bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Operational Strategies of a SOFC/MGT Hybrid Power Plant
Authors: Hohloch Martina , Huber Andreas , Aigner Manfred
Published: August 2017

The present work deals with the analysis of operational concepts for a SOFC/MGT hybrid power plant based on a test rig at the DLR, Institute of Combustion Technology. Here, a Turbec T100 micro gas turbine and a fuel cell emulator are used. The emulator is composed of two pressure vessels. The first represents the cathode volume of the fuel cell to simulate the residence time and pressure loss. The second is equipped with a natural gas combustor to emulate the varying heat input of the fuel cell. The MGT and the SOFC are connected via different piping paths.

The procedures start-up, load change and shutdown are analyzed in matters of temperature gradients, pressure gradients and fluctuations, as well as the air mass flow provided at the interconnections to the coupling elements. To achieve the required inlet conditions of the SOFC, transient operations, using the different piping paths, are investigated. Concepts for heating-up and cooling the SOFC using hot air from the recuperator and relatively cold air from the compressor outlet are experimentally tested and characterized. Selected critical situations and their effect on the SOFC are investigated. An emergency operation, its impact on both subsystems and limitations are shown. Further operational limits of the MGT control system and power electronic were observed and analyzed. Based on the experimental results, the applicability of the used MGT procedures in a hybrid power plant was reconsidered. Finally, adaptions and strategies for the operational concept are derived and discussed.
A Hybrid Flamelet Generated Manifold Model for Modeling Partially Premixed Turbulent Combustion Flames
Authors: Yadav Rakesh , De Ashoke , Jain Sandeep
Published: August 2017

In this work, a hybrid Flamelet Generated Manifold (FGM) method has been implemented in which both premixed and diffusion based laminar flame manifolds are generated independently and used within one solution framework to capture the multiple combustion regimes inside a combustor. The two manifolds are generated by solving the conservation of species and energy in a transformed space of mixture fraction and progress variable. The mixture averaged properties in a combustor are then calculated using a scalar weighted contribution of premixed and diffusion manifolds. This scalar represents the extent of premixing inside the combustor and its normalized value is obtained from a scalar product of the mean gradients of fuel and oxidizer mass fractions. A volume-weighted smoothing is performed on this normalized scalar to ensure smooth transition between the premixed to diffusion regimes and vice-versa, from one location to another location inside the combustor. This hybrid or multi-regime FGM approach is validated for two turbulent CH4-air partially premixed flames. The first flame chosen in the current work is a lifted turbulent flame, while the second flame is pilot-stabilized flame. First, the computations are performed for premixed- and diffusion-based laminar manifolds and then the results with hybrid models are presented. The results of the hybrid approach are compared for predicting the lift-off height, which is driven by the balance of turbulence and kinetics at any location. It is observed that the hybrid model leads to an improvement in the prediction of the lift-off height prediction. The new hybrid model is a generic representation of the FGM modeling, which enables its use without any a priori need to focus on a specific type of manifold creation for any combustor.
Simulation of Pneumatic Volumes for a Gas Turbine Transient State Analysis
Authors: Yepifanov Sergiy , Zelenskyi Roman , Sirenko Feliks , Loboda Igor
Published: August 2017

The problem of pneumatic volumes constituting a gas turbine engine gas path and their effect on an engine transient belongs to the topical problems of modern turbomachinery engineering. Many researchers have been trying to find the most resource efficient method of volume modeling. The associated urgent problem is the integration of the volume models with an engine model.

Following the world trends, the present paper deals with the pneumatic volume simulation that considers different dynamic factors described with the mass, energy, and momentum conservation laws.

The developed dynamic volume models were examined and compared. The comparison cases included temperature and pressure change at the volume entrance and pressure change at the volume discharge. To reduce the computation time, the linearization of model equations was also proposed and proved.

