bluuebunny/crossref_metadata_2025 huggingface dataset:
Vortex Flow Hypothesis for Rotor Blades in Reverse Flow
Authors: Mayo Michael , Motahari Nicholas , Raghav Vrishank , Komerath Narayanan
Published: April 2014

Slowed rotors are used to increase the cruise efficiency and maneuverability of rotorcraft at high speeds. Operation at high rotor advance ratios implies that the blades encounter reverse flow on the retreating side of the rotor disc. The resulting increased pitch link loads and bending moments could shorten component life. Previous studies have shown significant rotor blade pressure perturbations in the reverse flow region, which are not fully accounted for using current prediction methodologies. The hypothesis explored here is that the blade trailing edge in reverse flow produces a vortex similar to the leading edge vortex on a sharp-edged delta wing. The Polhamus model for delta wing lift is modified for use on yawed rotor blades. Lift, drag and pitching moment data acquired on a static yawed blade in reverse flow supports analytical results. Surface tuft flow visualization confirms the existence of an attached, span-wise vortex.
Fabrication of Complex Micro Channels by Micro Electric Discharge Milling (µ-ED Milling)
Authors: Shukla Vaibhav , Akhtar Syed Nadeem , Subbu S. Kanmani , Ramkumar J.
Published: April 2014

Micro electric discharge milling (μ-ED milling) is an effective and economic process for the fabrication of micro channels. In the present work, the bulk approach of μ-ED milling is being attempted to make complex shaped micro channels. For a straight channel the bulk approach of μ-ED milling was found to be a successful approach. A tungsten tool of diameter 500 μm was used to fabricate semi-circular micro channels on EN-24 steel. Important machining parameters had earlier been optimized to make straight channels on EN-24 steel by the same method. The effect of geometrical parameters such as radius of curved channel and aspect ratio on MRR and TWR were studied by full factorial experimental design for single pass at optimized machining parameters. Finally complex shapes like T-type and serpentine channels were made by using optimized conditions of straight and curved channels by bulk approach with multiple passes of μ-ED milling.
Skillful Operating of Working Plate to Control Ball Rolling Motion With a Dual Arm Robot
Authors: Kinoshita Shun , Hirogaki Toshiki , Aoyama Eiichi , Wu Wei
Published: April 2014

Industrial dual-arm robots have been gaining attention as novel tools in the field of new automation. Our past research has focused on using them flexibly to control both the linear and rotational motions of a working plate. However, it has been difficult to measure the synchronous accuracy of two rotary axes without a high-accuracy gyro sensor. We therefore developed a novel method to measure the synchronous accuracy of the two rotary axes of a working plate with a ball, in which the ball is kept rolling around a circular path by dual-arm cooperative control. In the present report, in order to widen the range of application, we tried to keep the ball rolling around a rhomboid path, which is one of the polygonal paths used on a working plate by dual-arm cooperative control. It could be seen that there is some possibility of generating an equal speed diamond motion by inputting wave as the odd power of a trigonometric function and considered a deceleration angle with the robot that we handled.
Development of Magnetic Polishing for Micro Channel With a Ball-Nose-Shaped Tool
Authors: Takebayashi Yusuke , Hirogaki Toshiki , Aoyama Eiichi , Ogawa Keiji , Melkote Shreyes N.
Published: April 2014

In recent years, a high quality and accurately manufactured surface is needed for micro channels for micro-TAS (micro-total analysis systems, a kind of MEMS technology) chips in medical fields. We demonstrated that the use of smaller machine tools is an effective method to reduce the environmental impact in the small parts manufacturing field. Then, in this report, we focus on magnetic polishing for micro channels with a ball-nose-shaped tool, integrating the end milling and polishing processes in a desktop-sized machine tool. The magnetic brush was formed by adhering a magnetic polishing paste, which was composed of abrasive grains (alumina, particle size 0.05 um), metallic particles (cast-iron, diameter 1–100 um), and solvating media (vegetal oil), to the tip (radius 2 mm) of the ball-nose-shaped tool, which was a permanent magnet and a prototype micro tool with a ball-nose end mill shape. We attempt to end mill and polish the surface of micro channels with a prototype magnetic tool and a desktop-sized machine tool. The quality of the machined surface is estimated with a high accuracy surface profile meter. As a result, it can be seen that the proposed method is effective to machine and finish the micro channel surface for micro-TAS chips.
Optimization of Kerf Surface and Material Removal Rate Using Abrasive Water-Slurry Jet Machining Setup
Authors: Patel Divyansh , Tandon Puneet
Published: April 2014

This work presents a description of abrasive water-slurry jet machining (AWSJM) to improve machining capabilities of conventional abrasive water jet machine. The present work proposes a new approach of AWSJM by equipping the conventional abrasive water jet machine (AWJM) with a programmable servomotor controlled abrasive flow control valve and fabricating a setup for injecting polymer solution into the abrasive water jet nozzle, which improves the performance of abrasive jet. Three types of concentrations are prepared to perform the experiments at different values of pressure, abrasive flow rate and abrasive size. The present work identifies the optimal range of process parameters for AWSJM, with natural gelatin as binder, with the response parameters being material removal rate and kerf width. Gelatin produces a coherent, 4-phase beam which leads to efficient energy transfer, improved cutting efficiency, increased material removal rate, reduced kerf width, reduced diversification of jet and better control of abrasive flow rate. The investigation shows that materials removal rate (MRR) tends to increase for approximate 20% (by weight) concentration of polymer in AWSJM. If the polymer is mixed in lower quantities, the MRR is almost equal or less than the MRR for AWJM.
Decomposition of High-Dimensional Shape Optimization Problems Through Quantifying Design Variable Correlation
Authors: Safari Amir , Hajikolaei Kambiz H. , Lemu Hirpa G. , Wang G. Gary , Assadi M.
Published: April 2014

