bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling and Experimental Investigation of a Helmholtz Resonator With a Flexible Plate
Authors: Nudehi Shahin S. , Duncan G. Scott , Farooq Umar
Published: June 2013

A Helmholtz resonator with a uniform, flexible end plate is studied in this work. This work shows that the flexible plate modifies the frequency response characteristics of the resonator, providing multiple distinct resonant frequencies instead of a single resonant frequency. Therefore, acoustical transmission loss will increase at each of the multiple resonant frequencies of the resonator and plate assembly versus at a single frequency for the unmodified Helmholtz resonator. By using receptance coupling as the modeling approach, the receptance of the Helmholtz resonator and flexible plate assembly is predicted by coupling receptance models of an unmodified Helmholtz resonator and a clamped plate. Finally, the predicted receptance of the Helmholtz resonator and flexible plate assembly is compared against experimental results.
Complete Bandgap in Three-Dimensional Holey Phononic Crystals With Resonators
Authors: Wang Yan-Feng , Wang Yue-Sheng
Published: June 2013

In this paper, the bandgap properties of three-dimensional holey phononic crystals with resonators are investigated by using the finite element method. The resonators are periodically arranged cubic lumps in the cubic holes connected to the matrix by narrow connectors. The influence of the geometry parameters of the resonators on the bandgap is discussed. In contrast to a system with cubic or spherical holes, which has no bandgaps, systems with resonators can exhibit complete bandgaps. The bandgaps are significantly dependent upon the geometry of the resonators. By the careful design of the shape and size of the resonator, a bandgap that is lower by an order of magnitude than the Bragg bandgap can be obtained. The vibration modes at the band edges of the lowest bandgaps are analyzed in order to understand the mechanism of the bandgap generation. It is found that the emergence of the bandgap is due to the local resonance of the resonators. Spring-mass models or spring-pendulum models are developed in order to evaluate the frequencies of the bandgap edges. The study in this paper is relevant to the optimal design of the bandgaps in light porous materials.
Topology Optimized Cloak for Airborne Sound
Authors: Andkjær Jacob , Sigmund Ole
Published: June 2013

Directional acoustic cloaks that conceal an aluminum cylinder for airborne sound waves are presented in this paper. Subwavelength cylindrical aluminum inclusions in air constitute the cloak design to aid practical realizations. The positions and radii of the subwavelength cylinders are determined by minimizing scattering from the cloak-structure and cylinder using the gradient-based topology optimization method. In the final optimization step, the radii of the subwavelength cylinders are constrained to three discrete values. A near-perfect narrow-banded and angular cloaking effect is obtained by optimizing for one target frequency. To get a larger bandwidth, the acoustic cloak is optimized for three frequencies at the cost of reduced peak cloaking performance at the center frequency.
Angular Band Gaps in Sonic Crystals: Evanescent Waves and Spatial Complex Dispersion Relation
Authors: Romero-García V. , Picó R. , Cebrecos A. , Staliunas K. , Sánchez-Morcillo V. J.
Published: June 2013

Phononic crystals are artificial materials made of a periodic distribution of solid scatterers embedded into a solid host medium with different physical properties. An interesting case of phononic crystals, known as sonic crystals (SCs), appears when the solid scatterers are periodically embedded in a fluid medium. In SCs only longitudinal modes are allowed to propagate and both the theoretical and the experimental studies of the properties of the system are simplified without loss of generality. The most celebrated property of these systems is perhaps the existence of spectral band gaps. However, the periodicity of the system can also affect to the spatial dispersion, making possible the control of the diffraction inside these structures. In this work we study the main features of the spatial dispersion in SCs from a novel point of view taking into account the evanescent properties of the system, i.e., studying the complex spatial dispersion relations. The evanescent behavior of the propagation of waves in the angular band gaps are theoretically and experimentally observed in this work. Both the numerical predictions and the experimental results show the presence of angular band gaps in good agreement with the complex spatial dispersion relation. The results shown in this work are independent of the spatial scale of the structure, and in principle the fundamental role of the evanescent waves could be also expected in micro- or nanoscale phononic crystals.
Modal Frequency Response of a Four-Pad Tilting Pad Bearing With Spherical Pivots, Finite Pivot Stiffness, and Different Pad Preloads
Authors: Dimond Timothy , Younan Amir A. , Allaire Paul , Nicholas John
Published: June 2013

