bluuebunny/crossref_metadata_2025 huggingface dataset:
The size distributions of nanoscale Fe‐Ni‐S droplets in Stardust melted grains from comet 81P/Wild 2
Authors: SANDERS Nathan E. , VELBEL Michael A.
Published: April 2012

Abstract– To constrain the effects of capture modification processes, the size distribution of nanoscale refractory Fe‐Ni‐S inclusions (“droplets”) was measured in five allocations extracted from throughout the depth of Stardust Track 35. The Fe/S ratio has been previously shown to increase significantly with penetration depth in this track, suggesting increasing capture‐related modification along the track. Astronomical image analysis tools were employed to measure the sizes of more than 8000 droplets from TEM images, and completeness simulations were used to correct the distribution for detection bias as a function of radius. The size distribution characteristics are found to be similar within independent regions of individual allocations, demonstrating uniformity within grains. The size distribution of the Fe‐Ni‐S droplets in each allocation is dominated by a mode near 11 nm, but is coarse‐skewed and leptokurtic with a mean of ∼17 nm and a standard deviation of ∼9 nm. The size distribution characteristics do not vary systematically with penetration depth, despite the strong trend in bulk Fe/S ratio. This suggests that the capture modification process is not primarily responsible for producing the morphology of these nanoscale droplets. The Stardust Track 35 droplet size distribution indicates slightly smaller sizes, but otherwise resembles those in carbonaceous chondrite Acfer 094, and chondritic porous interplanetary dust particles that escaped nebular annealing of sulfides. The size distribution of metal‐sulfide beads in Stardust’s quenched melted‐grain emulsions appears to be inherited from the size distribution of unmelted sulfide mineral grains in comet‐dust particles of chondritic character.
Experimental impact features in Stardust aerogel: How track morphology reflects particle structure, composition, and density
Authors: KEARSLEY Anton T. , BURCHELL Mark J. , PRICE Mark C. , COLE Michael J. , WOZNIAKIEWICZ Penelope J. , ISHII Hope A. , BRADLEY John P. , FRIES Marc , FOSTER Nicholas J.
Published: April 2012

Abstract– The Stardust collector shows diverse aerogel track shapes created by impacts of cometary dust. Tracks have been classified into three broad types (A, B, and C), based on relative dimensions of the elongate “stylus” (in Type A “carrots”) and broad “bulb” regions (Types B and C), with occurrence of smaller “styli” in Type B. From our experiments, using a diverse suite of projectile particles shot under Stardust cometary encounter conditions onto similar aerogel targets, we describe differences in impactor behavior and aerogel response resulting in the observed range of Stardust track shapes. We compare tracks made by mineral grains, natural and artificial aggregates of differing subgrain sizes, and diverse organic materials. Impacts of glasses and robust mineral grains generate elongate, narrow Type A tracks (as expected), but with differing levels of abrasion and lateral branch creation. Aggregate particles, both natural and artificial, of a wide range of compositions and volatile contents produce diverse Type B or C shapes. Creation of bulbous tracks is dependent upon impactor internal structure, grain size distribution, and strength, rather than overall grain density or content of volatile components. Nevertheless, pure organic particles do create Type C, or squat Type A* tracks, with length to width ratios dependent upon both specific organic composition and impactor grain size. From comparison with the published shape data for Stardust aerogel tracks, we conclude that the abundant larger Type B tracks on the Stardust collector represent impacts by particles similar to our carbonaceous chondrite meteorite powders.
Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems
Authors: Phillips Daniel J , Pygall Samuel R , Cooper V Brett , Mann James C
Published: April 2012

Objectives

The conventional dissolution test, particularly the USP apparatus I and II, remains an important tool in the armory of the pharmaceutical development scientist. For realistic dissolution characterization, sink conditions, where saturation solubility of a drug in the dissolution medium is at least three times more than the drug concentration, are critical. These conditions can be problematic to maintain with formulations containing poorly-soluble actives. This review summarizes the role of the dissolution test in the pharmaceutical industry, together with some traditional techniques/additives used to enhance solubility and facilitate the achievement of sink conditions. The biphasic dissolution system, an innovative model for the treatment of poorly-soluble species, will also be discussed.

Key findings

The biphasic dissolution model utilizes media comprising immiscible aqueous and organic layers whereby the drug, following initial aqueous dissolution, partitions into the organic layer. This step, which acts to remove all dissolved species from the aqueous layer, enables further aqueous dissolution to occur and hence the dissolution–partition cycle continues. Crucially, the aqueous layer does not saturate allowing sink conditions to be maintained and hence the experiment will, in theory, yield complete dissolution.

This review highlights important concepts regarding solubility/sink limitation and intends to provoke debate among analytical and formulation scientists as to the potential advantages, long-term development and widespread implementation of a biphasic dissolution system in drug development.
An Application of Dimensional Analysis to Entropy-Wear Relationship
Authors: Amiri M. , Khonsari M. M. , Brahmeshwarkar S.
Published: April 2012

The Buckingham’s dimensional analysis is applied to dry sliding contact to determine a relationship between wear and entropy flow. The obtained nondimensional groups are correlated using experimental results pertaining to wear tests of a sliding contact in a disk-on-disk configuration for two sets of contacting materials, namely, bronze SAE 40 on steel 4140 and cartridge brass on steel 4140. The results of analysis are employed to calculate the Archard’s wear coefficient K. The obtained wear coefficient is compared with the available data in literature.
Numerical Investigation of Forced Convective Heat Transfer Around and Through a Porous Circular Cylinder With Internal Heat Generation
Authors: Sadegh Valipour Mohammad , Zare Ghadi Ariyan
Published: April 2012