This paper proposes a novel strategy for the shape optimization procedures using a recently developed metamodel-based decomposition algorithm for High-dimensional, Expensive and Black-box (HEB) design problems. A metamodel named High Dimensional Model Representation (HDMR) is used for decomposition of design variables in a complex aerodynamic profile optimization process as a HEB design problem. The approach uncovers and quantifies design variable correlations. Weak correlations are neglected and strong ones are kept for grouping. In this way, the vast search space is decomposed to small ones, and the large-scale CFD simulation based optimization is replaced by smaller-scale sub-problems. Though a typical gas turbine compressor airfoil shape has been selected as the case study in this paper, the methodology is introduced as a general procedure for shape optimization problems. The obtained results from the decomposition also show good agreement with the aerodynamics of such turbomachinery airfoils and found promising.
Aircraft Fleet Maintenance Planning Using Combined Cost Benefit Model and Branch and Bound
Authors: Razavi Behnam , Sassani Farrokh
Published: April 2014

The tasks of maintenance and repair without optimal planning can be costly and result in prolonged maintenance times, reduced availability and possible flight delays. Aircraft manufacturers and maintainers see significant benefits in constantly improving Health Management and Maintenance (HMM) practices by deploying the most effective maintenance planning strategies. The planning of the maintenance and repair is a complex task due to chain dependency of engines to aircraft, and aircraft to the flight schedules. This paper presents a scheduling method for determining the time of maintenance based on the historical engine operation data in order to maximize the use of estimated remaining useful life of the engines as well as lowering the cost and duration of the downtime. The Time-on-Wing (TOW) data is used in conjunction with probability density functions to determine the shape of the respective distribution of the time of maintenance to minimize the loss of expected remaining useful life. Data from each engine with most chance of failure is then selected and fed into an extended Branch and Bound (B&B) routine to determine the best optimum sequence for entering the facility in order to minimize the waiting time.
Numerical Analysis of Droplet Impact, Deformation of a Droplet Train in Direct Print Technology
Authors: Hasan Muhammad Noman , Vatani Morteza , Lu Yanfeng , Kim Ho-Chan , Choi Jae-Won
Published: April 2014

Numerical analysis for a two dimensional case of two–phase fluid flow has been performed to investigate droplet impact, deformation for a droplet train. The purpose of this investigation is to study the phenomenon of liquid droplet impact on a liquid film created by a flattened droplet and the consequent deformation of the film while merging and advancing of the moving front of the film, during the manufacturing processes with jetting technology such as a direct printing process and inkjet printing. This investigation focuses on the analysis of interface tracking and the change of shape for an impacted droplet of a dispensed material. Investigations have been made on the performance of an adaptive quadtree spatial discretization with geometrical Volume–Of–Fluid (VOF) interface representation, continuum–surface–force surface tension formulation and height-function curvature estimation for interface tracking during droplet impact deformation and coalescence of droplet and liquid film produced by flattened droplets to form a printed line. Gerris flow solver, an open source finite volume code, has been used for the numerical analysis which uses a quadtree based adaptive mesh refinement for 2D. The results have been compared with an experimental result from the literature. The investigation has been performed for Reynolds number, Re of 21.1; Weber number, We of 93.8, and contact angle, θ of 30°. For the experimental result considered, the frequency of jetting is 12 kHz.
Growth and Characterization of Titanium Nitride Nanowires on Silicon Substrate Using Pulsed Laser Deposition Method for Biological Applications
Authors: Gbordzoe Seyram , Mensah-Darkwa K. , Gupta Ram , Kumar Dhananjay
Published: April 2014

The present work reports on the growth and characterization of titanium nitride (TiN) nanowires on silicon substrate using a pulsed laser deposition (PLD) method. The TiN nanowires were grown on single crystal silicon substrate with (100) and (111) orientations at a range of substrate temperatures and under both nitrogen ambient and vacuum. The different orientation of silicon was chosen to see the effect of the substrate orientation on the growth of TiN nanowires. The laser energy entering the vacuum chamber to impinge the TiN target for nanowire deposition was varied from 70 to 80 mJ. The TiN nanowires samples were characterized using Scanning Electron Microscopy (SEM) and X-ray Diffraction (XRD). The diameter of the nanowires was observed to increase from 25 nm to 40 nm with an increase in laser beam energy entering the chamber. The shape and orientation of the nanowires was observed to be the same for (100) and (111) oriented silicon substrates as observed in SEM images. Corrosion tests were also conducted on the TiN nanowires.
Comparison of Cartesian and Polar Kinematic Arrangements for Compensation of Scale Effects in Micromilling
Authors: Sodemann Angela A. , Chukewad Yogesh M.
Published: April 2014