Tilting pad journal bearings (TPJBs) provide radial support for rotors in high-speed machinery. Since the tilting pads cannot support a moment about the pivot, self-excited cross-coupled forces due to fluid-structure interactions are greatly reduced or eliminated. However, the rotation of the tilting pads about the pivots introduces additional degrees of freedom into the system. When the flexibility of the pivot results in pivot stiffness that is comparable to the equivalent stiffness of the oil film, then pad translations as well as pad rotations have to be considered in the overall bearing frequency response. There is significant disagreement in the literature over the nature of the frequency response of TPJBs due to nonsynchronous rotor perturbations. In this paper, a bearing model that explicitly considers pad translations and pad rotations is presented. This model is transformed to modal coordinates using state-space analysis to determine the natural frequencies and damping ratios for a four-pad tilting pad bearing. Experimental static and dynamic results were previously reported in the literature for the subject bearing. The bearing characteristics as tested are compared to a thermoelastohydrodynamic (TEHD) model. The subject bearing was reported as having an elliptical bearing bore and varying pad clearances for loaded and unloaded pads during the test. The TEHD analysis assumes a circular bearing bore, so the average bearing clearance was considered. Because of the ellipticity of the bearing bore, each pad has its own effective preload, which was considered in the analysis. The unloaded top pads have a leading edge taper. The loaded bottom pads have finned backs and secondary cooling oil flow. The bearing pad cooling features are considered by modeling equivalent convective coefficients for each pad back. The calculated bearing full stiffness and damping coefficients are also reduced nonsynchronously to the eight stiffness and damping coefficients typically used in rotordynamic analyses and are expressed as bearing complex impedances referenced to shaft motion. Results of the modal analysis are compared to a two-degree-of-freedom second-order model obtained via a frequency-domain system identification procedure. Theoretical calculations are compared to previously published experimental results for a four-pad tilting pad bearing. Comparisons to the previously published static and dynamic bearing characteristics are considered for model validation. Differences in natural frequencies and damping ratios resulting from the various models are compared, and the implications for rotordynamic analyses are considered.
Contribution of Primary Creep in Modeling the Mechanical Behavior of Polycrystalline Ice
Authors: Aryanpour G. , Farzaneh M.
Published: June 2013

In most of the models proposed for deformation of ice, in addition to instantaneous elastic and viscoelastic parts, a viscoplastic part is also considered. An expression used for material secondary creep is usually employed to describe the viscoplastic component. In this study, however, another viscoplastic deformation of primary creep type is also considered in addition to the secondary creep. Therefore the permanent contribution of deformation is suggested to consist of primary and secondary creep parts. The existence of the primary creep contribution is investigated and characterized by using experimental results reported in the literature. The identified primary creep contribution is then validated by other available experimental results. Finally, the significance of primary creep in the inelastic behavior will be discussed.
Exact Solution of AC Electro-Osmotic Flow in a Microannulus
Authors: Moghadam Ali Jabari
Published: June 2013

The time-periodic electro-osmotic flow in a microannulus is investigated based on the linearized Poisson–Boltzmann equation. An exact solution of the velocity distribution is obtained by using the Green's function approach. The influences of the geometric radius ratio, the wall ζ potential ratio, the electrokinetic radius, and the dimensionless frequency on velocity profiles are presented. Variations of the geometric radius ratio (between zero and one) can lead to quite different flow behaviors. The wall ζ potential ratio affects the magnitude and direction of the velocity profiles within the electric double layer near the two walls of a microannulus. Depending on the frequency and the geometric radius ratio, the walls identically and/or oppositely charged, both may result in the two-opposite-direction flow in the annulus. For high frequency, the electro-osmotic velocity variations are restricted mainly within a thin layer near the two cylindrical walls. Increasing the electrokinetic radius leads to decrease the electric double layer thickness as well as the maximum velocity near the walls.
Application of the Contour Line Method for Estimating Extreme Responses in the Mooring Lines of a Two-Body Floating Wave Energy Converter
Authors: Muliawan Made Jaya , Gao Zhen , Moan Torgeir
Published: June 2013

The ultimate limit state (ULS) is one of the design criteria used in the oil and gas industry in mooring system design for floating platforms. The 100 year level response in the mooring line should be applied for the ULS design check, which is ideally estimated by taking into account the dynamic mooring line tension in all sea states available at the operational site. This approach is known as a full long-term response analysis using the all-sea-state approach. However, this approach is time consuming, and therefore, the contour line method is proposed for estimation of the 100 year response by primarily studying the short-term response for the most unfavorable sea states along the 100 year environmental contour line. Experience in the oil and gas industry confirmed that this method could yield good predictions if the responses at higher percentiles than the median are used. In this paper, the mooring system of a two-body wave energy converter (WEC) is considered. Because this system involves the interaction between two bodies, the estimation of the ULS level response using the all-sea-state approach may be even more time consuming. Therefore, application of the contour line method for this case will certainly be beneficial. However, its feasibility for application to a WEC case must be documented first. In the present paper, the ULS level response in the mooring tension predicted by the contour line method is compared to that estimated by taking into account all sea states. This prediction is achieved by performing coupled time domain mooring analyses using Simo/Riflex for six cases with different mooring configurations and connections between two bodies. An axisymmetric Wavebob-type WEC is chosen for investigation, and the Yeu site in France is assumed as the operational site. Hydrodynamic loads including second-order forces are determined using Wamit. Finally, the applicability of the contour line method for prediction of the ULS level mooring tension for a two-body WEC is assessed and shown to yield accurate results with the proper choice of percentile level for the extreme response.
Monitoring radiofrequency ablation with ultrasound Nakagami imaging
Authors: Wang Chiao‐Yin , Geng Xiaonan , Yeh Ta‐Sen , Liu Hao‐Li , Tsui Po‐Hsiang
Published: June 2013

Purpose:

Radiofrequency ablation (RFA) is a widely used alternative modality in the treatment of liver tumors. Ultrasound B‐mode imaging is an important tool to guide the insertion of the RFA electrode into the tissue. However, it is difficult to visualize the ablation zone because RFA induces the shadow effect in a B‐scan. Based on the randomness of ultrasonic backscattering, this study proposes ultrasound Nakagami imaging, which is a well‐established method for backscattered statistics analysis, as an approach to complement the conventional B‐scan for evaluating the ablation region.