Based on the comparison results, the guidelines and recommendations on the volume effect mathematical modeling and the volume model integration with the engine model have been made.
Computational Assessment of a 3-Stage Axial Compressor Which Provides Airflow to the NASA 11- by 11-Foot Transonic Wind Tunnel, Including Design Changes for Increased Performance
Authors: Kulkarni Sameer , Beach Timothy A. , Jorgenson Philip C. , Veres Joseph P.
Published: August 2017

New rotor blades are to be fabricated for the 24 foot diameter, 3-stage axial compressor which provides airflow in the 11- by 11-Foot Transonic Wind Tunnel Facility at NASA Ames Research Center in Moffett Field, California. This presents an opportunity to increase the peak Mach number capability of the tunnel by redesigning the compressor for increased pressure ratio. Simulations of the existing compressor from the APNASA CFD code were compared to performance predictions from the HT0300 turbomachinery design code and to compressor performance data taken during a 1997 facility checkout test. It was found that the existing compressor is operating beyond the stability limits predicted by the analysis tools. Additionally, CFD simulations were sensitive to endwall leakages associated with stator button gaps and under-stator-platform flow recirculation. When stator button leakage and cavity recirculation were modeled, pressure rise at design point increased by over 25% due to a large reduction in aerodynamic blockage at the hub. After improving the CFD model and validating the tools against test data, a new design is proposed which achieved 10.5% increased total pressure rise and substantially reduced diffusion factors.
Sensitivity Analysis on the Effect of D32 and Dv90 on the Evaporation Efficiency of Gas Turbine Inlet Fogging for Power Augmentation
Authors: Chaker Mustapha
Published: August 2017

Gas Turbine output is strongly dependent of the ambient air temperature. This decrease is usually occurs in the hot afternoon during the peak demand for power. One way to counter this drop in output is to cool the inlet air using one of the available cooling technologies such as the inlet fog cooling of gas turbine engines for power augmentation.

This technology is well-established with over 1,000 fogging systems installed all around the world on gas turbines of various makes and sizes ranging from 5MW to 250MW.

Two droplet diameters are used to characterize the droplet sizes from nozzles used in the fogging systems, namely D32 (Sauter mean diameter) and Dv90 (diameter for which 90% of the water volume in the spray is less than or equal to).

This paper will show the importance of each diameter on the performance of fogging systems. For this purpose, a heat and mass transfer theoretical model is developed to analyze the dynamics of evaporation of fog droplets. The model will quantify the evaporative efficiency of fog droplets for different D32 and Dv90 values derived from experimentally measured droplet size distributions at two typical ambient psychrometric conditions: hot and dry, and cold and Humid.
Design of a Wide-Range Centrifugal Compressor Stage for Supercritical CO2 Power Cycles
Authors: Pelton Robert , Allison Tim , Jung Sewoong , Smith Natalie
Published: August 2017

Supercritical carbon dioxide (sCO2) power cycles require high compressor efficiency at both the design-point and over a wide operating range. Increasing the compressor efficiency and range helps maximize the power output of the cycle and allows operation over a broader range of transient and part-load operating conditions. For sCO2 cycles operating with compressor inlets near the critical point, large variations in fluid properties are possible with small changes in temperature or pressure. This leads to particular challenges for air-cooled cycles where compressor inlet temperature and associated fluid density are subject to daily and seasonal variations as well as transient events.

Design and off-design operating requirements for a wide-range compressor impeller are presented where the impeller is implemented on an integrally-geared compressor-expander (IGC) concept for a high temperature sCO2 recompression cycle. In order to satisfy the range and efficiency requirements of the cycle, a novel compressor stage design incorporating a semi-open impeller concept with a passive recirculating casing treatment is presented that mitigates inducer stall and extends the low flow operating range. The stage design also incorporates splitter blades and a vaneless diffuser to maximize efficiency and operating range. These advanced impeller design features are enabled through the use of direct metal laser sintering (DMLS) manufacturing. The resulting design increases the range from 45% to 73% relative to a conventional closed impeller design while maintaining high design point efficiency.
A Study of Loss Mechanism in a Linear Compressor Cascade at the Corner Stall Condition
Authors: Li Zhiyuan , Du Juan , Jemcov Aleksandar , Ottavy Xavier , Lin Feng
Published: August 2017