Many fields of active research such as biomedical engineering, electronics, and optics have need of small metallic parts less than 1mm in size, with features measured in hundreds or tens of microns, with tolerances as small as 0.1 micron. Such parts include devices for studying the processes in the human body, devices that can be implanted in the human body, small lenses, and other small components. Micromilling is a microscale manufacturing process that can be used to produce a wide range of small parts, including those that have complex 3-dimensional contours. Micromilling is a process that is, on the surface, similar to conventional-scale milling, except for the use of tools that are around two orders of magnitude smaller than conventional endmills, and spindle speeds that are one or two orders of magnitude faster than conventional milling spindles. However, the underlying physical processes which occur in micromilling are unique due to scale effects, which occur due to the unequal scaling of physical properties between the conventional and the micro scale. One of the more recently-uncovered scale effects in micromilling is the increased ratio of tool size to feature size [1]. This scale effect causes an exacerbation of a kind of geometric error known as chord error and places a fundamental limitation on achievable feedrates within allowable machining error constraints. In this research, we hypothesize that the increase of chord error in microscale milling can be alleviated by intelligent modification of the kinematic arrangement of the micromilling machine. Currently, all 3-axis micromilling machines are constructed with a Cartesian kinematic arrangement, in which three linear axes are mounted perpendicularly. In this paper, we propose an alternate kinematic arrangement consisting of two linear axes and one rotary axis, creating a Polar kinematic arrangement. Through numerical simulation, we show that there are distinct classes of curvilinear geometries in which the Polar kinematic arrangement is preferable, and allows significant gains in allowable feedrates and reduction in chord error, while other curvilinear geometries show reduced chord error with the Cartesian arrangement.
Experimental Characterization and Multi-Objective Optimization of the Orbital Drilling Process of CFRP
Authors: Sadek A. , Nassef A. O. , Meshreki M. , Attia M. H.
Published: April 2014

Defects associated with drilling of Carbon Fiber-Reinforced Polymers (CFRPs) are of major economic and safety concerns for aerospace manufacturers. One of the most critical defects associated with drilling of CFRP laminates is delamination of layers which can be avoided by keeping the drilling forces below some threshold levels. Orbital Drilling (OD) is an emerging drilling process that exhibits lower cutting forces and temperatures, easier chip removal, higher produced surface quality, longer tool life, and a high possibility for dry machining. The OD process is featured by cyclic engagement and disengagement between the tool and the workpiece whereby a considerable part of the work done by the tool is directed towards the tangential direction while the work done in the axial direction is reduced. This reduces the risk of delamination at the exit. The objective of this research work is to investigate the effect of the OD process key parameters with respect to the produced hole attributes (surface roughness, delamination, and hole accuracy), as well as the cutting forces and temperatures. All the OD tests were performed under dry conditions using a four-flute 6.35 mm end-mill. The cutting forces were recorded using a 3-component dynamometer Kistler 9255B and cutting temperatures were measured using a FLIR ThermoVision A20M Infrared camera at the holes exit. A full factorial design of the experiment was used whereby the feeds varied from 60 to 360 mm/min and the speeds from 6,000 to 16,000 rpm. The test material used was a quasi-isotropic laminate comprising woven graphite epoxy prepreg. Analysis of the results showed 45% reduction in the axial force component in orbital drilling (OD), compared to conventional drilling. None of the holes produced by the entire set of experiments has experienced any entry or exit delamination. ANOVA was used to identify the significance of the controllable variables on the experimental outputs. To overcome the challenge of optimizing the competing parameters of the hole quality attributes while maximizing the productivity, an algorithm was applied by hybridizing Kriging as a meta-modeling technique with evolutionary multi-objective optimization to optimize the cutting parameters.
Experimental Validation of Analytical Model for Electromagnetic Forming Using a Uniform Pressure Actuator
Authors: Thibaudeau E. , Kinsey B. L.
Published: April 2014

For certain applications, the welding of dissimilar metals is highly desired, e.g. an automotive shaft assembly with both steel and Aluminum components, so that material properties can be tailored to specific locations within the assembly where required. Fusion welding cannot be used in such applications due to the disparity of the material properties involved and the concern of cracking due to intermetallic phases. Electromagnetic welding is a solid-state process where a capacitor bank is charged and then quickly dissipated into a magnetic coil. Eddy currents in the workpiece are created which repel the material from the coil at a high velocity, on the order of 200–300 m/sec. At a critical velocity, the impact energy welds the two components together. In this paper, an analytical model to predict workpiece velocities, which is attractive for its simplicity and cost, is presented and compared to experimental data. The model focuses on a Uniform Pressure Actuator [1], which accelerates sheet metal workpieces. In addition, magnetic effects of workpiece thickness are evaluated.
Aging Expectations are Associated With Physical Activity and Health Among Older Adults of Low Socioeconomic Status
Authors: Dogra Shilpa , Al-Sahab Ban , Manson James , Tamim Hala
Published: April 2014

The purpose of the current study was to determine whether aging expectations (AE) are associated with physical activity participation and health among older adults of low socioeconomic status (SES). A cross-sectional analysis of a sample of 170 older adults (mean age 70.9 years) was conducted. Data on AE, physical activity, and health were collected using the 12 item Expectations Regarding Aging instrument, the Healthy Physical Activity Participation Questionnaire, and the Short Form-36, respectively. Adjusted linear regression models showed significant associations between AE and social functioning, energy/vitality, mental health, and self-rated general health, as well as physical activity. These results suggest that AE may help to better explain the established association between low SES, low physical activity uptake, and poor health outcomes among older adults.
The Immediate Effects of an Anterior-To-Posterior Talar Mobilization on Neural Excitability, Dorsiflexion Range of Motion, and Dynamic Balance in Patients With Chronic Ankle Instability
Authors: Harkey Matthew , McLeod Michelle , Van Scoit Ashley , Terada Masafumi , Tevald Michael , Gribble Phillip , Pietrosimone Brian
Published: April 2014

Context:

Altered neuromuscular function and decreased dorsiflexion range of motion (DFROM) have been observed in patients with chronic ankle instability (CAI). Joint mobilizations are indicated for restoring DFROM and dynamic postural control, yet it remains unknown if a mobilization can alter neuromuscular excitability in muscles surrounding the ankle.

