bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Distributions of Wave Heights From Nonlinear Schröedinger Equation Simulations and Laboratory Experiments
Authors: Zhang Huidong , Cherneva Zhivelina , Guedes Soares C. , Onorato Miguel
Published: November 2013

Numerical simulations of the nonlinear Schrödinger (NLS) equation are performed by using random initial wave conditions characterized by the JONSWAP spectrum and compared with four different sea states generated in the deep water wave basin of Marintek. The comparisons show that the numerical simulations have a high degree of agreement with the laboratory experiments although a little overestimation can be observed, especially in the severe sea state. Thus the simulations still catch the main characteristics of the extreme waves and provide an important physical insight into their generation. The coefficient of kurtosis λ40 presents a similar spatial evolution trend with the abnormal wave density and the nonlinear Gram-Charlier (GC) model is used to predict the wave height distribution. It is demonstrated again that the theoretical approximation based on the GC expansion can describe the larger wave heights reasonably well in most cases. However, if the sea state is severe, wave breaking can significantly decrease the tail of wave height distribution in reality and the discrepancy occurs comparing with the numerical simulation. Moreover, the number of waves also plays an important role on the prediction of extreme wave height.
Experimental and Numerical Extreme Motions and Vertical Bending Moments Induced by Abnormal Waves on a Bulk Carrier
Authors: Vasquez Guillermo , Fonseca Nuno , Guedes Soares Carlos
Published: November 2013

The present investigation focuses on the motions and global structural loads induced by abnormal waves on a bulk carrier. A nonlinear time domain method based on strip theory is used to predict the ship responses. The results are compared with experimental data obtained at the model scale. The time domain hydrodynamic forces are calculated by convolution of linear memory functions, while nonlinear contributions arise from Froude-Krylov forces, hydrostatic forces and shipping of green water. The time domain simulations are compared directly with experimental records from bulk carrier model tests with in head waves for two Froude numbers. Extreme wave conditions (such as the New Year Wave) previously measured at sea during real storms were replicated both at the seakeeping tank and by the numerical code. The comparison analyses show a good agreement between numerical and experimental with good accuracy.
High spatial resolution brain functional MRI using submillimeter balanced steady‐state free precession acquisitiona)
Authors: Wu Pei‐Hsin , Tsai Ping‐Huei , Wu Ming‐Long , Chuang Tzu‐Chao , Shih Yi‐Yu , Chung Hsiao‐Wen , Huang Teng‐Yi
Published: November 2013

Purpose:

One of the technical advantages of functional magnetic resonance imaging (fMRI) is its precise localization of changes from neuronal activities. While current practice of fMRI acquisition at voxel size around 3 × 3 × 3 mm3 achieves satisfactory results in studies of basic brain functions, higher spatial resolution is required in order to resolve finer cortical structures. This study investigated spatial resolution effects on brain fMRI experiments using balanced steady‐state free precession (bSSFP) imaging with 0.37 mm3 voxel volume at 3.0 T.

Methods:

In fMRI experiments, full and unilateral visual field 5 Hz flashing checkerboard stimulations were given to healthy subjects. The bSSFP imaging experiments were performed at three different frequency offsets to widen the coverage, with functional activations in the primary visual cortex analyzed using the general linear model. Variations of the spatial resolution were achieved by removing outerk‐space data components.

Results:

Results show that a reduction in voxel volume from 3.44 × 3.44 × 2 mm3 to 0.43 × 0.43 × 2 mm3 has resulted in an increase of the functional activation signals from (7.7 ± 1.7)% to (20.9 ± 2.0)% at 3.0 T, despite of the threefold SNR decreases in the original images, leading to nearly invariant functional contrast‐to‐noise ratios (fCNR) even at high spatial resolution. Activation signals aligning nicely with gray matter sulci at high spatial resolution would, on the other hand, have possibly been mistaken as noise at low spatial resolution.

Conclusions:

It is concluded that the bSSFP sequence is a plausible technique for fMRI investigations at submillimeter voxel widths without compromising fCNR. The reduction of partial volume averaging with nonactivated brain tissues to retain fCNR is uniquely suitable for high spatial resolution applications such as the resolving of columnar organization in the brain.
A comprehensive investigation of the accuracy and reproducibility of a multitarget single isocenter VMAT radiosurgery technique
Authors: Thomas Andrew , Niebanck Michael , Juang Titania , Wang Zhiheng , Oldham Mark
Published: November 2013

Purpose:

Recent trends in stereotactic radiosurgery use multifocal volumetric modulated arc therapy (VMAT) plans to simultaneously treat several distinct targets. Conventional verification often involves low resolution measurements in a single plane, a cylinder, or intersecting planes of diodes or ion chambers. This work presents an investigation into the consistency and reproducibility of this new treatment technique using a comprehensive commissioned high‐resolution 3D dosimetry system (PRESAGE®/Optical‐CT).