The loss-generating mechanism of a linear compressor cascade at the corner stall condition was numerically studied in this paper. The hybrid RANS/LES method was used to perform the high-fidelity simulations. By comparing the results captured by SSTDES, DDES, SAS models with the experimental data, the SSTDES model is proven to be more accurate in capturing the detailed flow structure of the corner stall than the other two models. Taking the turbulence dissipation term of SSTDES model into account, the volumetric entropy generation rate and a new dimensionless local loss coefficient are proposed and used to analyze the loss-generating mechanism in this work. It was found that the main flow loss generated in this cascade could be sorted as the wake flow loss, the profile loss, the secondary flow loss and the endwall loss according to their amounts. The corner separation significantly affects the secondary flow loss, wake flow loss and profile loss in the cascade passage. The mixing between the separated boundary layer flow and the main flow, the shear between a tornado vortex and the main flow are the main sources of the secondary flow loss. The wake flow loss is the largest loss source of the cascade, accounting for 41.8% of the total loss. There are two peaks of the wake flow loss along the spanwise direction near the corner stall region. This phenomenon is related to the appearance of large velocity gradient flows when the main flows and the corner separation flows mix together. The profile loss takes up 40.06 % of the total loss. The profile loss intensity in the corner region is lower than the mid blade span due to the interaction of the boundary layer on the suction side with the corner separation.
Computational Analysis of Two-Phase Mixing Inside a Twin-Fluid, Fuel-Flexible Atomizer
Authors: Vardaman Nathan J. , Agrawal Ajay K.
Published: August 2017

We have developed a twin-fluid atomizer for combustion that creates a two-phase mixture of fuel and atomizing air upstream of the injector exit where a high-pressure region is established. The static pressure decreases rapidly as the fuel-air mixture exits from the injector, which causes air bubbles in the mixture to expand and breakup the surrounding liquid. This type of fuel injector can effectively atomize various biofuels including highly viscous straight vegetable oil and glycerol. While the combustion benefits have been demonstrated in our prior studies, an understanding of the underlying flow field and mechanism of the two-phase mixture formation process within the injector remains elusive. In this study, a computational fluid dynamic (CFD) model is developed to investigate the two-phase mixing and how it is affected by the operating conditions, particularly the atomizing air to liquid ratio (ALR) by mass. The axisymmetric isothermal CFD model, based on the mixture model for two-phase flows and Reynolds averaged Navier-Stokes equations, utilizes air and water as the working fluids. Both fluids are treated as incompressible, with constant fluid properties. The analysis reveals the flow field within the injector and successfully replicates the upstream penetration of the atomizing air into the liquid supply tube observed experimentally. The penetration depth increases with increase in the ALR, which again agrees with the experimental results.
On the Assessment of Centrifugal Compressor Performance Parameters by Theoretical and Computational Models
Authors: Sundström Elias , Kerres Bertrand , Sanz Sergio , Mihăescu Mihai
Published: August 2017

1D performance prediction modeling and steady-state CFD are applied to assess a high-performance centrifugal compressor. Computed total pressure ratio is compared with experimental data obtained from a gas stand. The focus of the paper is to assess the validity range of the methodologies used. Another aim is to quantify the relative differences between experimental and predicted data, and distinguish differences in the conjectured loss budget. The RANS data manifest overall a higher degree of accuracy than the 1D model when compared with experiments. The 1D model considered shows comparable accuracy at design condition but larger discrepancies at higher speedlines towards surge and choke. Component-wise parametric losses are correlated to pinpoint flow regimes with larger differences between 1D and RANS data. The result exposes significant disparity in the, impeller, vaneless diffuser and the volute model, respectively, especially off-design. Improving these features in the 1D modeling would potentially be profitable for improved accuracy in the performance prognosis.
Rotordynamics Performance of Hybrid Foil Bearing Under Forced Vibration Input
Authors: Kim Daejong , Nicholson Brian , Rosado Lewis , Givan Garry
Published: August 2017