Methods:

Porcine liver samples (n = 6) were ablated using a RFA system and monitored by employing an ultrasound scanner equipped with a 7.5 MHz linear array transducer. During the stages of ablation (0–12 min) and postablation (12–24 min), the raw backscattered data were acquired at a sampling rate of 30 MHz for B‐mode, Nakagami imaging, and polynomial approximation of Nakagami imaging. The contrast‐to‐noise ratio (CNR) was also calculated to compare the image contrasts of the B‐mode and Nakagami images.

Results:

The results demonstrated that the Nakagami image has the ability to visualize changes in the backscattered statistics in the ablation zone, including the shadow region during RFA. The average Nakagami parameter increased from 0.2 to 0.6 in the ablation stage, and then decreased to approximately 0.3 at the end of the postablation stage. Moreover, the CNR of the Nakagami image was threefold that of the B‐mode image, showing that the Nakagami image has a better image contrast for monitoring RFA. Specifically, the use of the polynomial approximation equips the Nakagami image with an enhanced ability to estimate the range of the ablation region.

Conclusions:

This study demonstrated that ultrasound Nakagami imaging based on the analysis of backscattered statistics has the ability to visualize the RFA‐induced ablation zone, even if the shadow effect exists in the B‐scan.
Uncapping Conflict of Interest?
Authors: Wood Susan F. , Mador Jillian K.
Published: June 2013

The 2012 scaling back of limits on FDA advisory panel financial conflicts had no clear basis and may have unanticipated impacts.
Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors
Authors: Burguière Eric , Monteiro Patrícia , Feng Guoping , Graybiel Ann M.
Published: June 2013

What Causes Obsessive Compulsive Disorder?

Obsessive compulsive disorder is a severe, chronic mental illness that affects millions of individuals. However, the mechanisms underlying this disease are still largely unknown (see the Perspective by

Rauch and Carlezon Jr.

).

Ahmari
et al.

(p.
1234
) stimulated glutamatergic pathways between the orbitofrontal cortex and the ventromedial striatum and used grooming to assess obsessive compulsive behavior in mice. Repetitive stimulation over days triggered changes in the neuronal responses of the ventromedial striatum. Over time, the behavior of the animals became independent of stimulation and could be prevented by the antidepressant fluoxetine.

Burguière
et al.

(p.
1243
) investigated the neural basis of obsessive compulsive symptoms in a mutant mouse that showed excessive expression of a conditioned form of grooming.
Geniculocortical Input Drives Genetic Distinctions Between Primary and Higher-Order Visual Areas
Authors: Chou Shen-Ju , Babot Zoila , Leingärtner Axel , Studer Michele , Nakagawa Yasushi , O'Leary Dennis D. M.
Published: June 2013

Dividing the Brain

The cerebral cortex of the brain is organized into primary cortical areas, which receive direct inputs from the thalamus, and higher-order cortical areas, which in turn receive inputs from one or more primary cortical areas.

Chou
et al.

(p.
1239
) investigated the mechanisms underlying the specification of higher-order cortical areas. Input from the dorsal lateral geniculate nucleus into the primary visual area (V1) is required to drive the genetic and functional differentiation of a large visual cortical field into primary and higher-order visual areas. Thalamocortical axon input acts on a large visual cortical field. The afferents from the dorsal lateral geniculate are necessary to further refine the cortex into subareas that distinguish V1 from higher processing areas. In the relatively simple model that emerges from these findings, sensory input is essential to distinguish primary and higher-order cortical areas.
Structural Systems Biology Evaluation of Metabolic Thermotolerance in
Escherichia coli
Authors: Chang Roger L. , Andrews Kathleen , Kim Donghyuk , Li Zhanwen , Godzik Adam , Palsson Bernhard O.
Published: June 2013

Improve the System

A "systems biology" approach may clarify, for example, how particular proteins determine sensitivity of bacteria to extremes of temperature.

Chang
et al.

(p.
1220
) integrated information on protein structure with a model of metabolism, thus associating the protein structure of enzymes with their catalyzed metabolic reactions. The effects of temperature on susceptible proteins could be predicted and the key reactions that were likely to mediate sensitivity of bacteria to extremes of temperature were identified. Indeed, engineered thermotolerant proteins could be substituted for sensitive ones to improve the growth of thermosensitive strains of bacteria. Such control could come in handy when engineering strains of bacteria to produce compounds of industrial or therapeutic value.
From Sub-Rayleigh to Supershear Ruptures During Stick-Slip Experiments on Crustal Rocks
Authors: Passelègue François X. , Schubnel Alexandre , Nielsen Stefan , Bhat Harsha S. , Madariaga Raùl
Published: June 2013

Sonic Boom from Below

Seismic shear waves released by an earthquake typically far outpace motion along the fault surface. Occasionally, however, earthquakes along strike-slip faults appear to propagate so that the rupture velocity is faster than shear waves, creating a sort of sonic boom along the fault surface.

Passelègue
et al.

(p.
1208
) were able to reproduce and measure these so-called supershear ruptures in stick-slip experiments with two pieces of granite under high applied normal stress. Much like during a sonic boom when a plane travels faster than the speed of sound, the ruptures created a shock wave in the form of a Mach cone around the rupture front.
A Major Asymmetric Dust Trap in a Transition Disk
Authors: van der Marel Nienke , van Dishoeck Ewine F. , Bruderer Simon , Birnstiel Til , Pinilla Paola , Dullemond Cornelis P. , van Kempen Tim A. , Schmalzl Markus , Brown Joanna M. , Herczeg Gregory J. , Mathews Geoffrey S. , Geers Vincent
Published: June 2013

From Dust Grains to Planets

Almost 900 extrasolar planets have been identified, but we still struggle to understand exactly how planets form. Using data from the Atacama Large Millimeter Array,

van der Marel
et al.