Methods:

A complex VMAT plan consisting of a single isocenter but five separate targets was created in Eclipse for a head phantom containing a cylindrical PRESAGE® dosimetry insert of 11 cm diameter and height. The plan contained five VMAT arcs delivering target doses from 12 to 20 Gy. The treatment was delivered to four dosimeters positioned in the head phantom and repeated four times, yielding four separate 3D dosimetry verifications. Each delivery was completely independent and was given after image guided radiation therapy (IGRT) positioning using Brainlab ExacTrac and cone beam computed tomography. A final delivery was given to a modified insert containing a pin‐point ion chamber enabling calibration of PRESAGE® 3D data to dose. Dosimetric data were read out in an optical‐CT scanner. Consistency and reproducibility of the treatment technique (including IGRT setup) was investigated by comparing the dose distributions in the four inserts, and with the predicted treatment planning system distribution.

Results:

Dose distributions from the four dosimeters were registered and analyzed to determine the mean and standard deviation at all points throughout the dosimeters. A dose standard deviation of <3% was found from dosimeter to dosimeter. Global 3D gamma maps show that the predicted and measured dose matched well [3D gamma passing rate was 98.0% (3%, 2 mm)].

Conclusions:

The deliveries of the irradiation were found to be consistent and matched the treatment plan, demonstrating high accuracy and reproducibility of both the treatment machine and the IGRT procedure. The complexity of the treatment (multiple arcs) and dosimetry (multiple strong gradients) pose a substantial challenge for comprehensive verification. 3D dosimetry can be uniquely effective in this scenario.
Simultaneous reduction of radiation dose and scatter for CBCT by using collimators
Authors: Li Tianfang , Li Xiang , Yang Yong , Zhang Yongqian , Heron Dwight E. , Huq M. Saiful
Published: November 2013

Purpose:

On‐board cone‐beam CT (CBCT) imaging has been widely available in radiotherapy clinic for target localization. However, the extra radiation dose from CBCT is always a concern for its frequent use. Additionally, the relatively large scatter in CBCT often degrades the image quality. By using collimators, some of the X‐rays can be stopped from reaching the patient and the detectors, hence both the scatter and the patient doses are simultaneously reduced. The authors show in this work that the collimated CBCT data can be reconstructed without any noticeable artifacts for certain collimator blocking ratios and blocking patterns, and the focus of this work is to study the relationship between the image quality and these two collimator factors.

Methods:

A CBCT system with collimators was simulated following the typical geometry used in clinic. Different collimator designs were tested by varying the size and the number of the collimator slits, and at the same time, the ratio of transmitted beams to total beams was varied from 100% to 10%, resulting in hundreds of different simulation scenarios. Lung and pelvis phantoms created from patients CT images were used in the simulations, and an iterative reconstruction algorithm using the compressed sensing technique was adopted. The image quality was examined by root mean square errors (RMSEs) and compared with the conventional CBCT images.

Results:

The CBCT image quality increases as the amount of beams passing through the collimators increases, and decreases as the size of the collimator slits increases. With ultra‐high resolution collimators, the RMSEs were comparable to the conventional CBCT image quality until the beam transmission rate is reduced below 25%.

Conclusions:

Collimators can reduce the scatters and radiation dose, however, the collimated CBCT image quality is strongly dependent on both the collimator blocking ratio and the blocking pattern. To achieve image quality comparable to the conventional CBCT, the amount of information and data format must be adequate.
An Addictive Switch
Authors: Gough Nancy R.
Published: November 2013

A single exposure to cocaine induces a switch in NMDA receptor subunits.
Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem
Authors: Agudelo M. , Rodriguez C. A. , Pelaez C. A. , Vesga O.
Published: November 2013

Several studies with animal models have demonstrated that bioequivalence of generic products of antibiotics like vancomycin, as currently defined, do not guarantee therapeutic equivalence. However, the amounts and characteristics of impurities and degradation products in these formulations do not violate the requirements of the U.S. Pharmacopeia (USP). Here, we provide experimental data with three generic products of meropenem that help in understanding how these apparently insignificant chemical differences affect the
in vivo
efficacy. Meropenem generics were compared with the innovator
in vitro
by microbiological assay, susceptibility testing, and liquid chromatography/mass spectrometry (LC/MS) analysis and
in vivo
with the neutropenic guinea pig soleus infection model (
Pseudomonas aeruginosa
) and the neutropenic mouse thigh (
P. aeruginosa
), brain (
P. aeruginosa
), and lung (
Klebisella pneumoniae
) infection models, adding the dihydropeptidase I (DHP-I) inhibitor cilastatin in different proportions to the carbapenem. We found that the concentration and potency of the active pharmaceutical ingredient,
in vitro
susceptibility testing, and mouse pharmacokinetics were identical for all products; however, two generics differed significantly from the innovator in the guinea pig and mouse models, while the third generic was therapeutically equivalent under all conditions. Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-I hydrolysis and less stable at room temperature, explaining its therapeutic nonequivalence. We conclude that the therapeutic nonequivalence of generic products of meropenem is due to greater susceptibility to DHP-I hydrolysis. These failing generics are compliant with USP requirements and would remain undetectable under current regulations.
Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis
Authors: Forde Éanna , Humphreys Hilary , Greene Catherine M. , Fitzgerald-Hughes Deirdre , Devocelle Marc
Published: November 2013