Foil bearings are one type of hydrodynamic air/gas bearings but with a compliant bearing surface supported by structural material that provides stiffness and damping to the bearing. The hybrid foil bearing (HFB) in this paper is a combination of a traditional hydrodynamic foil bearing with externally-pressurized air/gas supply system to enhance load capacity during the start and to improve thermal stability of the bearing. The HFB is more suitable for relatively large and heavy rotors where rotor weight is comparable to the load capacity of the bearing at full speed and extra air/gas supply system is not a major added cost. With 4,448N∼22,240N thrust class turbine aircraft engines in mind, the test rotor is supported by HFB in one end and duplex rolling element bearings in the other end. This paper presents experimental work on HFB with diameter of 102mm performed at the US Air force Research Laboratory. Experimental works include: measurement of impulse response of the bearing to the external load corresponding to rotor’s lateral acceleration of 5.55g, forced response to external subsynchronous excitation, and high speed imbalance response. A non-linear rotordynamic simulation model was also applied to predict the impulse response and forced subsynchronous response. The simulation results agree well with experimental results. Based on the experimental results and subsequent simulations, an improved HFB design is also suggested for higher impulse load capability up to 10g and rotordynamics stability up to 30,000rpm under subsynchronous excitation.
Real-Time Fuel Cell Model Development Challenges for Cyber-Physical Systems in Hybrid Power Applications
Authors: Tucker David , Harun Nor Farida , Zaccaria Valentina , Bryden Kenneth M. , Haynes Comas
Published: August 2017

The use of cyber-physical systems to simulate novel hybrid power cycles provides a cost-effective means to develop and test control strategies at the pilot scale. One of the primary challenges of implementing a cyber-physical power system component is the seamless coupling of a real-time model with hardware that interacts with its environment. A real-time solid oxide fuel cell model integrated with a physical recuperated turbine cycle results in significant capability in exploring the operational limits of a hybrid system. The creation of a model that can interact with hardware requires a delicate balancing act between fidelity, speed, and stability. In this case, the developed model makes use of both implicit and explicit methods for solving the differential equations associated with heat transfer and electrochemistry in a solid oxide fuel cell system. Stability and computational speed are evaluated over some transient simulations. The balance between implicit and explicit methodologies for solving the differential equations associated with heat transfer and the temperature profiles was examined. The method is particularly relevant during simulations involving localized degradation distributed along the cell. The results provide some quantification of the challenges faced in applying cyber-physical systems to hardware simulation of advanced power systems.
Development of a Recuperated Flameless Combustor for an Inverted Brayton Cycle Microturbine Used in Residential Micro-CHP
Authors: Delanaye Michel , Giraldo Andrés , Nacereddine Rabia , Rouabah Mehdi , Fortunato Valentina , Parente Alessandro
Published: August 2017

The paper presents recent work in the development of a clean and efficient natural gas combustor for a micro-CHP system based on a gas turbine for the residential sector. The large scale deployment of natural gas micro-CHP systems represents a great opportunity to contribute to a reduction of CO2 emissions by a substantial increase of the efficiency of primary energy source conversion. A micro-CHP system, well designed for a residential application, which means a power of 1kWe output and high efficiency (larger than 20%), may reduce annual household emissions up to factors close to 2.5. The micro-CHP system developed in this work uses a small gas turbine and an inverted Brayton cycle which advantageously allows the use of substantially larger turbomachinery components than a conventional pressurized Brayton cycle. The paper presents a new counterflow recuperator. Its design has been thoroughly studied by advanced 3D CFD to obtain compactness and high efficiency at low cost. A new flameless combustor has been developed in order to reduce to single digits the emissions of pollutants (NOx and CO) and obtain a highly efficient and stable combustion for various gases. The design methodology based on 3D CFD modelling is presented as well as experimental results demonstrating the performance of the recuperated flameless combustor for various operationg conditions.
Speech produced in noise: Relationship between listening difficulty and acoustic and durational parameters
Authors: Graetzer Simone , Bottalico Pasquale , Hunter Eric J.
Published: August 2017