(p.
1199
; see the Perspective by

Armitage

) report a highly asymmetric distribution of millimeter-sized grains surrounding a young star. Modeling suggests that these particles—the material from which planets form—are being trapped within a protoplanetary disk by an anticyclonic vortex. Localized concentration of large grains within a protoplanetary disk is thought to be a step in planet formation.
Lovely Spam! Wonderful Spam!
Spam
A Shadow History of the Internet

by Finn Brunton

MIT Press, Cambridge, MA, 2013. 294 pp. $27.95, £19.95. ISBN 9780262018876.
Authors: Golbeck Jennifer
Published: June 2013

Examining the nature of spam and where it comes from, Brunton considers how it affects us and what it means.
Deserts and Waves in Gene Expression
Authors: Rodrigues Alan R. , Tabin Clifford J.
Published: June 2013

A gene cluster that regulates limb development is controlled in two phases by regulatory elements that flank the cluster and operate independently.

[Also see Research Article by

Andrey
et al.

]
Seas of Superoxide
Authors: Shaked Yeala , Rose Andrew
Published: June 2013

Superoxide in seawater may be produced by heterotrophic bacteria, with implications for trace metal cycling in the sea.

[Also see Report by

Diaz
et al.

]
Passing the Baton
Authors: McNutt Marcia
Published: June 2013

It is with awe and deep respect for the weighty accomplishments of those who have passed before me that I assume the title of Editor-in-Chief of
Science
, one of less than a handful of journals that can claim to represent the spectrum of scientific endeavors and a truly international audience of authors and readers. Each editor-in-chief has come to this position with his (and now her!) own vision of how to use this opportunity to benefit the scientific community. Bruce Alberts has left an important legacy that I hope to continue and build upon.
Accelerator Leak Halts Japanese Physics Experiments
Authors: Normile Dennis
Published: June 2013

After a delay in reporting a small radiation leak, Japan's J-PARC accelerator center has been shut down indefinitely; some are concerned about the impact on physics research.
How Do Organs Know When They Have Reached the Right Size?
Authors: Vogel Gretchen
Published: June 2013

Developmental biologists have found dozens of proteins and genes that play a role in the growth of plants and animals, such as imaginal discs and Hippo and morphogenetic proteins, but not what determines organ size.
How Do Microbes Shape Animal Development?
Authors: Pennisi Elizabeth
Published: June 2013

There is a growing realization that microbes and their genes are partners in each animal's journey from egg to adult.
How Does Fetal Environment Influence Later Health?
Authors: Couzin-Frankel Jennifer
Published: June 2013

There's broad agreement that the fetal world, the most rapid period of human growth and development, shapes one's risk of future disease, although how much influence it has remains uncertain.
Under Development
Authors: Vogel Gretchen
Published: June 2013

Much of what we know about the journey from single cell to mature organism involves what happens when things go awry. Here are five more mysteries of what happens when genes are working as they should.
The Cyborg Era Begins
Authors: Service Robert F.
Published: June 2013

Advances in flexible electronics now make it possible to integrate circuits with tissues.
Characterization and Protective Immunogenicity of the SzM Protein of Streptococcus zooepidemicus NC78 from a Clonal Outbreak of Equine Respiratory Disease
Authors: Velineni Sridhar , Timoney John F.
Published: June 2013

Streptococcus zooepidemicusof Lancefield group C is a highly variable tonsillar and mucosal commensal that usually is associated with opportunistic infections of the respiratory tract of vertebrate hosts. More-virulent clones have caused epizootics of severe respiratory disease in dogs and horses. The virulence factors of these strains are poorly understood. The antiphagocytic protein SeM is a major virulence factor and protective antigen ofStreptococcus equi, a clonal biovar of an ancestralS. zooepidemicusstrain. Although the genome ofS. zooepidemicusstrain H70, an equine isolate, contains a partial homolog (szm) ofsem, expression of the gene has not been documented. We have identified and characterized SzM from an encapsulatedS. zooepidemicusstrain from an epizootic of equine respiratory disease in New Caledonia. The SzM protein of strain NC78 (SzMNC78) has a predicted predominantly alpha-helical fibrillar structure with an LPSTG cell surface anchor motif and resistance to hot acid. A putative binding site for plasminogen is present in the B repeat region, the sequence of which shares homology with repeats of the plasminogen binding proteins of human group C and G streptococci. Equine plasminogen is activated in a dose-dependent manner by recombinant SzMNC78. Only 23.20 and 25.46% DNA homology is shared with SeM proteins ofS. equistrains CF32 and 4047, respectively, and homology ranges from 19.60 to 54.70% for SzM proteins of otherS. zooepidemicusstrains. As expected, SzMNC78reacted with convalescent-phase sera from horses with respiratory disease associated with strains ofS. zooepidemicus. SzMNC78resembles SeM in binding equine fibrinogen and eliciting strong protective antibody responses in mice. Sera of vaccinated mice opsonizedS. zooepidemicusstrains NC78 and W60, the SzM protein of which shared partial amino acid homology with SzMNC78. We conclude that SzM is a protective antigen of NC78; it was strongly reactive with serum antibodies from horses during recovery fromS. zooepidemicus-associated respiratory disease.
Dried Blood as an Alternative to Plasma or Serum for Trypanosoma cruzi IgG Detection in Screening Programs
Authors: Holguín Africa , Norman Francesca , Martín Leticia , Mateos María Luisa , Chacón Jesús , López-Vélez Rogelio , Pérez-Molina José A.
Published: June 2013