Objective:

To determine the immediate effects of a Maitland grade III anterior-to-posterior joint mobilization on spinal-reflex and corticospinal excitability in the fibularis longus (FL) and soleus (SOL), DFROM, and dynamic postural control.

Design:

Single-blinded randomized control trial.

Setting:

Research laboratory.

Patients:

30 patients with CAI randomized into a mobilization (n = 15) or control (n = 15) group.

Intervention:

Maitland grade III anterior-to-posterior joint mobilization.

Main Outcome Measures:

Spinal-reflex excitability was measured with the Hoffmann reflex, while corticospinal excitability was evaluated with transcranial magnetic stimulation. DFROM was measured seated with the knee extended, and dynamic postural control was quantified with the Star Excursion Balance Test. Separate 2 × 2 repeated-measures ANOVAs were performed for each outcome measure. Dependent t tests were used to evaluate individual differences within groups in the presence of significance.

Results:

Spinal-reflex and corticospinal excitability of the SOL and FL were not altered in the mobilization or control group (P > .05). DFROM increased immediately after the mobilization (P = .05) but not in the control group, while dynamic postural control was unchanged in both groups (P > .05).

Conclusion:

A single joint-mobilization treatment was efficacious at restoring DFROM in participants with CAI; however, excitability of spinal reflex and corticospinal pathways at the ankle and dynamic postural control were unaffected.
SRP RNA Remodeling by SRP68 Explains Its Role in Protein Translocation
Authors: Grotwinkel Jan Timo , Wild Klemens , Segnitz Bernd , Sinning Irmgard
Published: April 2014

Dissecting SRP

In the secretory pathway, inserting transmembrane and secretory proteins into and through hydrophobic cell membranes is facilitated by a highly conserved RNA and protein-containing molecular machine, the signal recognition particle (SRP).

Grotwinkel
et al.

(p.
101
) determined the x-ray crystal structures of human SRP RNA (7SL RNA) bound to the RNA-binding domain (RBD) of the protein SRP subunit SRP68, both in the presence and absence of the SRP19 subunit. The 7SL RNA is remodeled by the SRP68-RBD, which bends one domain of the RNA and remodels a loop, exposing two nucleotides, which allow direct interaction with the ribosome. The findings explain how the SRP RNA drives translation elongation arrest, which is required for membrane insertion.
Monolignol Ferulate Transferase Introduces Chemically Labile Linkages into the Lignin Backbone
Authors: Wilkerson C. G. , Mansfield S. D. , Lu F. , Withers S. , Park J.-Y. , Karlen S. D. , Gonzales-Vigil E. , Padmakshan D. , Unda F. , Rencoret J. , Ralph J.
Published: April 2014

Constructed for Deconstruction

Lignin provides strength to wood but also impedes efficient degradation when wood is used as biofuel.

Wilkerson
et al.

(p.
90
) engineered poplar to produce lignin that is more amenable to degradation. From a handful of plants that contain more digestible lignin monomers,
Angelica sinensis
was selected and its monolignol transferase activities analyzed. The enzyme involved, coniferyl ferulate feruloyl-CoA monolignol transferase, was then expressed in poplar. The resulting poplar trees showed no difference in growth habit under greenhouse conditions, but their lignin showed improved digestibility.
Misidentification of Saprochaete clavata as Magnusiomyces capitatus in Clinical Isolates: Utility of Internal Transcribed Spacer Sequencing and Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry and Importance of Reliable Databases
Authors: Desnos-Ollivier Marie , Blanc Catherine , Garcia-Hermoso Dea , Hoinard Damien , Alanio Alexandre , Dromer Françoise
Published: April 2014

Saprochaete clavataandMagnusiomyces capitatusare human pathogens that are frequently mistaken for each other due to their similar phenotypes and erroneous or limited databases. Based on internal transcribed spacer (ITS) sequences, we propose species-specific carbon assimilation patterns and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) fingerprints that enable the identification ofS. clavata,M. capitatus, andGalactomyces candidusto the species level.
Head-to-Head Comparison of Second-Generation Nucleic Acid Amplification Tests for Detection of Chlamydia trachomatis and Neisseria gonorrhoeae on Urine Samples from Female Subjects and Self-Collected Vaginal Swabs
Authors: Chernesky Max , Jang Dan , Gilchrist Jodi , Hatchette Todd , Poirier André , Flandin Jean-Frederic , Smieja Marek , Ratnam Sam
Published: April 2014