In this study, convective heat transfer around and through a porous circular cylinder together with internal heat generation has been investigated numerically. Governing equations containing continuity, momentum, and energy equations have been developed in polar coordinate system in both porous and nonporous media based on single-domain approach. However, governing equations in porous medium are derived using intrinsic volume averaging method. The equations are solved numerically based on finite volume method over staggered grid arrangement. Also, pressure correction-based iterative algorithm, SIMPLE, is applied for solving the pressure linked equations. Reynolds and Peclet numbers (based on cylinder diameter and velocity of free stream) are from 1 to 40. Also, Darcy number (Da) varies within the range of 10-6≤Da≤10-2 and porosity is considered 0.9 for all calculations. The influence of Da and Re numbers on local and average Nu numbers has been investigated. It is found that the local and average Nu numbers increase with any increase in Da number. Two correlations of average Nu number are presented for high and low Da numbers.
Investigation of Two-Dimensional Unsteady Stagnation-Point Flow and Heat Transfer Impinging on an Accelerated Flat Plate
Authors: Shokrgozar Abbassi Ali , Baradaran Rahimi Asghar
Published: April 2012

General formulation and solution of Navier–Stokes and energy equations are sought in the study of two-dimensional unsteady stagnation-point flow and heat transfer impinging on a flat plate when the plate is moving with variable velocity and acceleration toward main stream or away from it. As an application, among others, this accelerated plate can be assumed as a solidification front which is being formed with variable velocity. An external fluid, along z-direction, with strain rate a impinges on this flat plate and produces an unsteady two-dimensional flow in which the plate moves along z-direction with variable velocity and acceleration in general. A reduction of Navier–Stokes and energy equations is obtained by use of appropriate similarity transformations. Velocity and pressure profiles, boundary layer thickness, and surface stress-tensors along with temperature profiles are presented for different examples of impinging fluid strain rate, selected values of plate velocity, and Prandtl number parameter.
Comparison of Ultrasonic Wave Radiation Effects on Asphaltene Aggregation in Toluene–Pentane Mixture Between Heavy and Extra Heavy Crude Oils
Authors: Mousavi S. M. R. , Najafi I. , Ghazanfari M. H. , Amani M.
Published: April 2012

In this study, it is aimed to compare the efficiency of ultrasonic wave technology on asphaltene flocculation inhibition of crude oils with different American Petroleum Institute (API) gravities. A set of confocal microscopy test is performed and a series of statistical analysis is done. According to the results of this study, there is an optimum radiation time for both crudes at which the viscosity and the flocculation rate of asphaltenic crude oils reduces to its minimum. This optimum appears at later times of radiation for extra heavy oil. Also, it is shown that the rate of changes in the properties measured in this study is sharper for extra heavy crude oil. It could be concluded that the alternations caused by this technology is more significant for Kouh-e-Mond, which is heavier oil than Sarvak crude oil. Derjaguin–Ladau–Verwey–Overbeek (DLVO) kinetic model was also studied and it was understood that this model cannot be a validate model for radiated samples.
The Effect of Inhomogeneous Compression on Water Transport in the Cathode of a Proton Exchange Membrane Fuel Cell
Authors: Olesen Anders C. , Berning Torsten , Kær Søren K.
Published: April 2012

A three-dimensional, multicomponent, two-fluid model developed in the commercial CFD package CFX 13 (ANSYS Inc.) is used to investigate the effect of porous media compression on water transport in a proton exchange membrane fuel cell (PEMFC). The PEMFC model only consist of the cathode channel, gas diffusion layer, microporous layer, and catalyst layer, excluding the membrane and anode. In the porous media liquid water transport is described by the capillary pressure gradient, momentum loss via the Darcy-Forchheimer equation, and mass transfer between phases by a nonequilibrium phase change model. Furthermore, the presence of irreducible liquid water is taken into account. In order to account for compression, porous media morphology variations are specified based on the gas diffusion layer (GDL) through-plane strain and intrusion which are stated as a function of compression. These morphology variations affect gas and liquid water transport, and hence liquid water distribution and the risk of blocking active sites. Hence, water transport is studied under GDL compression in order to investigate the qualitative effects. Two simulation cases are compared; one with and one without compression.
Development of Direct Methanol Fuel Cell Systems for Material Handling Applications
Authors: Mergel J. , Janßen H. , Müller M. , Wilhelm J. , Stolten D.
Published: April 2012

Direct methanol fuel cells (DMFCs) are attractive for various applications, above all, however, as replacements for batteries or accumulators. They may be used in different power classes. A market analysis indicated that the use of a DMFC energy system in the kW class had the best chance of commercial realization if applied in forklift trucks for material handling in large distribution centers or warehouses. An advantage of such energy systems is that there is no need for the relatively time-consuming recharging of the lead-acid batteries, nor is it necessary to have spare batteries available for multishift operation. This calls for DMFC energy systems that are capable of replacing the existing Pb accumulators in terms of space requirements and energy. However, this requires considerable improvements to be made in terms of power and stability over time of DMFC systems and, in comparison to their present status, an increase of overall efficiency. Recent cost analyses for the overall system; for example, show that for the DMFC stack, a durability of at least 5000 h must be achieved with an overall efficiency for the DMFC system of at least 30%, with the constraint that the system can be operated in a water-autonomous manner up to an ambient temperature of 35 °C. As part of a joint R&D project with industrial partners, two systems were constructed and each subjected to long-term testing for 3000 and more than 8000 h, respectively, with realistic load profiles from driving cycles. In this test, the stack from the first system, DMFC V 3.3–1, displayed an aging rate of approximately 52 μV h−1 at a current density of 100 mA cm−2. This corresponds to a performance degradation of 25% over a period of 3,000 h. The DMFC V 3.3–2 system, a modified and optimized version of the first system, also underwent long-term testing. In this case, the aging rate of the stack was only approximately 9 μV h−1 at a current density of 100 mA cm−2. The system has thus been operated to date for more than 8000 h under realistic load profiles.
An Instrumented Bioreactor for Mechanical Stimulation and Real-Time, Nondestructive Evaluation of Engineered Cartilage Tissue
Authors: Popp Jenni R. , Roberts Justine J. , Gallagher Doug V. , Anseth Kristi S. , Bryant Stephanie J. , Quinn Timothy P.
Published: April 2012