Trypanosoma cruziserological screening is recommended for people potentially exposed to this parasite in countries whereTrypanosoma cruziis endemic and those where it is not endemic. Blood samples on filter paper may be a practical alternative to plasma/serum for antibody detection. Using the Architect Chagas assay, we detected the presence of IgG againstT. cruziin matched serum and dried blood spots (DBS) collected from 147 patients residing in Madrid, Spain, who had potential previous exposure toT. cruzi. The κ statistic for the DBS/serum proportion of agreement for the detection of antibodies againstT. cruziwas 0.803, considering an S/CO (assay result unit; chemiluminescent signal from the sample [S] divided by the mean chemiluminescent signal for the three calibrators used in the test [CO]) cutoff value of ≥1.00. The relative sensitivity of the Architect test using DBS increased from 95.2% to 98.8% when the cutoff was lowered from ≥1.00 to ≥0.88, while the relative specificity decreased from 84.1% to 71.6%. Overall, the median S/CO values for DBS were significantly lower than those for serum (2.6 versus 6.5;P< 0.001). Discrepancies that occurred with the use of DBS included 10 false positives (with low S/CO values in 9 cases [median, 2.13]) and 4 false negatives, with mean S/CO values of 0.905 (gray zone). Using DBS plus a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) may be a simple and reliable method for detecting IgG againstT. cruziwhen blood sampling by venipuncture is not feasible. This method may also reduce the false-negative rates observed with some rapid diagnostic tests. The lower relative sensitivity compared to the reference method may be increased by lowering the optical density threshold.
PCR-Based Diagnosis of Prosthetic Joint Infection
Authors: Qu Xinhua , Zhai Zanjing , Li Huiwu , Li Haowei , Liu Xuqiang , Zhu Zhenan , Wang You , Liu Guangwang , Dai Kerong
Published: June 2013

We performed a meta-analysis to evaluate use of PCR assays for diagnosis of prosthetic joint infection (PJI). The pooled sensitivity and specificity were 0.86 (95% confidence interval [CI], 0.77 to 0.92) and 0.91 (CI, 0.81 to 0.96), respectively. Subgroup analyses showed that use of tissue samples may improve sensitivity, and quantitative PCR and sonication of prostheses fluid may improve specificity. The results showed that PCR is reliable and accurate for detection of PJI.
In Vitro
Activities of Isavuconazole and Comparator Antifungal Agents Tested against a Global Collection of Opportunistic Yeasts and Molds
Authors: Pfaller Michael A. , Messer Shawn A. , Rhomberg Paul R. , Jones Ronald N. , Castanheira Mariana
Published: June 2013

Isavuconazole is a new broad-spectrum triazole with a favorable pharmacokinetic and safety profile. We report the MIC distributions for isavuconazole and 111 isolates of
Candida
(42
Candida albicans
, 25
Candida glabrata
, 22
Candida parapsilosis
, 14
Candida tropicalis
, and 8
Candida krusei
isolates), as determined by Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution (BMD) methods. Also, the relative activities of isavuconazole, itraconazole, fluconazole, posaconazole, voriconazole, and the three echinocandins were assessed against a recent (2011) global collection of 1,358 isolates of
Candida
spp., 101 of
Aspergillus
spp., 54 of non-
Candida
yeasts, and 21 of non-
Aspergillus
molds using CLSI BMD methods. The overall essential agreement (EA) (±2 log
2
dilutions) between the CLSI and EUCAST methods was 99.1% (EA at ±1 log
2
dilution, 90.1% [range, 80.0 to 100.0%]). The activities of isavuconazole against the larger collection of
Candida
spp. and
Aspergillus
spp. were comparable to those of posaconazole and voriconazole; the MIC
90
values for isavuconazole, posaconazole, and voriconazole against
Candida
spp. were 0.5, 1, and 0.25 μg/ml and against
Aspergillus
spp. were 2, 1, and 1 μg/ml, respectively. Isavuconazole showed good activities against
Cryptococcus neoformans
(MIC
90
, 0.12 μg/ml) and other non-
Candida
yeasts (MIC
90
, 1 μg/ml) but was less potent against non-
Aspergillus
molds (MIC
90
, >8 μg/ml). Isavuconazole MIC values for three mucormycete isolates were 4, 1, and 2 μg/ml, whereas all three were inhibited by 1 μg/ml posaconazole. Isavuconazole demonstrates broad-spectrum activity against this global collection of opportunistic fungi, and the CLSI and EUCAST methods can be used to test this agent against
Candida
, with highly comparable results.
Role of Immediate Early Protein ICP27 in the Differential Sensitivity of Herpes Simplex Viruses 1 and 2 to Leptomycin B
Authors: Park Donglim , Lengyel Joy , Rice Stephen A.
Published: June 2013

