (SI) research engine to investigate the potential of ABE as an SI engine fuel. Blends of pure gasoline and ABE, ranging from 0% to 80% vol. ABE, were created and the performance and emission characteristics were compared with pure gasoline as the baseline. Measurements of brake torque and exhaust gas temperature along with in-cylinder pressure traces were used to study the performance of the engine and measurements of emissions of unburned hydrocarbons, carbon monoxide, and nitrogen oxides were used to compare the fuels in terms of combustion byproducts. Experiments were performed at a constant engine speed and a comparison was made on the basis of similar power output (Brake Mean Effective Pressure (BMEP)). In-cylinder pressure data showed that the peak pressure of all the blends was slightly lower than that of gasoline, except for ABE80 which showed a slightly higher and advanced peak relative to gasoline. ABE showed an increase in brake specific fuel consumption (BSFC); while exhaust gas temperature and nitrogen oxide measurements show that ABE combusts at a lower peak temperature. The emissions of unburned hydrocarbons were higher compared to those of gasoline but the CO emissions were lower. Of particular interest is the combined effect of the higher laminar flame speed (LFS) and higher latent heat of vaporization of ABE fuels on the combustion process.
Investigation of High Percentage Acetone-Butanol-Ethanol (ABE) Blended With Diesel in a Constant Volume Chamber
Authors: Lin Yilu , Wu Han , Nithyanandan Karthik , Lee Timothy H. , Lee Chia-fon F. , Zhang Chunhua
Published: December 2014

Bio-butanol, a promising alternative transportation fuel, has its industrial-scale production hindered significantly by high cost component purification process from acetone-butanol-ethanol (ABE) broth. The purpose of this study is to investigate the possibility of using ABE-Diesel blends with high ABE percentages as an alternative transportation fuel. An optical-accessible constant volume chamber capable of controlling ambient temperature, pressure and oxygen concentration was used to mimic the environmental conditions inside a real diesel engine cylinder. ABE fuel with typical volumetric ratios of 30% acetone, 60% butanol and 10% ethanol were blended with ultra-low sulfur diesel at 80% vol. and were tested in this study. The ambient temperature was set to be at 1100K and 900K, which represents normal combustion conditions and low temperature combustion conditions respectively. The ambient oxygen concentrations were set to be at 21%, 16% and 11%, representing different EGR ratios. The in-cylinder pressure was recorded by using a pressure transducer and the time-resolved Mie-scattering image and natural flame luminosity was captured using a high-speed camera coupled with a copper vapor laser. The results show that the liquid penetration is reduced by the high percentage of ABE in the blends. At the same time, the soot formation is reduced significantly by increasing oxygen content in the ABE fuel. Even more interesting, a soot-free combustion was achieved by combining the low temperature combustion with the higher percentage ABE case. In terms of soot emission, high ABE ratio blends are a very promising alternative fuel to be directly used in diesel engines especially under low-temperature combustion conditions.
Computational Investigation of Diesel Combustion and Soot Formation With a Phenomenological Soot Model Under Different Temperatures in a Constant Volume Chamber
Authors: Zhao Zhichao , Lee Chia-Fon , Chi Yawei , Liu Jingping
Published: December 2014

The previous nine-step phenomenological soot model was revised by including the oxidation effect on soot number density. Using KIVA-3V Release 2 code coupled with this revised phenomenological soot model, multi-dimensional computational fluid dynamics (CFD) simulations of diesel spray combustion in a constant volume chamber was conducted to investigate the combustion physics and soot emission characteristics. Meanwhile, experiments were conducted in an optical constant volume combustion chamber under different ambient temperatures (800, 900, 1000 K), from which the combustion characteristics and soot distributions were obtained for validation. The results indicate that ignition retards with the decrease of ambient temperature, which results in more air-fuel mixing controlled diffusion combustion at high ambient temperature, and more premixed combustion at low ambient temperature. The corresponding soot formation and distribution shows that the soot emission is strongly related to the local equivalence ratio, which leads to lower soot emission in the lower initial temperature case with more homogeneous mixture. Compared to previous nine-step model, the revised model predicted lower soot number and bigger soot particles size.
Particulate Emissions From Karanja Biodiesel Fuelled Turbocharged CRDI SUV Engine
Authors: Gupta Jai Gopal , Agarwal Avinash Kumar , Aggarwal Suresh K.
Published: December 2014