Host defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities of
Pseudomonas aeruginosa
to parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates of
P. aeruginosa
. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 μg/ml). Cytotoxic effects on CFBE41o- cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme at
in vivo
concentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung.
Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To EvaluateIn VitroSusceptibility Test Interpretive Criteria for Ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae
Authors: Van Wart Scott A. , Ambrose Paul G. , Rubino Christopher M. , Khariton Tatiana , Riccobene Todd A. , Friedland H. David , Critchley Ian A. , Bhavnani Sujata M.
Published: November 2013

To provide support forin vitrosusceptibility test interpretive criteria decisions for ceftaroline againstStaphylococcus aureusandStreptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achievingf%T>MIC targets forS. aureusandS. pneumoniaebased on murine infection models were calculated by MIC. At MICs of 2 mg/liter forS. aureusand 1 mg/liter forS. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achievingf%T>MIC targets (≥26 forS. aureusand ≥44 forS. pneumoniae) exceeded 90%. The results of these analyses, which suggested thatin vitrosusceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline againstS. aureusandS. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.
Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 2. Cerebrospinal Fluid Concentration Measurements in Patients with External Ventricular Drain
Authors: Frasca Denis , Dahyot-Fizelier Claire , Adier Christophe , Mimoz Olivier , Debaene Bertrand , Couet William , Marchand Sandrine
Published: November 2013

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC
0–τ
ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC
0–τ
ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.
Function of the Loading Module in CorI and of the
O
-Methyltransferase CorH in Vinyl Carbamate Biosynthesis of the Antibiotic Corallopyronin A
Authors: Schäberle Till F. , Mir Mohseni Mahsa , Lohr Friederike , Schmitz Alexander , König Gabriele M.
Published: November 2013

Corallopyronin A is a promising
in vivo
active antibiotic, currently undergoing preclinical evaluation. This myxobacterial compound interferes with a newly identified drug target site, i.e., the switch region of the bacterial DNA-dependent RNA-polymerase (RNAP). Since this target site differs from that of known RNAP inhibitors such as the rifamycins, corallopyronin A shows no cross-resistance with other antibacterial agents. Corallopyronin A is a polyketide synthase- and nonribosomal peptide synthetase-derived molecule whose structure and biosynthesis is distinguished by several peculiarities, such as the unusual vinyl carbamate functionality whose formation involves carbonic acid as an unprecedented C1-starter unit. Using
in vitro
experiments the nature of this starter molecule was revealed to be the methyl ester of carbonic acid. Biochemical investigations showed that methylation of carbonic acid is performed by the
O
-methyltransferase CorH. These experiments shed light on the biosynthesis of the Eastern chain of α-pyrone antibiotics such as corallopyronin A.
Nutritional Control of Antibiotic Resistance via an Interface between the Phosphotransferase System and a Two-Component Signaling System
Authors: Snyder Holly , Kellogg Stephanie L. , Skarda Laura M. , Little Jaime L. , Kristich Christopher J.
Published: November 2013

Enterococci are ubiquitous inhabitants of the gastrointestinal (GI) tract. However, antibiotic-resistant enterococci are also major causes of hospital-acquired infections. Enterococci are intrinsically resistant to cephalosporins, enabling growth to abnormally high densities in the GI tract in patients during cephalosporin therapy, thereby promoting dissemination to other sites where they cause infection. Despite its importance, many questions about the underlying basis for cephalosporin resistance remain. A specific two-component signaling system, composed of the CroS sensor kinase and its cognate response regulator (CroR), is required for cephalosporin resistance in
Enterococcus faecalis
, but little is known about the factors that control this signaling system to modulate resistance. To explore the signaling network in which CroR participates to influence cephalosporin resistance, we employed a protein fragment complementation assay to detect protein-protein interactions in
E. faecalis
cells, revealing a previously unknown association of CroR with the HPr protein of the phosphotransferase system (PTS) responsible for carbohydrate uptake and catabolite control of gene expression. Genetic and physiological analyses indicate that association with HPr restricts the ability of CroR to promote cephalosporin resistance and gene expression in a nutrient-dependent manner. Mutational analysis suggests that the interface used by HPr to associate with CroR is distinct from the interface used to associate with other cellular partners. Our results define a physical and functional connection between a critical nutrient-responsive signaling system (the PTS) and a two-component signaling system that drives antibiotic resistance in
E. faecalis
, and they suggest a general strategy by which bacteria can integrate their nutritional status with diverse environmental stimuli.
In Vitro
Combination of Anti-Cytomegalovirus Compounds Acting through Different Targets: Role of the Slope Parameter and Insights into Mechanisms of Action
Authors: Cai Hongyi , Kapoor Arun , He Ran , Venkatadri Rajkumar , Forman Michael , Posner Gary H. , Arav-Boger Ravit
Published: November 2013