Leptomycin B (LMB) is a highly specific inhibitor of CRM1, a cellular karyopherin-β that transports nuclear export signal-containing proteins from the nucleus to the cytoplasm. Previous work has shown that LMB blocks herpes simplex virus 1 (HSV-1) replication in Vero cells and that certain mutations in viral immediate early protein ICP27 can confer LMB resistance. However, little is known of the molecular mechanisms involved. Here we report that HSV-2, a close relative of HSV-1, is naturally resistant to LMB. To see whether the ICP27 gene determines this phenotypic difference, we generated an HSV-1 mutant that expresses the HSV-2 ICP27 instead of the HSV-1 protein. This recombinant was fully sensitive to LMB, indicating that one or more other viral genes must be important in determining HSV-2's LMB-resistant phenotype. In additional work, we report several findings that shed light on how HSV-1 ICP27 mutations can confer LMB resistance. First, we show that LMB treatment of HSV-1-infected cells leads to suppression of late viral protein synthesis and a block to progeny virion release. Second, we identify a novel type of ICP27 mutation that can confer LMB resistance, that being the addition of a 100-residue amino-terminal affinity purification tag. Third, by studying infections where both LMB-sensitive and LMB-resistant forms of ICP27 are present, we show that HSV-1's sensitivity to LMB is dominant to its resistance. Together, our results suggest a model in which the N-terminal portion of ICP27 mediates a nonessential activity that interferes with HSV-1 replication when CRM1 is inactive. We suggest that LMB resistance mutations weaken or abrogate this activity.
Role of Cell-Type-Specific Endoplasmic Reticulum-Associated Degradation in Polyomavirus Trafficking
Authors: Bennett Shauna M. , Jiang Mengxi , Imperiale Michael J.
Published: June 2013

BK polyomavirus (BKPyV) is a widespread human pathogen that establishes a lifelong persistent infection and can cause severe disease in immunosuppressed patients. BKPyV is a nonenveloped DNA virus that must traffic through the endoplasmic reticulum (ER) for productive infection to occur; however, it is unknown how BKPyV exits the ER before nuclear entry. In this study, we elucidated the role of the ER-associated degradation (ERAD) pathway during BKPyV intracellular trafficking in renal proximal tubule epithelial (RPTE) cells, a natural host cell. Using proteasome and ERAD inhibitors, we showed that ERAD is required for productive entry. Altered trafficking and accumulation of uncoated viral intermediates were detected by fluorescence
in situ
hybridization and indirect immunofluorescence in the presence of an inhibitor. Additionally, we detected a change in localization of partially uncoated virus within the ER during proteasome inhibition, from a BiP-rich area to a calnexin-rich subregion, indicating that BKPyV accumulated in an ER subcompartment. Furthermore, inhibiting ERAD did not prevent entry of capsid protein VP1 into the cytosol from the ER. By comparing the cytosolic entry of the related polyomavirus simian virus 40 (SV40), we found that dependence on the ERAD pathway for cytosolic entry varied between the polyomaviruses and between different cell types, namely, immortalized CV-1 cells and primary RPTE cells.
MicroRNA 181 Suppresses Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Infection by Targeting PRRSV Receptor CD163
Authors: Gao Li , Guo Xue-kun , Wang Lianghai , Zhang Qiong , Li Ning , Chen Xin-xin , Wang Yongqiang , Feng Wen-hai
Published: June 2013

We previously showed that microRNA 181 (miR-181) can inhibit PRRSV replication by directly targeting its genomic RNA. Here, we report that miR-181 can downregulate the PRRSV receptor CD163 in blood monocytes and porcine alveolar macrophages (PAMs) through targeting the 3′ untranslated region (UTR) of CD163 mRNA. Downregulation of CD163 leads to the inhibition of PRRSV entry into PAMs and subsequently suppresses PRRSV infection. Our findings indicate that delivery of miR-181 can be used as antiviral therapy against PRRSV infection.
Adenovirus E1A Oncogene Induces Rereplication of Cellular DNA and Alters DNA Replication Dynamics
Authors: Singhal Ghata , Leo Elisabetta , Setty Saayi Krushna Gadham , Pommier Yves , Thimmapaya Bayar
Published: June 2013

The oncogenic property of the adenovirus (Ad) transforming E1A protein is linked to its capacity to induce cellular DNA synthesis which occurs as a result of its interaction with several host proteins, including pRb and p300/CBP. While the proteins that contribute to the forced induction of cellular DNA synthesis have been intensively studied, the nature of the cellular DNA replication that is induced by E1A in quiescent cells is not well understood. Here we show that E1A expression in quiescent cells leads to massive cellular DNA rereplication in late S phase. Using a single-molecule DNA fiber assay, we studied the cellular DNA replication dynamics in E1A-expressing cells. Our studies show that the DNA replication pattern is dramatically altered in E1A-expressing cells, with increased replicon length, fork velocity, and interorigin distance. The interorigin distance increased by about 3-fold, suggesting that fewer DNA replication origins are used in E1A-expressing cells. These aberrant replication events led to replication stress, as evidenced by the activation of the DNA damage response. In earlier studies, we showed that E1A induces c-Myc as a result of E1A binding to p300. Using an antisense c-Myc to block c-Myc expression, our results indicate that induction of c-Myc in E1A-expressing cells contributes to the induction of host DNA replication. Together, our results suggest that the E1A oncogene-induced cellular DNA replication stress is due to dramatically altered cellular replication events and that E1A-induced c-Myc may contribute to these events.
Arginine-Rich Motifs Are Not Required for Hepatitis Delta Virus RNA Binding Activity of the Hepatitis Delta Antigen
Authors: Daigh Leighton H. , Griffin Brittany L. , Soroush Ali , Mamedov Murad R. , Casey John L.
Published: June 2013