The use of biodiesel substantially reduces particulate matter (PM), hydrocarbon (HC) and carbon monoxide (CO) emissions, slightly reduces power output; increases fuel consumption and marginally increases oxides of nitrogen (NOx) emission in an unmodified common rail direct injection (CRDI) diesel engine. Lower blends of biodiesel demonstrated lower emissions, while easing pressure on scarce petroleum resources, without significantly sacrificing engine power output and fuel economy.

However due to adverse health effects of smaller size particulate matter (PM) emitted by internal combustion (IC) engines, most recent emission legislations restrict the PM mass emissions in addition to total particle numbers emitted. It is an overwhelming argument that usage of biodiesel leads to reduction in PM mass emissions. In this paper, experimental results of PM emissions using Karanja biodiesel blends (KB20 and KB40) in a modern CRDI transportation engine (maximum fuel injection pressure of 1600 bar) have been reported. This study also explores comparative effect of varying engine speed and load on PM emissions for biodiesel blends vis-à-vis baseline mineral diesel. Particulate size-number distribution, particle size-surface area distribution and total particulate number concentrations were experimentally determined under varying engine operating conditions and compared with baseline mineral diesel. KB20 showed highest particulate number concentration upto 80% rated engine loads, however at rated load, KB40 emitted highest number of particulates.
Multi-Dimensional Engine Modeling Study of EGR, Fuel Pressure, Post-Injection and Compression Ratio for a Light Duty Diesel Engine
Authors: Almeida Fabio L. , Zoldak Philip , Wang Yan , Sobiesiak Andrzej , Lacava Pedro T.
Published: December 2014

For copious levels of exhaust gas recirculation (EGR) (>30 %), oxides of nitrogen (NOx) emissions can be reduced from Euro V to Euro VI regulated levels at the expense of fuel economy and soot emissions. The Lifted-Flame Concept (LFC) has been demonstrated by several researchers to be successful in reducing NOx, while minimizing soot emissions and impact to fuel economy. By simultaneously applying increased EGR and fuel pressure the LFC extends the lift-off length of a diffusion flame and enhances fuel-air entrainment leading to improved fuel and oxygen utilization. When combined with advanced turbocharging and EGR systems the LFC applied to a modern light duty (LD) diesel engine can result in improved fuel economy and lower soot emissions and shows good potential for meeting low soot engine-out targets.

In the proposed paper a computational study was conducted using a multi-dimensional engine model. A modified 3D CFD KIVA code with detailed chemistry solver was used to model the diesel fuel spray, droplet breakup, vaporization, mixing, auto-ignition and subsequent heat release and emissions. The model uses inputs from 1D Amesim electro-hydraulic solver to generate the rate of injection (ROI) profile to raise pressure of 1800 bar to 2500 bar as well as to include a simulated post-injection. A 1D model using GT-Power was developed and utilized to provide air system boundary conditions for the 3D CFD model. Post-processing optimization was conducted using Matlab to identify minimum fuel economy and soot emissions for the study of several parameters.

The objective of the study was to demonstrate Euro VI emissions levels on a 3.2 L LD diesel engine without NOx aftertreatment and minimal impact to fuel economy using the lifted flame concept. The engine-out NOx emission level was targeted at 0.4 g/kWh and the soot levels were targeted at 0.2 g/kWh assuming diesel particulate filter would be used for after-treatment. The results of the computational study successfully demonstrate the potential of the lifted flame concept to meet Euro VI without the use of NOx aftertreatment technology.
Three Dimensional Piston Ring-Cylinder Bore Contact Modeling
Authors: Cheng Chao , Kharazmi Ali , Schock Harold , Wineland Richard , Brombolich Larry
Published: December 2014

Increasing durability, preventing knocking combustion, improving fuel efficiency and reducing pollutant emission characterize the needs for modern internal combustion engine design. These factors are highly influenced by the power cylinder system design. In particular, the piston ring to cylinder bore contact force distribution around the circumference of the piston rings must be optimized under all running conditions. To accomplish this, the ring manufacturers make the ring curvature non-constant along the circumference. Most existing analytical tools are not able to simulate the variation along the ring circumference. In order to improve the understanding of this contact distribution and provide a high-fidelity ring design tool, a three-dimensional finite element piston ring model was developed to accomplish this variation.