In a comparison of 4 second-generation nucleic acid amplification tests performed with self-collected vaginal swab (SCVS) and first-void urine (FVU) specimens from 575 women, SCVS specimens indicated more infections than did FVU specimens in all assays. The prevalence rates were 9% (53/575 patients) for
Chlamydia trachomatis
and 2% (11/575 patients) for
Neisseria gonorrhoeae
. The clinical sensitivities for testing SCVS specimens for
C. trachomatis
were 98.1% on a Tigris system and 96.2% on a Panther system for the Aptima Combo 2 assay (Hologic Gen-Probe), 98.0% for the RealTi
m
e CT/NG assay on an m2000 instrument (Abbott), 90.6% for the ProbeTec CT/GC Q

x

assay on the Viper system (Becton Dickinson), and 84.6% for the cobas CT/NG assay on the cobas 4800 platform (Roche). Clinical sensitivities for
C. trachomatis
in FVU specimens were 88.7% (Tigris) and 88.0% (Panther) for the Aptima Combo 2 assay, 76.9% for the RealTi
m
e CT/NG assay, 75.5% for the ProbeTec CT/GC Q

x

assay, and 81.1% for the cobas CT/NG assay. Clinical sensitivities of the assays for
N. gonorrhoeae
, with limited positive results, ranged from 63.6% to 100%. Specificities for both infections ranged from 98.4 to 100%. Differences in analytical sensitivities and levels of molecular targets in clinical samples but not inhibitors of amplification may explain the differences in clinical sensitivities.
Dysfunction of Bovine Endogenous Retrovirus K2 Envelope Glycoprotein Is Related to Unsuccessful Intracellular Trafficking
Authors: Nakaya Yuki , Miyazawa Takayuki
Published: April 2014

Endogenous retroviruses (ERVs) are the remnants of retroviral infection of ancestral germ cells. Mutations introduced into ERVs halt the production of infectious agents, but their effects on the function of retroviral proteins are not fully understood. Retroviral envelope glycoproteins (Envs) are utilized in membrane fusion during viral entry, and we recently identified intact coding sequences for bovine endogenous retrovirus K1 (BERV-K1) and BERV-K2 Envs. Amino acid sequences of BERV-K1 Env (also called Fematrin-1) and BERV-K2 Env are similar, and both viruses are classified in the genus
Betaretrovirus
. While Fematrin-1 plays an important role in cell-to-cell fusion in bovine placenta, the BERV-K2 envelope gene is marginally expressed
in vivo
, and its recombinant Env protein is defective in membrane fusion due to inefficient cleavage of surface (SU) and transmembrane subunits. Here, we conducted chimeric analyses of Fematrin-1 and BERV-K2 Envs and revealed that defective maturation of BERV-K2 Env contributed to failed intracellular trafficking. Fluorescence microscopy and flow cytometric analysis suggested that in contrast to Fematrin-1 Env, BERV-K2 Env could not be transported from the endoplasmic reticulum to the
trans
-Golgi network, where cellular proteases required for processing retroviral Envs are localized. We also identified that one of the responsive regions of this phenomenon resided within a 65-amino-acid region of BERV-K2 SU. This is the first report to identify that retroviral Env SU is involved in the regulation of intracellular trafficking, and it may help to elucidate the maturation process of Fematrin-1 and other related Envs.

IMPORTANCE
Retroviruses utilize envelope glycoproteins (Envs) to enter host target cells. Mature retroviral Env is a heterodimer, which consists of surface (SU) and transmembrane (TM) subunits that are generated by the cleavage of an Env precursor protein in the
trans
-Golgi network. SU and TM mediate the recognition of the entry receptor and virus-host membrane fusion, respectively. However, unexplained issues remain for the maturation process of retroviral Env. We previously reported that bovine endogenous retrovirus K2 (BERV-K2) Env lost fusogenicity due to a defect in the cleavage of SU and TM. In this study, we identified that mutations residing in BERV-K2 SU disturbed intracellular trafficking of BERV-K2 Env and resulted its inefficient cleavage. Because SU is not known to play an important role in this process, our study may provide novel insights into the maturation mechanism of retroviral Envs.
CD4-Mimetic Small Molecules Sensitize Human Immunodeficiency Virus to Vaccine-Elicited Antibodies
Authors: Madani Navid , Princiotto Amy M. , Schön Arne , LaLonde Judith , Feng Yu , Freire Ernesto , Park Jongwoo , Courter Joel R. , Jones David M. , Robinson James , Liao Hua-Xin , Moody M. Anthony , Permar Sallie , Haynes Barton , Smith Amos B. , Wyatt Richard , Sodroski Joseph
Published: April 2014

Approaches to prevent human immunodeficiency virus (HIV-1) transmission are urgently needed. Difficulties in eliciting antibodies that bind conserved epitopes exposed on the unliganded conformation of the HIV-1 envelope glycoprotein (Env) trimer represent barriers to vaccine development. During HIV-1 entry, binding of the gp120 Env to the initial receptor, CD4, triggers conformational changes in Env that result in the formation and exposure of the highly conserved gp120 site for interaction with the coreceptors, CCR5 and CXCR4. The DMJ compounds (+)-DMJ-I-228 and (+)-DMJ-II-121 bind gp120 within the conserved Phe 43 cavity near the CD4-binding site, block CD4 binding, and inhibit HIV-1 infection. Here we show that the DMJ compounds sensitize primary HIV-1, including transmitted/founder viruses, to neutralization by monoclonal antibodies directed against CD4-induced (CD4i) epitopes and the V3 region, two gp120 elements involved in coreceptor binding. Importantly, the DMJ compounds rendered primary HIV-1 sensitive to neutralization by antisera elicited by immunization of rabbits with HIV-1 gp120 cores engineered to assume the CD4-bound state. Thus, small molecules like the DMJ compounds may be useful as microbicides to inhibit HIV-1 infection directly and to sensitize primary HIV-1 to neutralization by readily elicited antibodies.