Mechanical stimulation is essential for chondrocyte metabolism and cartilage matrix deposition. Traditional methods for evaluating developing tissue in vitro are destructive, time consuming, and expensive. Nondestructive evaluation of engineered tissue is promising for the development of replacement tissues. Here we present a novel instrumented bioreactor for dynamic mechanical stimulation and nondestructive evaluation of tissue mechanical properties and extracellular matrix (ECM) content. The bioreactor is instrumented with a video microscope and load cells in each well to measure tissue stiffness and an ultrasonic transducer for evaluating ECM content. Chondrocyte-laden hydrogel constructs were placed in the bioreactor and subjected to dynamic intermittent compression at 1 Hz and 10% strain for 1 h, twice per day for 7 days. Compressive modulus of the constructs, measured online in the bioreactor and offline on a mechanical testing machine, did not significantly change over time. Deposition of sulfated glycosaminoglycan (sGAG) increased significantly after 7 days, independent of loading. Furthermore, the relative reflection amplitude of the loaded constructs decreased significantly after 7 days, consistent with an increase in sGAG content. This preliminary work with our novel bioreactor demonstrates its capabilities for dynamic culture and nondestructive evaluation.
Effect of reactor pressure on the electrical and structural properties of InN epilayers grown by high-pressure chemical vapor deposition
Authors: Indika Senevirathna M. K. , Gamage Sampath , Atalay Ramazan , Acharya Ananta R. , Unil Perera A. G. , Dietz Nikolaus , Buegler Max , Hoffmann Axel , Su Liqin , Melton Andrew , Ferguson Ian
Published: April 2012

The influence of super-atmospheric reactor pressures (2.5–18.5 bar) on the electrical and structural properties of InN epilayers deposited on GaN/sapphire (0001) templates by high-pressure chemical vapor deposition has been studied. The epilayers were analyzed by Raman, x-ray diffraction (XRD), and Fourier transform infrared reflectance spectrometry to determine the structural properties as well as the phonon frequencies, dielectric function, plasma frequency, layer thickness and damping parameters of the epilayers. For the studied process parameter space, best material properties were achieved at a reactor pressure of 12.5 bar and a group-V/III ratio of 2500 with a free carrier concentration of 1.5 × 1018 cm−3, a mobility of the bulk InN layer of 270 cm2 V−1  s−1, and a Raman (E2 high) FWHM value of 10.3 cm−1. This study shows that the crystalline layer properties—probed by XRD 2θ–ω scans—improve with increasing reactor pressure.
Scanning transmission electron microscope analysis of amorphous-Si insertion layers prepared by catalytic chemical vapor deposition, causing low surface recombination velocities on crystalline silicon wafers
Authors: Higashimine Koichi , Koyama Koichi , Ohdaira Keisuke , Matsumura Hideki , Otsuka N.
Published: April 2012

Microstructures of stacked silicon-nitride/amorphous-silicon/crystalline-silicon (SiNx/a-Si/c-Si) layers prepared by catalytic chemical vapor deposition were investigated with scanning transmission electron microscopy to clarify the origin of the sensitive dependence of surface recombination velocities (SRVs) of the stacked structure on the thickness of the a-Si layer. Stacked structures with a-Si layers with thicknesses greater than 10 nm exhibit long effective carrier lifetimes, while those with thin a-Si layers have very short effective carrier lifetimes. A remarkably close correlation was found between the dependence of interface structures on the thicknesses of a-Si layers and the SRVs. In samples with a-Si layers less than 10 nm thick, significant damage occurred in c-Si wafers close to the interfaces, while those near a-Si layers larger than 10 nm remained nearly defect-free during observations over long periods. The observation of stacked structures without an SiNx layer, along with energy dispersive spectroscopy and secondary ion mass spectroscopy analyses of nitrogen atom distributions, suggest that the preferential damage in c-Si wafers with thin a-Si layers is caused by nitrogen atoms in the interface regions of c-Si wafers that diffuse during the growth of SiNx layers.
Investigating the effects of proton exchange membrane fuel cell conditions on carbon supported platinum electrocatalyst composition and performance
Authors: Patel Anant , Artyushkova Kateryna , Atanassov Plamen , Colbow Vesna , Dutta Monica , Harvey David , Wessel Silvia
Published: April 2012