Hepatitis delta virus (HDV) replication and packaging require interactions between the unbranched rodlike structure of HDV RNA and hepatitis delta antigen (HDAg), a basic, disordered, oligomeric protein. The tendency of the protein to bind nonspecifically to nucleic acids has impeded analysis of HDV RNA protein complexes and conclusive determination of the regions of HDAg involved in RNA binding. The most widely cited model suggests that RNA binding involves two proposed arginine-rich motifs (ARMs I and II) in the middle of HDAg. However, other studies have questioned the roles of the ARMs. Here, binding activity was analyzedin vitrousing HDAg-160, a C-terminal truncation that binds with high affinity and specificity to HDV RNA segmentsin vitro. Mutation of the core arginines of ARM I or ARM II in HDAg-160 did not diminish binding to HDV unbranched rodlike RNA. These same mutations did not abolish the ability of full-length HDAg to inhibit HDV RNA editing in cells, an activity that involves RNA binding. Moreover, only the N-terminal region of the protein, which does not contain the ARMs, was cross-linked to a bound HDV RNA segmentin vitro. These results indicate that the amino-terminal region of HDAg is in close contact with the RNA and that the proposed ARMs are not required for binding HDV RNA. Binding was not reduced by mutation of additional clusters of basic amino acids. This result is consistent with an RNA-protein complex that is formed via numerous contacts between the RNA and each HDAg monomer.
Integrated Analyses of Genome-Wide DNA Occupancy and Expression Profiling Identify Key Genes and Pathways Involved in Cellular Transformation by a Marek's Disease Virus Oncoprotein, Meq
Authors: Subramaniam Sugalesini , Johnston John , Preeyanon Likit , Brown C. Titus , Kung Hsing-Jien , Cheng Hans H.
Published: June 2013

Marek's disease (MD) is an economically significant disease in chickens that is caused by the highly oncogenic Marek's disease virus (MDV). A major unanswered question is the mechanism of MDV-induced tumor formation. Meq, a bZIP transcription factor discovered in the 1990s, is critically involved in viral oncogenicity, but only a few of its host target genes have been described, impeding our understanding of MDV-induced tumorigenesis. Using chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray analysis, a high-confidence list of Meq binding sites in the chicken genome and a global transcriptome of Meq-responsive genes were generated. Meq binding sites were found to be enriched in the promoter regions of upregulated genes but not in those of downregulated genes. ChIP-seq was also performed for c-Jun, a known heterodimeric partner of Meq. The close location of binding sites of Meq and c-Jun was noted, suggesting cooperativity between these two factors in modulating transcription. Pathway analysis indicated that Meq transcriptionally regulates many genes that are part of several signaling pathways including the extracellular signal-regulated kinase /mitogen-activated protein kinase (ERK/MAPK), Jak-STAT, and ErbB pathways, which are critical for oncogenesis and/or include signaling mediators involved in apoptosis. Meq activates oncogenic signaling cascades by transcriptionally activating major kinases in the ERK/MAPK pathway and simultaneously repressing phosphatases, as verified using inhibitors of MEK and ERK1/2 in a cell proliferation assay. This study provides significant insights into the mechanistic basis of Meq-dependent cell transformation.
Lack of Prophylactic Efficacy of Oral Maraviroc in Macaques despite High Drug Concentrations in Rectal Tissues
Authors: Massud Ivana , Aung Wutyi , Martin Amy , Bachman Shanon , Mitchell James , Aubert Rachael , Solomon Tsegaye Theodros , Kersh Ellen , Pau Chou-Pong , Heneine Walid , García-Lerma J. Gerardo
Published: June 2013

Maraviroc (MVC) is a potent CCR5 coreceptor antagonist that is in clinical testing for daily oral pre-exposure prophylaxis (PrEP) for HIV prevention. We used a macaque model consisting of weekly SHIV
162p3
exposures to evaluate the efficacy of oral MVC in preventing rectal SHIV transmission. MVC dosing was informed by the pharmacokinetic profile seen in blood and rectal tissues and consisted of a human-equivalent dose given 24 h before virus exposure, followed by a booster postexposure dose. In rectal secretions, MVC peaked at 24 h (10,242 ng/ml) with concentrations at 48 h that were about 40 times those required to block SHIV infection of peripheral blood mononuclear cells (PBMCs)
in vitro
. Median MVC concentrations in rectal tissues at 24 h (1,404 ng/g) were 30 and 10 times those achieved in vaginal or lymphoid tissues, respectively. MVC significantly reduced macrophage inflammatory protein 1β-induced CCR5 internalization in rectal mononuclear cells, an indication of efficient binding to CCR5 in rectal lymphocytes. The half-life of CCR5-bound MVC in PBMCs was 2.6 days. Despite this favorable profile, 5/6 treated macaques were infected during five rectal SHIV exposures as were 3/4 controls. MVC treatment was associated with a significant increase in the percentage of CD3
+
/CCR5
+
cells in blood. We show that high and durable MVC concentrations in rectal tissues are not sufficient to prevent SHIV infection in macaques. The increases in CD3
+
/CCR5
+
cells seen during MVC treatment point to unique immunological effects of CCR5 inhibition by MVC. The implications of these immunological effects on PrEP with MVC require further evaluation.
Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28
Authors: King Christine A.
Published: June 2013