IMPORTANCE
Preventing HIV-1 transmission is a priority for global health. Eliciting antibodies that can neutralize many different strains of HIV-1 is difficult, creating problems for the development of a vaccine. We found that certain small-molecule compounds can sensitize HIV-1 to particular antibodies. These antibodies can be elicited in rabbits. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.
HIV-1 Tat Protein Induces PD-L1 (B7-H1) Expression on Dendritic Cells through Tumor Necrosis Factor Alpha- and Toll-Like Receptor 4-Mediated Mechanisms
Authors: Planès Rémi , BenMohamed Lbachir , Leghmari Kaoutar , Delobel Pierre , Izopet Jacques , Bahraoui Elmostafa
Published: April 2014

Chronic human immunodeficiency virus type 1 (HIV-1) infection is associated with induction of T-cell coinhibitory pathways. However, the mechanisms by which HIV-1 induces upregulation of coinhibitory molecules remain to be fully elucidated. The aim of the present study was to determine whether and how HIV-1 Tat protein, an immunosuppressive viral factor, induces the PD-1/PD-L1 coinhibitory pathway on human dendritic cells (DCs). We found that treatment of DCs with whole HIV-1 Tat protein significantly upregulated the level of expression of PD-L1. This PD-L1 upregulation was observed in monocyte-derived dendritic cells (MoDCs) obtained from either uninfected or HIV-1-infected patients as well as in primary myeloid DCs from HIV-negative donors. In contrast, no effect on the expression of PD-L2 or PD-1 molecules was detected. The induction of PD-L1 on MoDCs by HIV-1 Tat (i) occurred in dose- and time-dependent manners, (ii) was mediated by the N-terminal 1–45 fragment of Tat, (iii) did not require direct cell-cell contact but appeared rather to be mediated by soluble factor(s), (iv) was abrogated following neutralization of tumor necrosis factor alpha (TNF-α) or blocking of Toll-like receptor 4 (TLR4), (v) was absent in TLR4-knockoout (KO) mice but could be restored following incubation with Tat-conditioned medium from wild-type DCs, (vi) impaired the capacity of MoDCs to functionally stimulate T cells, and (vii) was not reversed functionally following PD-1/PD-L1 pathway blockade, suggesting the implication of other Tat-mediated coinhibitory pathways. Our results demonstrate that HIV-1 Tat protein upregulates PD-L1 expression on MoDCs through TNF-α- and TLR4-mediated mechanisms, functionally compromising the ability of DCs to stimulate T cells. The findings offer a novel potential molecular target for the development of an anti-HIV-1 treatment.

IMPORTANCE
The objective of this study was to investigate the effect of human immunodeficiency virus type 1 (HIV-1) Tat on the PD-1/PD-L1 coinhibitory pathway on human monocyte-derived dendritic cells (MoDCs). We found that treatment of MoDCs from either healthy or HIV-1-infected patients with HIV-1 Tat protein stimulated the expression of PD-L1. We demonstrate that this stimulation was mediated through an indirect mechanism, involving tumor necrosis factor alpha (TNF-α) and Toll-like receptor 4 (TLR4) pathways, and resulted in compromised ability of Tat-treated MoDCs to functionally stimulate T-cell proliferation.
Airborne Transmission of Highly Pathogenic H7N1 Influenza Virus in Ferrets
Authors: Sutton Troy C. , Finch Courtney , Shao Hongxia , Angel Matthew , Chen Hongjun , Capua Ilaria , Cattoli Giovanni , Monne Isabella , Perez Daniel R.
Published: April 2014

Avian H7 influenza viruses are recognized as potential pandemic viruses, as personnel often become infected during poultry outbreaks. H7 infections in humans typically cause mild conjunctivitis; however, the H7N9 outbreak in the spring of 2013 has resulted in severe respiratory disease. To date, no H7 viruses have acquired the ability for sustained transmission among humans. Airborne transmission is considered a requirement for the emergence of pandemic influenza, and advanced knowledge of the molecular changes or signature required for transmission would allow early identification of pandemic vaccine seed stocks, screening and stockpiling of antiviral compounds, and eradication efforts focused on flocks harboring threatening viruses. Thus, we sought to determine if a highly pathogenic influenza A H7N1 (A/H7N1) virus with no history of human infection could become capable of airborne transmission among ferrets. We show that after 10 serial passages, A/H7N1 developed the ability to be transmitted to cohoused and airborne contact ferrets. Four amino acid mutations (PB2 T81I, NP V284M, and M1 R95K and Q211K) in the internal genes and a minimal amino acid mutation (K/R313R) in the stalk region of the hemagglutinin protein were associated with airborne transmission. Furthermore, transmission was not associated with loss of virulence. These findings highlight the importance of the internal genes in host adaptation and suggest that natural isolates carrying these mutations be further evaluated. Our results demonstrate that a highly pathogenic avian H7 virus can become capable of airborne transmission in a mammalian host, and they support ongoing surveillance and pandemic H7 vaccine development.