The modeling procedure and results are presented in this work. Experiments using a commercially available ring with negative ovality were conducted to validate the model. The ring free shape profile and the ring cross-section geometries were used as inputs to the model. Typical piston ring groove and cylinder wall temperatures were also model inputs to characterize thermal influences on the ring/bore interface forces. The ring/bore conformability was analyzed as a function of the ring radial displacements, cylinder bore constraint forces and thermal load changes to the ring. The model output showed radially separation gaps between the ring front face and the bore. This analysis provides an insight to evaluate the piston ring design. Together with an optimizer, the model can be used as a ring design tool to predict the ring free shape with a specified constraint force distribution pattern. Examples are given to demonstrate the capabilities of this numerical analytical tool. In addition, the 3D ring model can be used to improve the accuracy of existing lubrication, friction and wear analysis tools and therefore improve the entire internal combustion engine power cylinder system design.
Improving the Methodology for 3D Fluid-Thermal Analyses of Large-Bore Engine Cylinder Heads
Authors: Toninel Stefano , Calvert Ian , Phukan Atanu
Published: December 2014

Efficient use of three-dimensional CFD (Computational Fluid Dynamics) and CHT (Conjugate Heat Transfer) analyses is becoming increasingly critical, in order to compress the development process required for either on-going development, or the design of new large-bore engines for power generation applications.

Engine performance and reliability targets force engine developers to progressively refine and screen design iterations, from the conceptual stage up to the design-freeze, by means of CAE (Computer Aided Engineering) methods, which have to be accurate, robust and cost-effective, in order for them to effectively contribute to the product design. An efficient deployment of these tools usually requires extensive efforts to consolidate the analysis procedures and allow loosening of particular accuracy requirements, in favor of a shorter overall turn-around time. Finally, validation of the models against measurements enables the definition of best-practice guidelines for future programs.

The aim of this paper is to summarize the three-dimensional thermal-fluid simulation methodologies developed in GE’s Distributed Power business, for supporting the design of reciprocating engine cylinder-heads. The work reviews the two main types of analyses which are carried out during the defined development process.

Isothermal simulations are performed in order to estimate the flow-field velocities in the cylinder-head water jacket, without modeling the wall heat-transfer. If backed up by consolidated guidelines, they can be highly efficient for down-selecting design variants, simply by looking at bulk results, with minimum requirements in terms of turbulence modeling.

On the other end of the complexity spectrum, CHT simulations are used to model the thermal behavior of the cylinder-head assembly, by coupling and solving at run-time the RANS (Reynolds Averaged Navier-Stokes) equation set in the fluid domain and Fourier’s equation for the heat-transfer in the solid domain.

The challenging timeline associated to a new engine development program induced the authors to carefully review and adapt, on a case-by-case basis, general CFD best-practice guidelines for near-wall turbulence modeling, well-established in the CFD community. This mitigation was driven by the high complexity of a typical water-jacket geometry and by a number of uncertainties in the real-world application, related to manufacturing tolerances, material properties and operating conditions, which should be considered in order to find the optimal trade-off between absolute accuracy and computational costs.