Changes that carbon-supported platinum electrocatalysts undergo in a proton exchange membrane fuel cell environment were simulated by ex situ heat treatment of catalyst powder samples at 150 °C and 100% relative humidity. In order to study modifications that are introduced to chemistry, morphology, and performance of electrocatalysts, XPS, HREELS and three-electrode rotating disk electrode experiments were performed. Before heat treatment, graphitic content varied by 20% among samples with different types of carbon supports, with distinct differences between bulk and surface compositions within each sample. Following the aging protocol, the bulk and surface chemistry of the samples were similar, with graphite content increasing or remaining constant and Pt-carbide decreasing for all samples. From the correlation of changes in chemical composition and losses in performance of the electrocatalysts, we conclude that relative distribution of Pt particles on graphitic and amorphous carbon is as important for electrocatalytic activity as the absolute amount of graphitic carbon present.
Amorphous and nanocrystalline silicon thin film photovoltaic technology on flexible substrates
Authors: Yan Baojie , Yang Jeffrey , Guha Subhendu
Published: April 2012

This paper reviews our thin film silicon-based photovoltaic (PV) technology, including material and device studies as well as roll-to-roll manufacturing on a flexible substrate. Our current thin film silicon PV products are made with hydrogenated amorphous silicon (a-Si:H) and amorphous silicon germanium (a-SiGe:H) alloys. The advantages of a-Si:H-based technology are low cost, capability of large scale manufacturing, abundance of raw materials, and no environmental concerns. One disadvantage of a-Si:H PV technology is lower energy conversion efficiency than solar panels made of crystalline and polycrystalline silicon and compound crystal thin film semiconductors. Significant efforts have been made to improve efficiency. First, a-Si:H and a-SiGe:H material quality has been improved by optimizing deposition conditions, especially using high hydrogen dilution to deposit the amorphous materials close to the amorphous/nanocrystalline transition. Second, cell efficiency has been improved by engineering the device structure, such as bandgap profiling. In order to use the solar spectrum effectively, multijunction structures that incorporate a-SiGe:H in the middle and bottom cells have been used. The authors achieved record high solar cell efficiency with an a-Si:H/a-SiGe:H/a-SiGe:H triple-junction structure. Using the same structure, we fabricated solar laminates on flexible stainless steel coils with roll-to-roll production systems. Our current product has a stable aperture area efficiency of 8.2%. In recent years, hydrogenated nanocrystalline silicon (nc-Si:H) has emerged as a potential replacement for the a-SiGe:H bottom cell in multijunction structures. The authors have conducted a great deal of research and development of a-Si:H- and nc-Si:H-based multijunction PV technology. The authors have significantly improved the efficiency of a-Si:H and nc-Si:H multijunction solar cells and modules by optimizing the nc-Si:H material quality and device structure. The authors achieved an initial active-area (∼0.25 cm2) solar cell efficiency of 16.3% using an a-Si:H/a-SiGe:H/nc-Si:H triple-junction structure and an initial aperture-area module (∼400 cm2) efficiency of 12.0% and a stable aperture-area module (∼800 cm2) efficiency of 11.3% using an a-Si:H/nc-Si:H/nc-Si:H triple-junction structure. The authors expect to launch a new a-Si:H/nc-Si:H/nc-Si:H triple-junction product in near future with much higher efficiency than the current product.
Response to Comment on “Universality in the Evolution of Orientation Columns in the Visual Cortex“
Authors: Keil Wolfgang , Kaschube Matthias , Schnabel Michael , Kisvarday Zoltan F. , Löwel Siegrid , Coppola David M. , White Leonard E. , Wolf Fred
Published: April 2012

Meng
et al
. conjecture that pinwheel density scales with body and brain size. Our data, spanning a 40-fold range of body sizes in Laurasiatheria and Euarchonta, do not support this conclusion. The noncolumnar layout in Glires also appears size-insensitive. Thus, body and brain size may be understood as a constraint on the evolution of visual cortical circuitry, but not as a determining factor.
Analytic Thinking Promotes Religious Disbelief
Authors: Gervais Will M. , Norenzayan Ara
Published: April 2012

Overthinking Religion?

Many theories of human cognition make a distinction between System I, which tends to be rapid and to rely on heuristics or rules of thumb, and System II, which tends to be more deliberative and analytic. This dual-process framework, within which both processes may operate simultaneously and competitively, has been used to explain a variety of situational influences upon decision-making.
Gervais and Norenzayan
(p. 493) studied the application of a dual-process framework to religious disbelief and found that triggering analytic thinking processes through a variety of experimental manipulations resulted in a tendency for subjects to report lower levels of religious belief.
Monitoring EU Emerging Infectious Disease Risk Due to Climate Change
Authors: Lindgren Elisabet , Andersson Yvonne , Suk Jonathan E. , Sudre Bertrand , Semenza Jan C.
Published: April 2012

Climate change, globalization, and other drivers have made Europe a “hot spot” for emerging infectious diseases, which calls for changes in monitoring systems.
The Inhibitory Receptor PD-1 Regulates IgA Selection and Bacterial Composition in the Gut
Authors: Kawamoto Shimpei , Tran Thinh H. , Maruya Mikako , Suzuki Keiichiro , Doi Yasuko , Tsutsui Yumi , Kato Lucia M. , Fagarasan Sidonia
Published: April 2012

Gut Reaction

The gut needs to keep its trillions of microbial inhabitants contained. The immune system has evolved a multifaceted approach to this problem, which includes the production of large quantities of immunoglobulin A (IgA) in the intestinal mucosa. In a process that is not well understood, plasma cells that produce IgA specific for the gut microflora are selected in Peyer's patches in the gut.

Kawamoto
et al.