Conventional therapy for human cytomegalovirus (CMV) relies on inhibition of the viral DNA polymerase. Ganciclovir (GCV) is the first-line therapy, but when GCV-resistant strains emerge, alternative therapies are extremely limited and are associated with significant toxicities. Combination of anti-CMV agents that act on different targets or stages of virus replication has not been well studied, mostly because of the limited number of anti-CMV agents. We report our investigation of combinations of agents that inhibit CMV by targeting the viral DNA polymerase, cellular kinases, or other cell/virus mechanisms yet to be discovered. The selected compounds differed by the slopes of their dose-response curve: compounds with a slope of 1 (GCV) representing one target or noncooperativity and compounds with high slopes indicating positive cooperativity. Analysis of anti-CMV drug combinations using the Bliss model (which accounts for the slope parameter) distinguished between combinations with synergistic, antagonistic, and additive activities. The combination of GCV and foscarnet was slightly synergistic; strong synergism was found when GCV was used with artemisinin-derived monomers or dimers or the MEK inhibitor U0126. The combination of GCV and cardiac glycosides (digoxin, digitoxin, and ouabain) was additive. The monomeric artemisinin artesunate was synergistic when combined with U0126 or the multikinase inhibitor sunitinib. However, the combination of artemisinin-derived dimers (molecular weights, 606 and 838) and U0126 or sunitinib was antagonistic. These results demonstrate that members of a specific drug class show similar patterns of combination with GCV and that the slope parameter plays an important role in the evaluation of drug combinations. Lastly, antagonism between different classes of CMV inhibitors may assist in target identification and improve the understanding of CMV inhibition by novel compounds.
Role of the
mecA
Gene in Oxacillin Resistance in a Staphylococcus aureus Clinical Strain with a
pvl
-Positive ST59 Genetic Background
Authors: Chen Feng-Jui , Wang Chen-Her , Chen Ching-Yi , Hsu Yu-Chieh , Wang Kaun-Ting
Published: November 2013

The most prevalent community-associated methicillin-resistant
Staphylococcus aureus
(C-MRSA) strains in Taiwan, sequence type 59 (ST59) clones, carry staphylococcal cassette chromosome
mec
(SCC
mec
) type V and, to a lesser extent, type IV. These strains show wide variation in sensitivity to oxacillin, but the reasons for this variation are unknown. Here we compared the sequences of the
mecA
genes from clinical strains of different SCC
mec
types and found that they contain different
mecA
promoter mutations. Analysis of
mecA
promoter activity by reporter gene fusions showed that single base substitutions in the promoter have a strong influence on
mecA
transcription. The different
mecA
variants, including promoter sequences, were expressed in the methicillin-sensitive
Staphylococcus aureus
(MSSA) strain C195 (ST59 background). PBP 2a production among the parental strains and strains with promoter mutant
mecA
genes showed a close correlation with
mecA
transcription levels. Furthermore, the quantity of PBP 2a also closely correlated with the level of oxacillin resistance in the C195 background. Our data suggest that
mecA
promoter mutations play an important role in determining the level of oxacillin resistance. The
mecA
promoter mutation G-25A (25 bases upstream of the
mecA
translation start site) was found to be associated with a high oxacillin MIC (256 μg/ml), G-7T conferred a moderate oxacillin MIC (32 to 64 μg/ml), strains with C-33T showed a low oxacillin MIC (4 to 8 μg/ml), and A-38G reversed the effect of the C-33T mutation, restoring the oxacillin resistance level in the A-38G C-33T double mutant. These observations may explain why C-MRSA strains in Taiwan carrying SCC
mec
type IV or V have such enormous variations in oxacillin MICs.
Phosphate-Containing Polyethylene Glycol Polymers Prevent Lethal Sepsis by Multidrug-Resistant Pathogens
Authors: Zaborin Alexander , Defazio Jennifer R. , Kade Matthew , Kaiser Brooke L. Deatherage , Belogortseva Natalia , Camp David G. , Smith Richard D. , Adkins Joshua N. , Kim Sangman M. , Alverdy Alexandria , Goldfeld David , Firestone Millicent A. , Collier Joel H. , Jabri Bana , Tirrell Matthew , Zaborina Olga , Alverdy John C.
Published: November 2013