Verification and validation CHT test-cases were carried out in order to support this approach. In particular, a comparison between the predicted CHT temperature solution and thermocouple measurements, performed on a GE Jenbacher engine, is described, in order to check the effectiveness of the proposed methodology and identifying opportunities for future developments.
Individual chain dynamics of a polyethylene melt undergoing steady shear flow
Authors: Nafar Sefiddashti M. H. , Edwards B. J. , Khomami B.
Published: December 2014

Individual molecule dynamics have been shown to influence significantly the bulk rheological and microstructural properties of short-chain, unentangled, linear polyethylene liquids undergoing high strain-rate flows. The objective of this work was to extend this analysis to a linear polyethylene composed of macromolecules of a much greater length and entanglement density; i.e., a liquid consisting of C400H802 molecules, with approximately ten kinks per chain at equilibrium, as calculated by the Z1 code of Kröger [Comput. Phys. Commun. 168, 209–232 (2005)]. To achieve this, we performed nonequilibrium molecular dynamics (NEMD) simulations of a model system using the well-established potential model of Siepmann et al. [Nature 365, 330–332 (1993)] for a wide range of Weissenberg numbers (Wi) under steady shear flow. A recent study by Baig et al. [Macromolecules 43, 6886–6902 (2010)] examined this same system using NEMD simulations, but focused on the bulk rheological and microstructural properties as calculated from ensemble averages of the chains comprising the macromolecular liquids. In so doing, some key features of the system dynamics were not fully elucidated, which this article aims to highlight. Specifically, it was found that this polyethylene liquid displays multiple timescales associated with not only the decorrelation of the end-to-end vector (commonly related to the Rouse time or disengagement time, depending on the entanglement density of the liquid), but also ones associated with the retraction and rotation cycles of the individual molecules. Furthermore, when accounting for these individual chain dynamics, the “longest” relaxation time of the system was higher by a factor of 1.7, independent of shear rate, when calculated self-consistently due to the coupling of relaxation modes. Brownian dynamics (BD) simulations were also performed on an analogous free-draining bead-rod chain model to compare the rotation and retraction dynamics of a single chain in dilute solution with individual molecular motions in the melt. These BD simulations revealed that the dynamics of the free-draining chain are qualitatively and quantitatively similar to those of the individual chains comprising the polyethylene melt at strain rates in excess of Wi ≈ 50, implying a possible breakdown of reptation theory in the high shear limit. An examination of the bulk-average properties revealed the effects of the chain rotation and retraction cycles upon commonly modeled microstructural properties, such as the distribution function of the chain end-to-end vector and the entanglement number density.
The PPFIA1-PP2A protein complex promotes trafficking of Kif7 to the ciliary tip and Hedgehog signaling
Authors: Liu Yulu C. , Couzens Amber L. , Deshwar Ashish R. , B. McBroom-Cerajewski Linda D. , Zhang Xiaoyun , Puviindran Vijitha , Scott Ian C. , Gingras Anne-Claude , Hui Chi-chung , Angers Stephane
Published: December 2014

Dephosphorylation of the kinesin protein Kif7 stimulates Hedgehog signaling.
Histone deacetylases in memory and cognition
Authors: Penney Jay , Tsai Li-Huei
Published: December 2014

Histone deacetylase inhibition shows promise to treat learning and memory impairments associated with aging and neurological disease.
Neuregulin 1–activated ERBB4 as a “dedicated” receptor for the Hippo-YAP pathway
Authors: Sudol Marius
Published: December 2014

An intracellular proteolytic fragment of a growth factor receptor activates the transcriptional regulator YAP.
Pharmacokinetic-Pharmacodynamic Analysis of Spiroindolone Analogs and KAE609 in a Murine Malaria Model
Authors: Lakshminarayana Suresh B. , Freymond Céline , Fischli Christoph , Yu Jing , Weber Sebastian , Goh Anne , Yeung Bryan K. S. , Ho Paul C. , Dartois Véronique , Diagana Thierry T. , Rottmann Matthias , Blasco Francesca
Published: December 2014