(p. 485) used genetically manipulated mice to show that the inhibitory co-receptor, programmed cell death-1 (PD-1), is required for the proper selection IgA-secreting cells in the gut. The effect of PD-1 deletion, however, was not intrinsic to the B cells that produce IgA. Instead, the absence of PD-1 affected the differentiation of T follicular helper cells, which provide important signals to B cells that help guide them as they develop the capacity to produce microflora-specific IgA. Mice deficient in PD-1 exhibited alterations in the composition in their microflora, which suggests that defective selection of IgA can perturb the careful balance that exists between the immune system and resident bacteria.
Coils and Polygonal Crust in the Athabasca Valles Region, Mars, as Evidence for a Volcanic History
Authors: Ryan Andrew J. , Christensen Philip R.
Published: April 2012

A Volcanic Valley on Mars

The formation of the Athabasca Valles, a valley network near the equator of Mars, has been debated for over a decade; both lava and water ice have been implicated. Some studies have attributed the polygonally patterned ground in this region to frost wedging in an ice-rich soil. Using images of the Athabasca region from the High Resolution Imaging Science Experiment onboard Mars Reconnaissance Orbiter,
Ryan and Christensen
(p. 449) detected numerous spirals on polygonally patterned ground. The spiral shapes are consistent with those of lava coils that form on the surface of Hawaiian lava flows, and cannot be explained by ice-related activities.
Using Cell-to-Cell Variability—A New Era in Molecular Biology
Authors: Pelkmans Lucas
Published: April 2012

Studying the phenotypic differences between genetically identical cells rather than their general features can reveal novel regulatory mechanisms for diverse cellular processes.
Europe's Embarrassing Problem
Authors: Kupferschmidt Kai
Published: April 2012

Measles, an easily preventable disease, has made a comeback in one of the richest parts of the world. Public health experts are unsure how to fight back.
Sequence in the Influenza A Virus Nucleoprotein Required for Viral Polymerase Binding and RNA Synthesis
Authors: Marklund Jesper K. , Ye Qiaozhen , Dong Jinhui , Tao Yizhi Jane , Krug Robert M.
Published: April 2012

Many proposed mechanisms for influenza A viral RNA synthesis include an interaction of the nucleoprotein (NP) with the viral polymerase. To identify an NP sequence required for this interaction, we used the cryoelectron microscopic structure of an influenza virus miniribonucleoprotein as a guide for choosing promising surface-exposed sequences. We show that three amino acids (R204, W207, and R208) located in a loop at the top of the head domain of NP are required for functional interaction with the viral polymerase. Quantitative reverse transcription-PCR (RT-PCR) measurements of RNAs synthesized in minigenome assays established that each of these NP amino acids is required for viral RNA synthesis. The mutation of these three amino acids does not affect nuclear localization or RNA-binding and oligomerization activities of NP.
In vitro
binding experiments with purified virus polymerase and NPs established that these three amino acids are required for NP binding to the viral polymerase.
Comparable Polyfunctionality of Ectromelia Virus- and Vaccinia Virus-Specific Murine T Cells despite Markedly DifferentIn VivoReplication and Pathogenicity
Authors: Hersperger Adam R. , Siciliano Nicholas A. , Eisenlohr Laurence C.
Published: April 2012

Vaccinia virus (VACV) stimulates long-term immunity against highly pathogenic orthopoxvirus infection of humans (smallpox) and mice (mousepox [ectromelia virus {ECTV}]) despite the lack of a natural host-pathogen relationship with either of these species. Previous research revealed that VACV is able to induce polyfunctional CD8+T-cell responses after immunization of humans. However, the degree to which the functional profile of T cells induced by VACV is similar to that generated during natural poxvirus infection remains unknown. In this study, we monitored virus-specific T-cell responses following the dermal infection of C57BL/6 mice with ECTV or VACV. Using polychromatic flow cytometry, we measured levels of degranulation, cytokine expression (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]), and the cytolytic mediator granzyme B. We observed that the functional capacities of T cells induced by VACV and ECTV were of a similar quality in spite of the markedly different replication abilities and pathogenic outcomes of these viruses. In general, a significant fraction (≥50%) of all T-cell responses were positive for at least three functions both during acute infection and into the memory phase.In vivokilling assays revealed that CD8+T cells specific for both viruses were equally cytolytic (∼80% target cell lysis after 4 h), consistent with the similar levels of granzyme B and degranulation detected among these cells. Collectively, these data provide a mechanism to explain the ability of VACV to induce protective T-cell responses against pathogenic poxviruses in their natural hosts and provide further support for the use of VACV as a vaccine platform able to induce polyfunctional T cells.
Envelope Variable Region 4 Is the First Target of Neutralizing Antibodies in Early Simian Immunodeficiency Virus mac251 Infection of Rhesus Monkeys
Authors: Yeh Wendy W. , Brassard Laura M. , Miller Caroline A. , Basavapathruni Aravind , Zhang Jinrong , Rao Srinivas S. , Nabel Gary J. , Mascola John R. , Letvin Norman L. , Seaman Michael S.
Published: April 2012