Antibiotic resistance among highly pathogenic strains of bacteria and fungi is a growing concern in the face of the ability to sustain life during critical illness with advancing medical interventions. The longer patients remain critically ill, the more likely they are to become colonized by multidrug-resistant (MDR) pathogens. The human gastrointestinal tract is the primary site of colonization of many MDR pathogens and is a major source of life-threatening infections due to these microorganisms. Eradication measures to sterilize the gut are difficult if not impossible and carry the risk of further antibiotic resistance. Here, we present a strategy to contain rather than eliminate MDR pathogens by using an agent that interferes with the ability of colonizing pathogens to express virulence in response to host-derived and local environmental factors. The antivirulence agent is a phosphorylated triblock high-molecular-weight polymer (here termed Pi-PEG 15–20) that exploits the known properties of phosphate (P
i
) and polyethylene glycol 15-20 (PEG 15-20) to suppress microbial virulence and protect the integrity of the intestinal epithelium. The compound is nonmicrobiocidal and appears to be highly effective when tested both
in vitro
and
in vivo
. Structure functional analyses suggest that the hydrophobic bis-aromatic moiety at the polymer center is of particular importance to the biological function of Pi-PEG 15-20, beyond its phosphate content. Animal studies demonstrate that Pi-PEG prevents mortality in mice inoculated with multiple highly virulent pathogenic organisms from hospitalized patients in association with preservation of the core microbiome.
Novel Method To Identify the Optimal Antimicrobial Peptide in a Combination Matrix, Using Anoplin as an Example
Authors: Munk J. K. , Ritz C. , Fliedner F. P. , Frimodt-Møller N. , Hansen P. R.
Published: November 2013

Microbial resistance is an increasing health concern and a true danger to human well-being. A worldwide search for new compounds is ongoing, and antimicrobial peptides are promising lead candidates for tomorrow's antibiotics. The decapeptide anoplin (GLLKRIKTLL-NH
2
) is an especially interesting candidate because of its small size as well as its antimicrobial and nonhemolytic properties. Optimization of the properties of an antimicrobial peptide such as anoplin requires multidimensional searching in a complex chemical space. Typically, such optimization is performed by labor-intensive and costly trial-and-error methods. In this study, we show the benefit of fractional factorial design for identification of the optimal antimicrobial peptide in a combination matrix. We synthesized and analyzed a training set of 12 anoplin analogs, representative of 64 analogs in total. Using MIC, hemolysis, and high-performance liquid chromatography retention time data, we constructed analysis-of-variance models that describe the relationship between these properties and the structural characteristics of the analogs. We show that the mathematical models derived from the training set data can be used to predict the properties of other analogs in the chemical space. Hence, this method provides an efficient means of identification of the optimal peptide in the searched chemical space.
A Toxoplasma Patatin-Like Protein Changes Localization and Alters the Cytokine Response during Toxoplasmic Encephalitis
Authors: Tobin Magle Crystal , Pittman Kelly J. , Moser Lindsey A. , Boldon Kyle M. , Knoll Laura J.
Published: November 2013

Toxoplasma gondiiis an obligate intracellular parasite that forms a lifelong infection within the central nervous system of its host. TheT. gondiigenome encodes six members of the patatin-like phospholipase family; related proteins are associated with host-microbe interactions in bacteria.T. gondiipatatin-like protein 1 (TgPL1) was previously determined to be necessary for parasites to suppress nitric oxide and prevent degradation in activated macrophages. Here, we show that in the rapidly replicating tachyzoite stage, TgPL1 is localized within vesicles inside the parasite that are distinct from the dense granules; however, in the encysted bradyzoite stage, TgPL1 localizes to the parasitophorous vacuole (PV) and cyst wall. While we had not previously seen a defect of the TgPL1 deletion mutant (ΔTgPL1) during acute and early chronic infection, the localization change of TgPL1 in bradyzoites caused us to reevaluate the ΔTgPL1 mutant during late chronic infection and in a toxoplasmic encephalitis (TE) mouse model. Mice infected with ΔTgPL1 are more resistant to TE and have fewer inflammatory lesions than mice infected with the wild type and ΔTgPL1 genetically complemented withTgPL1. This increased resistance to TE could result from several contributing factors. First, we found that ΔTgPL1 bradyzoites did not convert back to tachyzoites readily in tissue culture. Second, a subset of cytokine levels were higher in ΔTgPL1-infected mice, including gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemotactic protein 1 (MCP-1). These studies suggest that TgPL1 plays a role in the maintenance of chronicT. gondiiinfection.
Adding heat to the live-high train-low altitude model: a practical insight from professional football
Authors: Buchheit M , Racinais S , Bilsborough J , Hocking J , Mendez-Villanueva A , Bourdon P C , Voss S , Livingston S , Christian R , Périard J , Cordy J , Coutts A J
Published: November 2013

Objectives

To examine with a parallel group study design the performance and physiological responses to a 14-day off-season ‘live high-train low in the heat’ training camp in elite football players.