Limited information is available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters driving the efficacy of antimalarial drugs. Our objective in this study was to determine dose-response relationships of a panel of related spiroindolone analogs and identify the PK-PD index that correlates best with the efficacy of KAE609, a selected class representative. The dose-response efficacy studies were conducted in the
Plasmodium berghei
murine malaria model, and the relationship between dose and efficacy (i.e., reduction in parasitemia) was examined. All spiroindolone analogs studied displayed a maximum reduction in parasitemia, with 90% effective dose (ED
90
) values ranging between 6 and 38 mg/kg of body weight. Further, dose fractionation studies were conducted for KAE609, and the relationship between PK-PD indices and efficacy was analyzed. The PK-PD indices were calculated using the
in vitro
potency against
P. berghei
(2× the 99% inhibitory concentration [IC
99
]) as a threshold (TRE). The percentage of the time in which KAE609 plasma concentrations remained at >2× the IC
99
within 48 h (%
T
>TRE
) and the area under the concentration-time curve from 0 to 48 h (AUC
0–48
)/TRE ratio correlated well with parasite reduction (
R
2
= 0.97 and 0.95, respectively) but less so for the maximum concentration of drug in serum (
C
max
)/TRE ratio (
R
2
= 0.88). The present results suggest that for KAE609 and, supposedly, for its analogs, the dosing regimens covering a
T
>TRE
of 100%, AUC
0–48
/TRE ratio of 587, and a
C
max
/TRE ratio of 30 are likely to result in the maximum reduction in parasitemia in the
P. berghei
malaria mouse model. This information could be used to prioritize analogs within the same class of compounds and contribute to the design of efficacy studies, thereby facilitating early drug discovery and lead optimization programs.
Bacteriophage-Mediated Control of a Two-Species Biofilm Formed by Microorganisms Causing Catheter-Associated Urinary Tract Infections in anIn VitroUrinary Catheter Model
Authors: Lehman Susan M. , Donlan Rodney M.
Published: December 2014

Microorganisms from a patient or their environment may colonize indwelling urinary catheters, forming biofilm communities on catheter surfaces and increasing patient morbidity and mortality. This study investigated the effect of pretreating hydrogel-coated silicone catheters with mixtures ofPseudomonas aeruginosaandProteus mirabilisbacteriophages on the development of single- and two-species biofilms in a multiday continuous-flowin vitromodel using artificial urine. Novel phages were purified from sewage, characterized, and screened for their abilities to reduce biofilm development by clinical isolates of their respective hosts. Our screening data showed that artificial urine medium (AUM) is a valid substitute for human urine for the purpose of evaluating uropathogen biofilm control by these bacteriophages. Defined phage cocktails targetingP. aeruginosaandP. mirabiliswere designed based on the biofilm inhibition screens. Hydrogel-coated catheters were pretreated with one or both cocktails and challenged with approximately 1 × 103CFU/ml of the corresponding pathogen(s). The biofilm growth on the catheter surfaces in AUM was monitored over 72 to 96 h. Phage pretreatment reducedP. aeruginosabiofilm counts by 4 log10CFU/cm2(P≤ 0.01) andP. mirabilisbiofilm counts by >2 log10CFU/cm2(P≤ 0.01) over 48 h. The presence ofP. mirabiliswas always associated with an increase in lumen pH from 7.5 to 9.5 and with eventual blockage of the reactor lines. The results of this study suggest that pretreatment of a hydrogel urinary catheter with a phage cocktail can significantly reduce mixed-species biofilm formation by clinically relevant bacteria.
Mycobacterium abscessus Phospholipase C Expression Is Induced during Coculture within Amoebae and Enhances M. abscessus Virulence in Mice
Authors: Bakala N'Goma Jean Claude , Le Moigne Vincent , Soismier Nathalie , Laencina Laura , Le Chevalier Fabien , Roux Anne-Laure , Poncin Isabelle , Serveau-Avesque Carole , Rottman Martin , Gaillard Jean-Louis , Etienne Gilles , Brosch Roland , Herrmann Jean-Louis , Canaan Stéphane , Girard-Misguich Fabienne
Published: December 2014