A major goal of AIDS vaccine development is to design vaccination strategies that can elicit broad and potent protective antibodies. The initial viral targets of neutralizing antibodies (NAbs) early after human or simian immunodeficiency virus (HIV/SIV) infection are not known. The identification of early NAb epitopes that induce protective immunity or retard the progression of disease is important for AIDS vaccine development. The aim of this study was to determine the Env residues targeted by early SIV NAbs and to assess the influence of prior vaccination on neutralizing antibody kinetics and specificity during early infection. We previously described stereotypic
env
sequence variations in SIVmac251-infected rhesus monkeys that resulted in viral escape from NAbs. Here, we defined the early viral targets of neutralization and determined whether the ability of serum antibody from infected monkeys to neutralize SIV was altered in the setting of prior vaccination. To localize the viral determinants recognized by early NAbs, a panel of mutant pseudoviruses was assessed in a TZM-bl reporter gene neutralization assay to define the precise changes that eliminate recognition by SIV Env-specific NAbs in 16 rhesus monkeys. Changing R420 to G or R424 to Q in V4 of Env resulted in the loss of recognition by NAbs in vaccinated monkeys. In contrast, mutations in the V1 region of Env did not alter the NAb profile. These findings indicate that early NAbs are directed toward SIVmac251 Env V4 but not the V1 region, and that this
env
vaccination regimen did not alter the kinetics or the breadth of NAbs during early infection.
Reovirus Variants with Mutations in Genome Segments S1 and L2 Exhibit Enhanced Virion Infectivity and Superior Oncolysis
Authors: Shmulevitz Maya , Gujar Shashi A. , Ahn Dae-Gyun , Mohamed Adil , Lee Patrick W. K.
Published: April 2012

Reovirus preferentially replicates in transformed cells and is being explored as a cancer therapy. Immunological and physical barriers to virotherapy inspired a quest for reovirus variants with enhanced oncolytic potency. Using a classical genetics approach, we isolated two reovirus variants (T3v1 and T3v2) with superior replication relative to wild-type reovirus serotype 3 Dearing (T3wt) on various human and mouse tumorigenic cell lines. Unique mutations in reovirus λ2 vertex protein and σ1 cell attachment protein were associated with the large plaque-forming phenotype of T3v1 and T3v2, respectively. Both T3v1 and T3v2 exhibited higher infectivity (i.e., a higher PFU-to-particle ratio) than T3wt. A detailed analysis of virus replication revealed that virus cell binding and uncoating were equivalent for variant and wild-type reoviruses. However, T3v1 and T3v2 were significantly more efficient than T3wt in initiating productive infection. Thus, when cells were infected with equivalent input virus particles, T3v1 and T3v2 produced significantly higher levels of early viral RNAs relative to T3wt. Subsequent steps of virus replication (viral RNA and protein synthesis, virus assembly, and cell death) were equivalent for all three viruses. In a syngeneic mouse model of melanoma, both T3v1 and T3v2 prolonged mouse survival compared to wild-type reovirus. Our studies reveal that oncolytic potency of reovirus can be improved through distinct mutations that increase the infectivity of reovirus particles.
Antibodies against the gH/gL/UL128/UL130/UL131 Complex Comprise the Majority of the Anti-Cytomegalovirus (Anti-CMV) Neutralizing Antibody Response in CMV Hyperimmune Globulin
Authors: Fouts Ashley E. , Chan Pamela , Stephan Jean-Philippe , Vandlen Richard , Feierbach Becket
Published: April 2012

Anti-cytomegalovirus (anti-CMV) hyperimmune globulin (HIG) has demonstrated efficacy in preventing CMV disease in solid-organ transplant patients as well as congenital disease when administered to pregnant women. To identify the neutralizing component of cytomegalovirus hyperimmune globulin (CMV-HIG), we performed serial depletions of CMV-HIG on cell-surface-expressed CMV antigens as well as purified antigens. Using this approach, we demonstrate that the major neutralizing antibody response is directed at the gH/gL/UL128/UL130/UL131 complex, suggesting little role for anti-gB antibodies in CMV-HIG neutralization.
RNA Structural Elements Determine Frequency and Sites of Nonhomologous Recombination in an Animal Plus-Strand RNA Virus
Authors: Austermann-Busch Sophia , Becher Paul
Published: April 2012

For highly variable RNA viruses, RNA recombination significantly contributes to genetic variations which may lead to changes of virulence, adaptation to new hosts, escape from the host immune response, and emergence of new infectious agents. Using a system based on transfection of cells with synthetic nonreplicable subgenomic transcripts derived from bovine viral diarrhea virus (family
Flaviviridae
), the existence of a replication-independent mechanism of RNA recombination, in addition to the commonly accepted replicative copy-choice recombination, has been previously proven (A. Gallei et al., J. Virol. 78:6271–6281, 2004). To identify RNA signals involved in efficient joining of RNA molecules, RNA recombination in living cells was targeted to the 3′ nontranslated region. Molecular characterization of 40 independently emerged recombinant viruses revealed that the majority of recombination sites are located in single-stranded regions of the RNA molecules. Furthermore, the results of this study showed that the frequency of RNA recombination directly correlated with the RNA amounts of both recombination partners. The frequency can be strongly increased by modification of the 5′ triphosphates and 3′ hydroxyls of the recombining RNA molecules to 5′ hydroxyl and 3′ monophosphoryl ends, respectively. Analysis of recombinants that emerged after transfection with such modified RNA molecules revealed a complete integration and efficient end-to-end joining of the recombination partner(s) in at least 80% of recombinants, while unmodified RNA molecules recombined exclusively at internal positions. These results are in line with the hypothesis that endoribonucleolytic cleavage and a subsequent ligation reaction can cause RNA recombination.
Pathogenic Old World Arenaviruses Inhibit TLR2/Mal-Dependent Proinflammatory Cytokines
In Vitro
Authors: Hayes Melissa W. , Carrion Ricardo , Nunneley Jerritt , Medvedev Andrei E. , Salvato Maria S. , Lukashevich Igor S.
Published: April 2012