Methods

Seventeen professional Australian Rules Football players participated in outdoor football-specific skills (32±1°C, 11.5 h) and indoor strength (23±1°C, 9.3 h) sessions and slept (12 nights) and cycled indoors (4.3 h) in either normal air (NORM, n=8) or normobaric hypoxia (14±1 h/day, FiO215.2–14.3%, corresponding to a simulated altitude of 2500–3000 m, hypoxic (HYP), n=9). They completed the Yo-Yo Intermittent Recovery level 2 (Yo-YoIR2) in temperate conditions (23±1°C, normal air) precamp (Pre) and postcamp (Post). Plasma volume (PV) and haemoglobin mass (Hbmass) were measured at similar times and 4 weeks postcamp (4WPost). Sweat sodium concentration ((Na+)sweat) was measured Pre and Post during a heat-response test (44°C).

Results

Both groups showed very large improvements in Yo-YoIR2 at Post (+44%; 90% CL 38, 50), with no between-group differences in the changes (−1%; −9, 9). Postcamp, large changes in PV (+5.6%; −1.8, 5.6) and (Na+)sweat(−29%; −37, −19) were observed in both groups, while Hbmassonly moderately increased in HYP (+2.6%; 0.5, 4.5). At 4WPost, there was a likely slightly greater increase in Hbmass(+4.6%; 0.0, 9.3) and PV (+6%; −5, 18, unclear) in HYP than in NORM.

Conclusions

The combination of heat and hypoxic exposure during sleep/training might offer a promising ‘conditioning cocktail’ in team sports.
Advancing hypoxic training in team sports: from intermittent hypoxic training to repeated sprint training in hypoxia
Authors: Faiss Raphaël , Girard Olivier , Millet Grégoire P
Published: November 2013

Over the past two decades, intermittent hypoxic training (IHT), that is, a method where athletes live at or near sea level but train under hypoxic conditions, has gained unprecedented popularity. By adding the stress of hypoxia during ‘aerobic’ or ‘anaerobic’ interval training, it is believed that IHT would potentiate greater performance improvements compared to similar training at sea level. A thorough analysis of studies including IHT, however, leads to strikingly poor benefits for sea-level performance improvement, compared to the same training method performed in normoxia. Despite the positive molecular adaptations observed after various IHT modalities, the characteristics of optimal training stimulus in hypoxia are still unclear and their functional translation in terms of whole-body performance enhancement is minimal. To overcome some of the inherent limitations of IHT (lower training stimulus due to hypoxia), recent studies have successfully investigated a new training method based on the repetition of short (<30 s) ‘all-out’ sprints with incomplete recoveries in hypoxia, the so-called repeated sprint training in hypoxia (RSH). The aims of the present review are therefore threefold: first, to summarise the main mechanisms for interval training and repeated sprint training in normoxia. Second, to critically analyse the results of the studies involving high-intensity exercises performed in hypoxia for sea-level performance enhancement by differentiating IHT and RSH. Third, to discuss the potential mechanisms underpinning the effectiveness of those methods, and their inherent limitations, along with the new research avenues surrounding this topic.
Update in the understanding of altitude-induced limitations to performance in team-sport athletes
Authors: Billaut François , Aughey Robert J
Published: November 2013

The internationalism of field-based team sports (TS) such as football and rugby requires teams to compete in tournaments held at low to moderate altitude (∼1200–2500 m). In TS, acceleration, speed and aerobic endurance are physical characteristics associated with ball possession and, ultimately, scoring. While these qualities are affected by the development of neuromuscular fatigue at sea level, arterial hypoxaemia induced by exposure to altitude may further hinder the capacity to perform consecutive accelerations (CAC) or sprint endurance and thereby change the outcome of a match. The higher the altitude, the more severe the hypoxaemia, and thus, the larger the expected decline in aerobic endurance, CAC and match running performance. Therefore, it is critical for athletes and coaches to understand how arterial hypoxaemia affects aerobic endurance and CAC and the magnitude of decline they may face at altitude for optimal preparation and increased chances of success. This mini review summarises the effects of acute altitude/hypoxia exposure on aerobic endurance, CAC and activity profiles of TS athletes performing in the laboratory and during matches at natural altitude, and analyses the latest findings about the consequences of arterial hypoxaemia on the relationship between peripheral perturbations, neural adjustments and performance during repeated sprints or CAC. Finally, we briefly discuss how altitude training can potentially help athletes prepare for competition at altitude.
A retrospective cohort study of mode of delivery among public and private patients in an integrated maternity hospital setting
Authors: Murphy Deirdre J , Fahey Tom
Published: November 2013

Objective

To examine the associations between mode of delivery and public versus privately funded obstetric care within the same hospital setting.

Design

Retrospective cohort study.

Setting

Urban maternity hospital in Ireland.

Population

A total of 30 053 women with singleton pregnancies who delivered between 2008 and 2011.

Methods

The study population was divided into those who booked for obstetric care within the public (n=24 574) or private clinics (n=5479). Logistic regression analyses were performed to examine the associations between operative delivery and type of care, adjusting for potential confounding factors.

Main outcome measures

Caesarean section (scheduled or emergency), operative vaginal delivery (vacuum or forceps), indication for caesarean section as classified by the operator.