Conversational speech produced in noise can be characterised by increases in intelligibility relative to such speech produced in quiet. Listening difficulty (LD) is a metric that can be used to evaluate speech transmission performance more sensitively than intelligibility scores in situations in which performance is likely to be high. The objectives of the present study were to evaluate the LD of speech produced in different noise and style conditions, to evaluate the spectral and durational speech modifications associated with these conditions, and to determine whether any of the spectral and durational parameters predicted LD. Nineteen subjects were instructed to speak at normal and loud volumes in the presence of background noise at 40.5 dB(A) and babble noise at 61 dB(A). The speech signals were amplitude-normalised, combined with pink noise to obtain a signal-to-noise ratio of −6 dB, and presented to twenty raters who judged their LD. Vowel duration, fundamental frequency and the proportion of the spectral energy in high vs low frequencies increased with the noise level within both styles. LD was lowest when the speech was produced in the presence of high level noise and at a loud volume, indicating improved intelligibility. Spectrum balance was observed to predict LD.
Superposition rheology and anisotropy in rheological properties of sheared colloidal gels
Authors: Colombo Gabriele , Kim Sunhyung , Schweizer Thomas , Schroyen Bram , Clasen Christian , Mewis Jan , Vermant Jan
Published: August 2017

Gelling colloidal suspensions represent an important class of soft materials. Their mechanical response is characterized by a solid-to-liquid transition at a given shear stress level. Moreover, they often exhibit a complex time-dependent rheological behavior known as thixotropy. The viscosity changes find their origin in the microstructure, which depends on flow history. Yet, the structural response of colloidal gels to flow differs fundamentally from most complex fluids, where flow induces orientation. Upon yielding, low to intermediate volume fraction gels break down in a spatially anisotropic way. Bonds in the velocity-velocity gradient plane are broken, whereas microstructural features in other planes are less affected. The subsequent flow-induced microstructural anisotropy is characterized by typical butterfly scattering patterns. However, as yet there was no evidence for the pertinence of this anisotropy for the rheological properties of these systems. In the present work, orthogonal superposition rheometry was first used to evaluate how the flow-induced microstructure affects the viscoelastic properties. It was shown to retain significant elasticity in the velocity-vorticity plane, even when the structure liquefied. Further, the shear-induced mechanical anisotropy was measured using two-dimensional small amplitude oscillatory shear, exploiting the fact that for suitable thixotropic samples the recovery after arresting the flow is relatively slow. It was hence possible to measure the anisotropy of the moduli upon cessation of flow. The mechanical anisotropy was shown to be spectacular, with the storage moduli in perpendicular directions differing by as much as 2 orders of magnitude.
Adult-onset obesity is triggered by impaired mitochondrial gene expression
Authors: Perks Kara L. , Ferreira Nicola , Richman Tara R. , Ermer Judith A. , Kuznetsova Irina , Shearwood Anne-Marie J. , Lee Richard G. , Viola Helena M. , Johnstone Victoria P. A. , Matthews Vance , Hool Livia C. , Rackham Oliver , Filipovska Aleksandra
Published: August 2017