Mycobacterium abscessus
is a pathogenic, rapidly growing mycobacterium involved in pulmonary and cutaneo-mucous infections worldwide, to which cystic fibrosis patients are exquisitely susceptible. The analysis of the genome sequence of
M. abscessus
showed that this bacterium is endowed with the metabolic pathways typically found in environmental microorganisms that come into contact with soil, plants, and aquatic environments, where free-living amoebae are frequently present.
M. abscessus
also contains several genes that are characteristically found only in pathogenic bacteria. One of them is
MAB_0555
, encoding a putative phospholipase C (PLC) that is absent from most other rapidly growing mycobacteria, including
Mycobacterium chelonae
and
Mycobacterium smegmatis
. Here, we report that purified recombinant
M. abscessus
PLC is highly cytotoxic to mouse macrophages, presumably due to hydrolysis of membrane phospholipids. We further showed by constructing and using an
M. abscessus
PLC knockout mutant that loss of PLC activity is deleterious to
M. abscessus
intracellular survival in amoebae. The importance of PLC is further supported by the fact that
M. abscessus
PLC was found to be expressed only in amoebae. Aerosol challenge of mice with
M. abscessus
strains that were precultured in amoebae enhanced
M. abscessus
lung infectivity relative to
M. abscessus
grown in broth culture. Our study underlines the importance of PLC for the virulence of
M. abscessus
. Despite the difficulties of isolating
M. abscessus
from environmental sources, our findings suggest that
M. abscessus
has evolved in close contact with environmental protozoa, which supports the argument that amoebae may contribute to the virulence of opportunistic mycobacteria.
Genetic Analysis Reveals the Identity of the Photoreceptor for Phototaxis in Hormogonium Filaments of Nostoc punctiforme
Authors: Campbell Elsie L. , Hagen Kari D. , Chen Rui , Risser Douglas D. , Ferreira Daniela P. , Meeks John C.
Published: December 2014

In cyanobacterial
Nostoc
species, substratum-dependent gliding motility is confined to specialized nongrowing filaments called hormogonia, which differentiate from vegetative filaments as part of a conditional life cycle and function as dispersal units. Here we confirm that
Nostoc punctiforme
hormogonia are positively phototactic to white light over a wide range of intensities.
N. punctiforme
contains two gene clusters (clusters 2 and 2i), each of which encodes modular cyanobacteriochrome–methyl-accepting chemotaxis proteins (MCPs) and other proteins that putatively constitute a basic chemotaxis-like signal transduction complex. Transcriptional analysis established that all genes in clusters 2 and 2i, plus two additional clusters (clusters 1 and 3) with genes encoding MCPs lacking cyanobacteriochrome sensory domains, are upregulated during the differentiation of hormogonia. Mutational analysis determined that only genes in cluster 2i are essential for positive phototaxis in
N. punctiforme
hormogonia; here these genes are designated
ptx
(for
p
hoto
t
a
x
is) genes. The cluster is unusual in containing complete or partial duplicates of genes encoding proteins homologous to the well-described chemotaxis elements CheY, CheW, MCP, and CheA. The cyanobacteriochrome-MCP gene (
ptxD
) lacks transmembrane domains and has 7 potential binding sites for bilins. The transcriptional start site of the
ptx
genes does not resemble a sigma 70 consensus recognition sequence; moreover, it is upstream of two genes encoding gas vesicle proteins (
gvpA
and
gvpC
), which also are expressed only in the hormogonium filaments of
N. punctiforme
.
Mep72, a Metzincin Protease That Is Preferentially Secreted by Biofilms of Pseudomonas aeruginosa
Authors: Passmore Ian J. , Nishikawa Kahoko , Lilley Kathryn S. , Bowden Steven D. , Chung Jade C. S. , Welch Martin
Published: December 2014