IMPORTANCE
The major findings of this report are that a highly pathogenic strain of H7N1 avian influenza virus can be adapted to become capable of airborne transmission in mammals without mutations altering receptor specificity. Changes in receptor specificity have been shown to play a role in the ability of avian influenza viruses to cross the species barrier, and these changes are assumed to be essential. The work reported here challenges this paradigm, at least for the influenza viruses of the H7 subtype, which have recently become the focus of major attention, as they have crossed to humans.
Two Membrane-Associated Regions within the Nodamura Virus RNA-Dependent RNA Polymerase Are Critical for both Mitochondrial Localization and RNA Replication
Authors: Gant Vincent U. , Moreno Stephanie , Varela-Ramirez Armando , Johnson Kyle L.
Published: April 2014

Viruses with positive-strand RNA genomes amplify their genomes in replication complexes associated with cellular membranes. Little is known about the mechanism of replication complex formation in cells infected with Nodamura virus. This virus is unique in its ability to lethally infect both mammals and insects. In mice and in larvae of the greater wax moth (
Galleria mellonella
), Nodamura virus-infected muscle cells exhibit mitochondrial aggregation and membrane rearrangement, leading to disorganization of the muscle fibrils on the tissue level and ultimately in hind limb/segment paralysis. However, the molecular basis for this pathogenesis and the role of mitochondria in Nodamura virus infection remains unclear. Here, we tested the hypothesis that Nodamura virus establishes RNA replication complexes that associate with mitochondria in mammalian cells. Our results showed that Nodamura virus replication complexes are targeted to mitochondria, as evidenced in biochemical, molecular, and confocal microscopy studies. More specifically, we show that the Nodamura virus RNA-dependent RNA polymerase interacts with the outer mitochondrial membranes as an integral membrane protein and ultimately becomes associated with functional replication complexes. These studies will help us to understand the mechanism of replication complex formation and the pathogenesis of Nodamura virus for mammals.

IMPORTANCE
This study will further our understanding of
Nodamura virus
(NoV) genome replication and its pathogenesis for mice. NoV is unique among the
Nodaviridae
in its ability to infect mammals. Here we show that NoV establishes RNA replication complexes (RCs) in association with mitochondria in mammalian cells. These RCs contain newly synthesized viral RNA and feature a physical interaction between mitochondrial membranes and the viral RNA-dependent RNA polymerase (RdRp), which is mediated by two membrane-associated regions. While the nature of the interaction needs to be explored further, it appears to occur by a mode distinct from that described for the insect nodavirus Flock House virus (FHV). The interaction of the NoV RdRp with mitochondrial membranes is essential for clustering of mitochondria into networks that resemble those described for infected mouse muscle and that are associated with fatal hind limb paralysis. This work therefore provides the first link between NoV RNA replication complex formation and the pathogenesis of this virus for mice.
Murine Gammaherpesvirus 68 Encoding Open Reading Frame 11 Targets TANK Binding Kinase 1 To Negatively Regulate the Host Type I Interferon Response
Authors: Kang Hye-Ri , Cheong Woo-Chang , Park Ji-Eun , Ryu Seungbo , Cho Hye-Jeong , Youn Hyunyee , Ahn Jin-Hyun , Song Moon Jung
Published: April 2014

Upon viral infection, type I interferons, such as alpha and beta interferon (IFN-α and IFN-β, respectively), are rapidly induced and activate multiple antiviral genes, thereby serving as the first line of host defense. Many DNA and RNA viruses counteract the host interferon system by modulating the production of IFNs. In this study, we report that murine gammaherpesvirus 68 (MHV-68), a double-stranded DNA virus, encodes open reading frame 11 (ORF11), a novel immune modulator, to block IFN-β production. ORF11-deficient recombinant viruses induced more IFN-β production in fibroblast and macrophage cells than the MHV-68 wild type or a marker rescue virus. MHV-68 ORF11 decreased IFN-β promoter activation by various factors, the signaling of which converges on TBK1-IRF3 activation. MHV-68 ORF11 directly interacted with both overexpressed and endogenous TBK1 but not with IRF3. Physical interactions between ORF11 and endogenous TBK1 were further confirmed during virus replication in fibroblasts using a recombinant virus expressing FLAG-ORF11. ORF11 efficiently reduced interaction between TBK1 and IRF3 and subsequently inhibited activation of IRF3, thereby negatively regulating IFN-β production. Our domain-mapping study showed that the central domain of ORF11 was responsible for both TBK1 binding and inhibition of IFN-β induction, while the kinase domain of TBK1 was sufficient for ORF11 binding. Taken together, these results suggest a mechanism underlying inhibition of IFN-β production by a gammaherpesvirus and highlight the importance of TBK1 in DNA virus replication.