Lymphocytic choriomeningitis virus (LCMV), the prototype arenavirus, and Lassa virus (LASV), the causative agent of Lassa fever (LF), have extensive strain diversity and significant variations in pathogenicity for humans and experimental animals. The WE strain of LCMV (LCMV-WE), but not the Armstrong (Arm) strain, induces a fatal LF-like disease in rhesus macaques. We also demonstrated that LASV infection of human macrophages and endothelial cells resulted in reduced levels of proinflammatory cytokines. Here we have shown that cells infected with LASV or with LCMV-WE suppressed Toll-like receptor 2 (TLR2)-dependent proinflammatory cytokine responses. The persisting isolate LCMV clone 13 (CL13) also failed to stimulate interleukin-6 (IL-6) in macrophages. In contrast, nonpathogenic Mopeia virus, which is a genetic relative of LASV and LCMV-Arm induced robust responses that were TLR2/Mal dependent, required virus replication, and were enhanced by CD14. Superinfection experiments demonstrated that the WE strain of LCMV inhibited the Arm-mediated IL-8 response during the early stage of infection. In cells transfected with the NF-κB–luciferase reporter, infection with LCMV-Arm resulted in the induction of NF-κB, but cells infected with LCMV-WE and CL13 did not. These results suggest that pathogenic arenaviruses suppress NF-κB-mediated proinflammatory cytokine responses in infected cells.
HIV-1 Infection
Ex Vivo
Accelerates Measles Virus Infection by Upregulating Signaling Lymphocytic Activation Molecule (SLAM) in CD4
+
T Cells
Authors: Mitsuki Yu-ya , Terahara Kazutaka , Shibusawa Kentaro , Yamamoto Takuya , Tsuchiya Takatsugu , Mizukoshi Fuminori , Ishige Masayuki , Okada Seiji , Kobayashi Kazuo , Morikawa Yuko , Nakayama Tetsuo , Takeda Makoto , Yanagi Yusuke , Tsunetsugu-Yokota Yasuko
Published: April 2012

Measles virus (MV) infection in children harboring human immunodeficiency virus type 1 (HIV-1) is often fatal, even in the presence of neutralizing antibodies; however, the underlying mechanisms are unclear. Therefore, the aim of the present study was to examine the interaction between HIV-1 and wild-type MV (MVwt) or an MV vaccine strain (MVvac) during dual infection. The results showed that the frequencies of MVwt- and MVvac-infected CD4
+
T cells within the resting peripheral blood mononuclear cells (PBMCs) were increased 3- to 4-fold after HIV-1 infection, and this was associated with a marked upregulation of signaling lymphocytic activation molecule (SLAM) expression on CD4
+
T cells but not on CD8
+
T cells. SLAM upregulation was induced by infection with a replication-competent HIV-1 isolate comprising both the X4 and R5 types and to a lesser extent by a pseudotyped HIV-1 infection. Notably, SLAM upregulation was observed in HIV-infected as well as -uninfected CD4
+
T cells and was abrogated by the removal of HLA-DR
+
cells from the PBMC culture. Furthermore, SLAM upregulation did not occur in uninfected PBMCs cultured together with HIV-infected PBMCs in compartments separated by a permeable membrane, indicating that no soluble factors were involved. Rather, CD4
+
T cell activation mediated through direct contact with dendritic cells via leukocyte function-associated molecule 1 (LFA-1)/intercellular adhesion molecule 1 (ICAM-1) and LFA-3/CD2 was critical. Thus, HIV-1 infection induces a high level of SLAM expression on CD4
+
T cells, which may enhance their susceptibility to MV and exacerbate measles in coinfected individuals.
Inhibition of Interferon Regulatory Factor 3 Activation by Paramyxovirus V Protein
Authors: Irie Takashi , Kiyotani Katsuhiro , Igarashi Tomoki , Yoshida Asuka , Sakaguchi Takemasa
Published: April 2012

The V protein of Sendai virus (SeV) suppresses innate immunity, resulting in enhancement of viral growth in mouse lungs and viral pathogenicity. The innate immunity restricted by the V protein is induced through activation of interferon regulatory factor 3 (IRF3). The V protein has been shown to interact with melanoma differentiation-associated gene 5 (MDA5) and to inhibit beta interferon production. In the present study, we infected MDA5-knockout mice with V-deficient SeV and found that MDA5 was largely unrelated to the innate immunity that the V protein suppresses
in vivo
. We therefore investigated the target of the SeV V protein. We previously reported interaction of the V protein with IRF3. Here we extended the observation and showed that the V protein appeared to inhibit translocation of IRF3 into the nucleus. We also found that the V protein inhibited IRF3 activation when induced by a constitutive active form of IRF3. The V proteins of measles virus and Newcastle disease virus inhibited IRF3 transcriptional activation, as did the V protein of SeV, while the V proteins of mumps virus and Nipah virus did not, and inhibition by these proteins correlated with interaction of each V protein with IRF3. These results indicate that IRF3 is important as an alternative target of paramyxovirus V proteins.
Single and Coexpression of CXCR4 and CXCR5 Identifies CD4 T Helper Cells in Distinct Lymph Node Niches during Influenza Virus Infection
Authors: Elsner Rebecca A. , Ernst David N. , Baumgarth Nicole
Published: April 2012