In this work, we compared the profile of proteins secreted by planktonic and biofilm cultures of
Pseudomonas aeruginosa
using two-dimensional difference gel electrophoresis (2D-DiGE). This revealed that a novel metzincin protease, Mep72, was secreted during biofilm growth. Subsequent Western blotting and reverse transcription-PCR (RT-PCR) analyses demonstrated that Mep72 was expressed only during biofilm growth. Mep72 has a tridomain structure comprised of a metzincin protease-like domain and two tandem carbohydrate-binding domains. Unlike the only other metzincin (alkaline protease; AprA) in
P. aeruginosa
, Mep72 is secreted through the type II pathway and undergoes processing during export. During this processing, the metzincin domain is liberated from the carbohydrate-binding domains. This processing may be self-catalyzed, since purified Mep72 autodegraded
in vitro
. This autodegradation was retarded in the presence of alginate (an extracellular matrix component of many
P. aeruginosa
biofilms). The expression of full-length
mep72
in
Escherichia coli
was toxic. However, this toxicity could be alleviated by coexpression of
mep72
with the adjacent gene,
bamI
. Mep72 and BamI were found to form a protein-protein complex
in vitro
. 2D-DiGE revealed that the electrophoretic mobility of several discrete protein spots was altered in the biofilm secretome of an
mep72
mutant, including type III secretion proteins (PopD, PcrV, and ExoS) and a flagellum-associated protein (FliD). Mep72 was found to bind directly to ExoS and PcrV and to affect the processing of these proteins in the biofilm secretome. We conclude that Mep72 is a secreted biofilm-specific regulator that affects the processing of a very specific subset of virulence factors.
Bacteria in Solitary Confinement
Authors: Mullineaux Conrad W.
Published: December 2014

Even in clonal bacterial cultures, individual bacteria can show substantial stochastic variation, leading to pitfalls in the interpretation of data derived from millions of cells in a culture. In this issue of the
Journal of Bacteriology
, as part of their study on osmoadaptation in a cyanobacterium, Nanatani et al. describe employing an ingenious microfluidic device that gently cages individual cells (J Bacteriol 197:676–687, 2015,
http://dx.doi.org/10.1128/JB.02276-14
). The device is a welcome addition to the toolkit available to probe the responses of individual cells to environmental cues.
Prevalence of risk factors for coronary artery disease in an urban Indian population
Authors: Sekhri T , Kanwar R S , Wilfred R , Chugh P , Chhillar M , Aggarwal R , Sharma Y K , Sethi J , Sundriyal J , Bhadra K , Singh S , Rautela N , Chand Tek , Singh M , Singh S K
Published: December 2014

Objective

The objective of this study was to assess the prevalence of risk factors for coronary artery disease (CAD) in government employees across India.

Methods

The study population consisted of government employees in different parts of India ({n=10 642 men and n=1966 women; age 20–60 years}) and comprised various ethnic groups living in different environmental conditions. Recruitment was carried out in 20 cities across 14 states, and in one union territory. All selected individuals were subjected to a detailed questionnaire, medical examinations and anthropometric measurements. Blood samples were collected for blood glucose and serum lipid profile estimation, and resting ECG was recorded. Results were analysed using appropriate statistical tools.

Results

The study revealed that 4.6% of the study population had a family history of premature CAD. The overall prevalence of diabetes was 16% (5.6% diagnosed during the study and the remaining 10.4% already on medication). Hypertension was present in 21% of subjects. The prevalence of dyslipidemia was significantly high, with 45.6% of study subjects having a high total cholesterol/high density lipoprotein ratio. Overall, 78.6% subjects had two or more risk factors for CAD.

Conclusions

The present study demonstrates a high prevalence of CAD risk factors in the Indian urban population. Therefore, there is an immediate need to initiate measures to raise awareness of these risk factors so that individuals at high risk for future CAD can be managed.
Exposure to genocide and risk of suicide in Rwanda: a population-based case–control study
Authors: Rubanzana Wilson , Hedt-Gauthier Bethany L , Ntaganira Joseph , Freeman Michael D
Published: December 2014

Background

In Rwanda, an estimated one million people were killed during the 1994 genocide, leaving the country shattered and social fabric destroyed. Large-scale traumatic events such as wars and genocides have been linked to endemic post-traumatic stress disorder, depression and suicidality. The study objective was to investigate whether the 1994 genocide exposure is associated with suicide in Rwanda.

Methods

We conducted a population-based case–control study. Suicide victims were matched to three living controls for sex, age and residential location. Exposure was defined as being a genocide survivor, having suffered physical/sexual abuse in the genocide, losing a first-degree relative in the genocide, having been convicted for genocide crimes or having a first-degree relative convicted for genocide. From May 2011 to May 2013, 162 cases and 486 controls were enrolled countrywide. Information was collected from the police, local village administrators and family members.