Results

Compared with public patients, private patients were more likely to be delivered by caesarean section (34.4% vs 22.5%, OR 1.81; 95% CI 1.70 to 1.93) or operative vaginal delivery (20.1% vs 16.5%, OR 1.28; 95% CI 1.19 to 1.38). The greatest disparity was for scheduled caesarean sections; differences persisted for nulliparous and parous women after controlling for medical and social differences between the groups (nulliparous 11.9% vs 4.6%, adjusted (adj) OR 1.82; 95% CI 1.49 to 2.24 and parous 26% vs 12.2%, adj OR 2.08; 95% CI 1.86 to 2.32). Scheduled repeat caesarean section accounted for most of the disparity among parous patients. Maternal request per se was an uncommonly reported indication for caesarean section (35 in each group, p<0.000).

Conclusions

Privately funded obstetric care is associated with higher rates of operative deliveries that are not fully accounted for by medical or obstetric risk differences.
Serovars, bacteriophage types and antimicrobial sensitivities associated with salmonellosis in dogs in the UK (1954–2012)
Authors: Philbey A. W. , Mather H. A. , Gibbons J. F. , Thompson H. , Taylor D. J. , Coia J. E.
Published: November 2013

Serovars and bacteriophage (phage) types were determined for 442 isolates of Salmonella enterica from dogs in the UK submitted to the Scottish Salmonella Reference Laboratory from 1954 to 2012. The most frequent serovars were Salmonella Typhimurium (196 isolates; 44.3 per cent), Dublin (40 isolates; 9.0 per cent), Enteritidis (28 isolates; 6.3 per cent), Montevideo (19 isolates; 4.3 per cent), Virchow (10 isolates; 2.3 per cent), Heidelberg (8 isolates; 1.8 per cent) and Derby (8 isolates; 1.8 per cent), along with 55 other recognised serovars among 127 other isolates, and six incompletely classified isolates. Serovars were frequently represented by strains commonly associated with poultry, cattle or pigs and their products. Among 196 Salmonella Typhimurium isolates from dogs, the most frequent phage types (definitive types) were the multiple antimicrobial‐resistant strains DT104 (62 isolates), DT204c (18 isolates) and DT193 (8 isolates), along with antimicrobial sensitive wild finch strains DT40 (13 isolates) and DT56 variant (8 isolates). Eleven of 28 isolates of Salmonella Enteritidis were phage type 4. S enterica was frequently recovered from faecal or intestinal samples of dogs with diarrhoea, although many dogs had concurrent infection with other enteric pathogens. Salmonella Dublin was recovered from the brain and/or cerebrospinal fluid of two dogs with meningoencephalitis. Salmonella Kedougou was isolated from the joint fluid of a dog with septic arthritis. Salmonella Typhimurium and Salmonella Dublin were each recovered from the vaginas of bitches that had aborted. Isolates of Salmonella Enteritidis phage types 1, 4 and 8, Salmonella Typhimurium DT104, Salmonella Dublin and Salmonella Indiana were isolated from clinically healthy dogs in households where the same strains were recovered from human beings with diarrhoea. The pattern ampicillin‐chloramphenicol‐spectinomycin‐streptomycin‐sulfamethoxazole‐tetracycline (ACSpSSuT) was the most frequent resistance phenotype and was observed in 44 (13.3 per cent) of 330 isolates. Dogs in the UK are exposed to a wide variety of serovars of S enterica, sometimes associated with clinical disease, and represent a zoonotic risk.
Investigation on use of recycled asphalt shingles in Ontario hot mix asphalt: a Canadian case study
Authors: Yang Jun , Ddamba Shirley , UL-Islam Riyad , Safiuddin Md. , Tighe Susan L.
Published: November 2013

The usage of recycled asphalt shingles (RAS) in hot mix asphalt (HMA) pavements provides many benefits as long as they are properly engineered into the various HMA mixes. Contractors, consultants, and Departments of Transportation have evaluated the performance of these various materials, although they are still only used in a limited number of areas. Alternatively, recycled asphalt pavement (RAP) is recognized as a high value recycled material and is actually the most recycled material in North America. In Ontario, RAP is successfully used in most HMA. Related studies on HMA containing RAS and RAP are limited in Canada although recently studies and field trials on effectively using RAS in HMA in Ontario have been completed by the Centre of Pavement and Transportation Technology (CPATT) at University of Waterloo in partnership with Miller Paving Ltd and the Ontario Centre of Excellence. This paper presents key findings from a comprehensive laboratory investigation and analysis of six asphalt mixes with RAS and RAP in Ontario through dynamic modulus, resilient modulus, thermal stress restrained specimen, and flexural fatigue testing. Using RAS alone or combining with RAP makes the asphalt stiffer at high and low temperatures respectively. Lowering the low temperature performance grade of the asphalt binder by 6 °C and incorporating 3% RAS or less with RAP in HMA mix design can result in meeting the appropriate specification. While field testing of RAS pavements demonstrated that surface friction properties are in good condition in various environmental and loading conditions, the laboratory test results and field performances indicate that RAS can be a useful additive to asphalt mixes in Ontario hot mix pavement through reasonable mix design.
Vardenafil ameliorates immunologic- and non-immunologic-induced allergic reactions
Authors: El-Awady Mohammed S. , Said Eman
Published: November 2013