Influenza virus infection results in strong, mainly T-dependent, extrafollicular and germinal center B cell responses, which provide lifelong humoral immunity against the homotypic virus strain. Follicular T helper cells (T
FH
) are key regulators of humoral immunity. Questions remain regarding the presence, identity, and function of T
FH
subsets regulating early extrafollicular and later germinal center B cell responses. This study demonstrates that ICOS but not CXCR5 marks T cells with B helper activity induced by influenza virus infection and identifies germinal center T cells (T
GC
) as lymph node-resident CD4
+
ICOS
+
CXCR4
+
CXCR5
+
PSGL-1
lo
PD-1
hi
cells. The CXCR4 expression intensity further distinguished their germinal center light and dark zone locations. This population emerged strongly in regional lymph nodes and with kinetics similar to those of germinal center B cells and were the only T
FH
subsets missing in influenza virus-infected, germinal center-deficient SAP
−/−
mice, mice which were shown previously to lack protective memory responses after a secondary influenza virus challenge, thus indicting the nonredundant functions of CXCR4- and CXCR5-coexpressing CD4 helper cells in antiviral B cell immunity. CXCR4-single-positive T cells, present in B cell-mediated autoimmunity and regarded as “extrafollicular” helper T cells, were rare throughout the response, despite prominent extrafollicular B cell responses, revealing fundamental differences in autoimmune- and infection-induced T-dependent B cell responses. While all ICOS
+
subsets induced similar antibody levels
in vitro
, CXCR5-single-positive T cells were superior in inducing B cell proliferation. The regulation of T cell localization, marked by the single and coexpression of CXCR4 and CXCR5, might be an important determinant of T
FH
function.
Enhanced Mammalian Transmissibility of Seasonal Influenza A/H1N1 Viruses Encoding an Oseltamivir-Resistant Neuraminidase
Authors: Bouvier Nicole M. , Rahmat Saad , Pica Natalie
Published: April 2012

Between 2007 and 2009, oseltamivir resistance developed among seasonal influenza A/H1N1 (sH1N1) virus isolates at an exponential rate, without a corresponding increase in oseltamivir usage. We hypothesized that the oseltamivir-resistant neuraminidase (NA), in addition to being relatively insusceptible to the antiviral effect of oseltamivir, might confer an additional fitness advantage on these viruses by enhancing their transmission efficiency among humans. Here we demonstrate that an oseltamivir-resistant clinical isolate, an A/Brisbane/59/2007(H1N1)-like virus isolated in New York State in 2008, transmits more efficiently among guinea pigs than does a highly similar, contemporaneous oseltamivir-sensitive isolate. With reverse genetics reassortants and point mutants of the two clinical isolates, we further show that expression of the oseltamivir-resistant NA in the context of viral proteins from the oseltamivir-sensitive virus (a 7:1 reassortant) is sufficient to enhance transmissibility. In the guinea pig model, the NA is the critical determinant of transmission efficiency between oseltamivir-sensitive and -resistant Brisbane/59-like sH1N1 viruses, independent of concurrent drift mutations that occurred in other gene products. Our data suggest that the oseltamivir-resistant NA (specifically, one or both of the companion mutations, H275Y and D354G) may have allowed resistant Brisbane/59-like viruses to outtransmit sensitive isolates. These data provide
in vivo
evidence of an evolutionary mechanism that would explain the rapidity with which oseltamivir resistance achieved fixation among sH1N1 isolates in the human reservoir.
Acupuncture and Small Needle Scalpel Therapy in the Treatment of Calcifying Tendonitis of the Gluteus Medius: A Case Report
Authors: Lin Weichun , Liu Chia-Yu , Tang Ching-Lin , Hsu Chung-Hua
Published: April 2012

The case is presented of a 68-year-old man with calcifying tendonitis involving the lateral part of the gluteus medius. The presenting symptoms were chronic pain in the posterolateral region of the right hip and limitation of movement of the right hip. The patient was treated with acupuncture and small needle scalpel therapy. Three months after the procedure the patient was completely pain-free and had full range of motion. Radiographic evaluation revealed complete disappearance of the calcific deposits with no recurrence after 6 months. The use of combined acupuncture and small needle scalpel therapy to treat calcifying tendonitis of the gluteus medius may lead to a good clinical outcome without surgery.
Hyperthyrotropinaemia in untreated subjects with down's syndrome aged 6 months to 64 years: a comparative analysis
Authors: Meyerovitch Joseph , Antebi Felice , Greenberg-Dotan Sari , Bar-Tal Ornit , Hochberg Ze'ev
Published: April 2012

Objectives

To determine whether an altered hypothalamic-pituitary-thyroid axis is inherent to Down's syndrome or if a high level of thyroid-stimulating hormone (TSH) is a feature in a subset of patients with Down's syndrome.

Design

Comparative analysis.

Setting

Major health maintenance organisation (3.8 million insured).

Patients

A data warehouse search identified all subjects with Down's syndrome who attended Clalit Health Services in 2006 and were tested for TSH and free thyroxine (T4) level on the day of diagnosis (intention-to-treat population). The study group consisted of patients who were not diagnosed with thyroid disease or did not receive thyroid-modulating medication (n=428). Their findings were compared with a control group of healthy age- and sex-matched subjects who were randomly selected from the general population.

Main outcome measures

Distribution of free T4, TSH and total T3 levels.

Results

The distribution plot for TSH showed a significant shift of the curve to higher values in the study group compared with the controls (p≤0.0001). This finding held true on further analysis of the whole intention-to-treat population (p<0.006). The free T4 distribution curve also shifted significantly to higher levels in patients with Down's syndrome (p≤0.0001).

Conclusions

Down's syndrome is associated with higher TSH levels. The results suggest that hyperthyrotropinaemia is an innate attribute of chromosome 21 trisomy. Therefore, T4 treatment should not be contemplated in Down's Syndrome unless the TSH is >95th centile in the presence of normal-range free T4 levels.