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and the inflammation-driven neoplasm Kaposi's sarcoma (KS). A triad of processes, including abnormal proliferation of endothelial cells, aberrant angiogenesis, and chronic inflammation, characterize KS lesions. STAT3 is a key transcription factor governing these processes, and deregulation of STAT3 activity is linked to a wide range of cancers, including PEL and KS. Using primary human endothelial cells (ECs), I demonstrate that KSHV infection modulated STAT3 activation in two ways: (i) KSHV induced uncoupling of canonical tyrosine (Y) and serine (S) phosphorylation events while (ii) concomitantly inducing the phosphorylation and inactivation of TRIM28 (also known as KAP-1 or TIF-1β), a newly identified negative regulator of STAT3 activity. KSHV infection of primary ECs induced chronic STAT3 activation characterized by a shift from the canonical dual P-STAT3 Y705 S727 form to a mono P-STAT3 S727 form. Expression of the latent protein kaposin B promoted the unique phosphorylation of STAT3 at S727, in the absence of Y705, activated the host kinase mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), and stimulated increased expression of STAT3-dependent genes, includingCCL5, in ECs. TRIM28-mediated repression of STAT3 is relieved by phosphorylation of S473, andin vitrokinase assays identified TRIM28 S473 as a bona fide target of MK2. Together, these data suggest that kaposin B significantly contributes to the chronic inflammatory environment that is a hallmark of KS by unique activation of the proto-oncogeneSTAT3, coupled with MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28.
Susceptibility and Pathogenesis of Little Brown Bats (Myotis lucifugus) to Heterologous and Homologous Rabies Viruses
Authors: Davis April D. , Jarvis Jodie A. , Pouliott Craig E. , Morgan Shannon, M. D. , Rudd Robert J.
Published: June 2013

Rabies virus (RABV) maintenance in bats is not well understood. Big brown bats (
Eptesicus fuscus
), little brown bats (
Myotis lucifugus
), and Mexican free-tailed bats (
Tadarida brasiliensis
) are the most common bats species in the United States. These colonial bat species also have the most frequent contact with humans and domestic animals. However, the silver-haired bat (
Lasionycteris noctivagans
) RABV is associated with the majority of human rabies virus infections in the United States and Canada. This is of interest because silver-haired bats are more solitary bats with infrequent human interaction. Our goal was to determine the likelihood of a colonial bat species becoming infected with and transmitting a heterologous RABV. To ascertain the potential of heterologous RABV infection in colonial bat species, little brown bats were inoculated with a homologous RABV or one of two heterologous RABVs. Additionally, to determine if the route of exposure influenced the disease process, bats were inoculated either intramuscularly (i.m.) or subcutaneously (s.c.) with a homologous or heterologous RABV. Our results demonstrate that intramuscular inoculation results in a more rapid progression of disease onset, whereas the incubation time in bats inoculated s.c. is significantly longer. Additionally, cross protection was not consistently achieved in bats previously inoculated with a heterologous RABV following a challenge with a homologous RABV 6 months later. Finally, bats that developed rabies following s.c. inoculation were significantly more likely to shed virus in their saliva and demonstrated increased viral dissemination. In summary, bats inoculated via the s.c. route are more likely to shed virus, thus increasing the likelihood of transmission.
Absolute constipation caused by sigmoid volvulus in a young man
Authors: Nuevo Sergio Pozo , Macías Robles María Dolores , Sevillano Ramón Delgado , Pérez-Gallarza Susana Serrano
Published: June 2013

We describe a challenging case of sigmoid volvulus where a previously unrecognised anatomical condition, rather than the patient's age, was the main predisposing factor. A man in his thirties presented to the emergency department with a 3-day history of constipation and acute abdominal pain. Initial assessment and studies were inconclusive, but a CT scan revealed torsion of the large bowelSigmoid volvulus is a frequent cause of bowel obstruction that can be missed if appropriate imaging is not available. Clinical presentation and blood analysis can be similar to the findings in acute abdomen caused by other more common causes.
Management of a simple renal cyst in a complex patient
Authors: Khan Mohammad Qasim , Ponor Ileana Lucia , Ross Ashley E , Khaliq Waseem
Published: June 2013

Renal cysts are generally classified as simple or complex and are further characterised under the Bosniak classification system. Most simple cysts are benign, asymptomatic and discovered incidentally. However, over time, these simple cysts can enlarge, become symptomatic and develop complications, requiring intervention. We present a case of a 70-year-old man with multiple comorbidities who presented with left lower quadrant abdominal pain and haematuria. An abdominal CT scan revealed a large, 26 cm exophytic cyst with high attenuation areas, septations and haemorrhage. Given the patient's tenuous condition and poor functional status, an interventional radiology-guided renal cyst aspiration was performed, resulting in successful reduction of size and symptom resolution. A follow-up ultrasound at 6 months showed no evidence of recurrence. Primary care providers should be aware of the prevalence of renal cysts and their complications, especially haemorrhage, particularly in high risk and elderly patients on anticoagulation or antiplatelet therapy.