Results

After adjusting for potential confounders, having been convicted for genocide crimes was a significant predictor for suicide (OR=17.3, 95% CI 3.4 to 88.1). Being a survivor, having been physically or sexually abused during the genocide, and having lost a first-degree family member to genocide were not significantly associated with suicide.

Conclusions

These findings demonstrate that individuals convicted for genocide crimes are experiencing continued psychological disturbances that affect their social reintegration into the community even 20 years after the event. Given the large number of genocide perpetrators reintegrated after criminal courts and Gacaca traditional reconciling trials, suicide could become a serious public health burden if preventive remedial action is not identified.
Characterisation of the aerobic bacterial flora of boid snakes: application of MALDI‐TOF mass spectrometry
Authors: Plenz Bastian , Schmidt Volker , Grosse‐Herrenthey Anke , Krüger Monika , Pees Michael
Published: December 2014

The aim of this study was to identify aerobic bacterial isolates from the respiratory tract of boids with matrix‐assisted laser desorption ionisation‐time‐of‐flight mass spectrometry (MALDI‐TOF MS). From 47 boid snakes, swabs from the oral cavity, tracheal wash samples and, in cases in which postmortem examination was performed, pulmonary tissue samples were taken. Each snake was classified as having inflammation of the respiratory tract and/or oral cavity, or without evidence of inflammation based on combination of clinical, cytological and histopathological findings. Samples collected from the respiratory tract and oral cavity were inoculated onto routine media and bacteria were cultured aerobically. All morphologically distinct individual colonies obtained were analysed using MALDI‐TOF MS. Unidentified isolates detected in more than three snakes were selected for further 16S rDNA PCR and sequencing. Among all examined isolates (n=243), 49 per cent (n=119) could be sufficiently speciated using MALDI‐TOF MS. Molecular biology revealed several bacterial species that have not been previously described in reptiles. With an average of 6.3 different isolates from the respiratory tract and/or oral cavity, boids with inflammatory disease harboured significantly more bacterial species than boids without inflammatory disease (average 2.8 isolates).
Revisiting the usefulness of thromboxane-A2modulation in the treatment of bronchoconstriction in asthma
Authors: Hernandez Jeremy Mark , Janssen Luke Jeffrey
Published: December 2014

Airway smooth muscle (ASM) is the effector cell in the bronchoconstrictory pathway. It is believed that the bronchoconstriction present in asthma is associated with changes in the airway milieu that affect ASM excitation–contraction coupling and Ca2+-handling. Asthmatics also react differently to ventilatory mechanical strain. Deep inspiration (DI), which produces bronchodilation in healthy individuals, is less effective in asthmatics, and even enhances bronchoconstriction in moderate to severely affected patients. Our laboratory has previously studied the mechanotransductory pathway of airway stretch-activated contractions (Rstretch) leading to DI-induced bronchoconstriction. We demonstrated the ability of agonists acting through thromboxane A2(TxA2) receptors to amplify airway Rstretchresponses. Despite the involvement of excitatory prostanoids in bronchoconstriction, clinical trials on treatments targeting TxA2-synthase inhibition and TP-receptor antagonism have produced mixed results. Studies in Western populations produced mostly negative results, whereas studies performed in Asian populations showed mostly positive outcomes. In this review, we discuss the role of TxA2-synthase inhibition and TP-receptor antagonism in the treatment of asthmatics. We present information regarding variations in study designs and the possible role of TP-receptor gene polymorphisms in previous study outcome discrepancies. Perhaps future studies should focus on asthmatic patients with DI-induced bronchoconstriction in particular, planting the seed for the individualized treatments for asthmatics.
Tractability of quantified temporal constraints to the max
Authors: Bodirsky Manuel , Chen Hubie , Wrona Michał
Published: December 2014

A temporal constraint language is a set of relations that are first-order definable over (ℚ;<). We show that several temporal constraint languages whose constraint satisfaction problem is maximally tractable are also maximally tractable for the more expressive quantified constraint satisfaction problem. These constraint languages are defined in terms of preservation under certain binary polymorphisms. We also present syntactic characterizations of the relations in these languages.