Cyclic nucleotides, such as cAMP and cGMP, play a protective role in the modulation of the activity of some inflammatory cells in allergic disorders. Their intracellular concentrations are tightly regulated by the phosphodiesterases (PDEs). The protective efficacy of the selective PDE5 inhibitor vardenafil against mast-cell-mediated allergic reactions in murine models has been investigated. Compound 48/80 was used as a direct mast cell degranulator to induce anaphylaxis. Vardenafil (administered orally at 5, 10, 20, 40, and 80 mg/kg body mass) significantly (P < 0.05, n = 12) increased protection against compound-48/80-induced anaphylaxis in mice to 33.33%, 66.67%, 66.67%, 83.33%, and 66.67% respectively compared with the control (vehicle). In passive cutaneous anaphylaxis (PCA) in rats, vardenafil (10 mg/kg body mass) significantly (P < 0.05, n = 6) decreased Evans’ blue dye extravasation (4.6-fold). Pre-incubation of isolated rat peritoneal mast cells (RPMCs) with vardenafil (10 and 100 μmol/L) significantly (P < 0.05, n = 6) reduced compound-48/80-induced histamine release by 2.8- and 3-fold, respectively. Moreover, histamine release by immunogenic stimulation of sensitized RPMCs by egg albumin significantly declined following pre-incubation with vardenafil (10 and 100 μmol/L) by 1.94- and 1.99-fold, respectively. In conclusion, inhibition of PDE5 by vardenafil ameliorated immunologic and non-immunologic mast-cell-mediated allergic reactions and reduced histamine release, providing evidence for the potential anti-allergic properties of vardenafil.
Group size and dispersal ploys: an analysis of commuting behaviour of the pond bat (Myotis dasycneme)
Authors: Haarsma A.-J. , Siepel H.
Published: November 2013

Like most bat species, the pond bat (Myotis dasycneme (Boie, 1825)) lives in roosts more or less in the centre of their foraging habitat and are considered central-place foragers. Commuting routes, or flyways, between roosts and hunting areas have an essential ecological function for bats. We summarize the results of research performed on the commuting routes of pond bats between 2002 and 2009. We give, among others, a description on how bats disperse, how to recognize a commuting route, and details about the effort needed to make a complete survey of one commuting route. Furthermore, we make a relation between number of animals on the route and size of their respective roost. The results suggest pond bats are not completely reliant on waterways for reaching their foraging habitat; they use directional dispersal, following commuting routes over waterways in combination with shortcuts over land. These results provide information that can be used to better understand how bats use their commuting routes. Also, the knowledge can be applied to survey work.
On a Class of Non-Markovian Langevin Equations
Authors: Lizama Carlos , Rebolledo Rolando
Published: November 2013

This paper proposes a generalized Langevin's equation for a small classical mechanical system embedded in a reservoir. The interaction of the main system with the reservoir is given by a Gaussian transform as introduced in our previous paper [8]. Thus, a first result proves the existence of a strong solution to this equation in the space where the Gaussian transform (or non-Markovian noise) is defined. The interpretation of the noise is obtained by considering a finite number n of oscillating particles with discrete frequencies in the reservoir. The action of this discrete reservoir on the small system is described by a memory kernel and a sequence of zero-mean Gaussian processes. So, an integro-differential equation for the evolution of a generic particle in the main system arises for each n. This equation has a unique solution Xn which converges in distribution towards the solution of the initial non-Markovian Langevin's equation.
THE EFFECTS OF ELASTIC STIFFENING ON THE EVOLUTION OF THE STRESS FIELD WITHIN A SPHERICAL ELECTRODE PARTICLE OF LITHIUM-ION BATTERIES
Authors: ZHOU WENBIN , HAO FENG , FANG DAINING
Published: November 2013

Poor cyclic performance of lithium-ion batteries is calling for efforts to study its capacity attenuation mechanism. The internal stress field produced in the lithium-ion battery during its charging and discharging process is a major factor for its capacity attenuation, research on it appears especially important. We established an electrochemical –mechanical coupling model with the consideration of the influence of elastic stiffening on diffusion for graphite anode materials. The results show that the inner stress field strongly depends on the lithium-ion concentration field, greater concentration gradients lead to greater stresses. The evolution of the stress field is similar to that of the concentration gradient but lags behind it, which shows hysteresis phenomenon. Elastic stiffening can lower the concentration gradient and increase elastic modulus, which are two major factors influencing the inner stress field. We conclude that the latter is more dominant compared to the former, and elastic stiffening acts to increasing the internal stress.