IMPORTANCE
Gammaherpesviruses are important human pathogens, as they are associated with various kinds of tumors. Upon virus infection, the type I interferon pathway is activated by a series of signaling molecules and stimulates antiviral gene expression. To subvert such interferon antiviral responses, viruses are equipped with multiple factors that can inhibit its critical steps. In this study, we took an unbiased genomic approach using a mutant library of murine gammaherpesvirus 68 to screen a novel viral immune modulator that negatively regulates the type I interferon pathway and identified ORF11 as a strong candidate. ORF11-deficient virus infection produced more interferon than the wild type in both fibroblasts and macrophages. During virus replication, ORF11 directly bound to TBK1, a key regulatory protein in the interferon pathway, and inhibited TBK1-mediated interferon production. Our results highlight a crucial role of TBK1 in controlling DNA virus infection and a viral strategy to curtail host surveillance.
Eosinophilic granuloma of the mandible: a diagnostic dilemma
Authors: Sherwani Rana K , Akhtar Kafil , Qadri Shagufta , Ray Prasenjit Sen
Published: April 2014

Eosinophilic granuloma (EG) is a rare histiocytic disorder resulting from clonal proliferation of Langerhans cells. It accounts for less than 1% of all osseous neoplasms and has a predilection for involving the axial skeleton. Although suspicion of the disease may arise from clinical features and radiographic demonstration of destructive bone lesions, it is still difficult to make a correct diagnosis without proper pathological evaluation. This is more evident when common differentials mimicking EG, both clinically and radiologically, need to be ruled out. This report describes a case of unifocal EG of the mandible occurring in a 4-year-old boy whose initial presentation led to confusion between osteomyelitis, primary bone tumour and lymphoma. A final diagnosis of EG was established after histopathological examination of the biopsy specimen.
Opioid substitution therapy as a strategy to reduce deaths in prison: retrospective cohort study
Authors: Larney Sarah , Gisev Natasa , Farrell Michael , Dobbins Timothy , Burns Lucinda , Gibson Amy , Kimber Jo , Degenhardt Louisa
Published: April 2014

Objectives

To describe deaths in prison among opioid-dependent people, and examine associations between receipt of opioid substitution therapy (OST) and risk of death in prison.

Design

Retrospective cohort study.

Setting

Adult prisons in New South Wales (NSW), Australia.

Participants

16 715 opioid-dependent people who were received to prison between 2000 and 2012.

Interventions

Opioid substitution therapy.

Primary outcome measures

Natural and unnatural (suicide, drug-induced, violent and other injury) deaths in prison.

Results

Cohort members were in prison for 30 998 person-years (PY), during which time there were 51 deaths. The all-cause crude mortality rate (CMR) in prison was 1.6/1000 PY (95% CI 1.2 to 2.2/1000 PY), and the unnatural death CMR was 1.1/1000 PY (95% CI 0.8 to 1.6/1000 PY). Compared to time out of OST, the hazard of all-cause death was 74% lower while in OST (adjusted HR (AHR): 0.26; 95% CI 0.13 to 0.50), and the hazard of unnatural death was 87% lower while in OST (AHR: 0.13; 95% CI 0.05 to 0.35). The all-cause and unnatural death CMRs during the first 4 weeks of incarceration were 6.6/1000 PY (95% CI 3.8 to 10.6/1000 PY) and 5.5/1000 PY (95% CI 2.9 to 9.4/1000 PY), respectively. Compared to periods not in OST, the hazard of all-cause death during the first 4 weeks of incarceration was 94% lower while in OST (AHR: 0.06; 95% CI 0.01 to 0.48), and the hazard of unnatural death was 93% lower while in OST (AHR: 0.07; 95% CI 0.01 to 0.53).

Conclusions

Mortality of opioid-dependent prisoners was significantly lower while in receipt of OST.
The limits of checklists: handoff and narrative thinking
Authors: Hilligoss Brian , Moffatt-Bruce Susan D
Published: April 2014

Concerns about the role of communication failures in adverse events coupled with the success of checklists in addressing safety hazards have engendered a movement to apply structured tools to a wide variety of clinical communication practices. While standardised, structured approaches are appropriate for certain activities, their usefulness diminishes considerably for practices that entail constructing rich understandings of complex situations and the handling of ambiguities and unpredictable variation. Drawing on a prominent social science theory of cognition, this article distinguishes between two radically different modes of human thought, each with its own strengths and weaknesses. The paradigmatic mode organises context-free knowledge into categorical hierarchies that emphasise member-to-category relations in order to apply universal truth conditions. The narrative mode, on the other hand, organises context-sensitive knowledge into temporal plots that emphasise part-to-whole relations in order to develop meaningful, holistic understandings of particular events or identities. Both modes are crucial to human cognition but are appropriate responses for different kinds of tasks and situations. Many communication-intensive practices in which patient cases are communicated, such as handoffs, rely heavily on the narrative mode, yet most interventions assume the paradigmatic mode. Improving the safety and effectiveness of these practices, therefore, necessitates greater attention to narrative thinking.
Health service support in the future operating environment 2035
Authors: Connolly Michael J
Published: April 2014

The period to 2035 is likely to be characterised by instability between states and in relations between groups within states. It is predicted to include climate change, rapid population growth, resource scarcity, resurgence in ideology, and shifts in power from west to east. Many of these changes are likely to have an impact on the health of civil societies and those military personnel deployed by states to counter these challenges. This paper considers the potential impact of emerging global strategic trends on health service support (HSS) in the Future Operating Environment 2035. Global Strategic Trends—Out to 2040, The Future Character of Conflict and NATO Strategic Foresight Analysis Report 2013 provide the foundations of the paper. The study concludes that future impacts on HSS are neither completely predictable nor predetermined, and there is always a possibility of a strategic shock. Knowledge of vulnerability, however, allows an informed approach to the development and evaluation of adaptive strategies to lessen risks to health.