Reduction in an RNA binding protein impairs mitochondrial biogenesis and alters cell signaling, resulting in obesity.
Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5
Authors: Gilbert Andrew S. , Seoane Paula I. , Sephton-Clark Poppy , Bojarczuk Aleksandra , Hotham Richard , Giurisato Emanuele , Sarhan Adil R. , Hillen Amy , Velde Greetje Vande , Gray Nathanael S. , Alessi Dario R. , Cunningham Debbie L. , Tournier Cathy , Johnston Simon A. , May Robin C.
Published: August 2017

ERK5 regulates nonlytic expulsion of live pathogens from phagocytes to limit dissemination of infections.
Comprehensive single-cell transcriptional profiling of a multicellular organism
Authors: Cao Junyue , Packer Jonathan S. , Ramani Vijay , Cusanovich Darren A. , Huynh Chau , Daza Riza , Qiu Xiaojie , Lee Choli , Furlan Scott N. , Steemers Frank J. , Adey Andrew , Waterston Robert H. , Trapnell Cole , Shendure Jay
Published: August 2017

Sequencing each cell of the nematode

Single-cell sequencing is challenging owing to the limited biological material available in an individual cell and the high cost of sequencing across multiple cells. Cao
et al.
developed a two-step combinatorial barcoding method to profile both single-cell and single-nucleus transcriptomes without requiring physical isolation of each cell. The authors profiled almost 50,000 single cells from an individual
Caenorhabditis elegans
larval stage and were able to identify and recover information from different, even rare, cell types.

Science
, this issue p.
661
Methanogenic heterodisulfide reductase (HdrABC-MvhAGD) uses two noncubane [4Fe-4S] clusters for reduction
Authors: Wagner Tristan , Koch Jürgen , Ermler Ulrich , Shima Seigo
Published: August 2017

Methanogenic archaea metabolism

Most of the methane on Earth is produced by the metabolism of methanogenic archaea. The final step involves a reaction between methyl-coenzyme M and coenzyme B to give CoM-S-S-CoB and methane. Wagner
et al.
report a high-resolution structure of the methanogenic heterodisulfide reductase (HdtABC)-[NiFe]-hydrogenase, the enzyme that reduces the disulfide and couples this to the reduction of ferredoxin in an energy-conserving process known as flavin-based electron bifurcation (FBEB) (see the Perspective by Dobbek). The reduced ferredoxin, in turn, drives the first step of methanogenesis. The structure shows how two noncubane [4Fe-4S] clusters perform disulfide cleavage and gives insight into the mechanism of FBEB.

Science
, this issue p.
699
; see also p.
642
Conversion of object identity to object-general semantic value in the primate temporal cortex
Authors: Tamura Keita , Takeda Masaki , Setsuie Rieko , Tsubota Tadashi , Hirabayashi Toshiyuki , Miyamoto Kentaro , Miyashita Yasushi
Published: August 2017

Faulty remembrance of objects past

The primate brain analyzes visual input along the ventral processing stream to extract the identity of an object. The final stage of this stream, the perirhinal cortex, plays a crucial role in object recognition. Tamura
et al.
systematically biased the judgments of monkeys in an old-new object recognition task by using either optogenetic or electrical stimulation. The monkeys judged an encountered object as familiar when the stimulation site was in a hotspot where memory neurons were clustered. However, at the hotspot's fringe region, where neurons lost selective responses to the learned objects, electrical microstimulation led the monkeys to mistakenly judge an object as never seen before.

Science
, this issue p.
687
In situ architecture, function, and evolution of a contractile injection system
Authors: Böck Désirée , Medeiros João M. , Tsao Han-Fei , Penz Thomas , Weiss Gregor L. , Aistleitner Karin , Horn Matthias , Pilhofer Martin
Published: August 2017

Identification of a new injection system

To interact with other cells, bacteria use contractile machines that function similarly to membrane-puncturing bacteriophages. The so-called type 6 secretion system (T6SS) functions from inside a bacterial cell. Böck
et al.
used modern electron microscopy methods and functional assays to resolve the structure and function of a T6SS in the cellular context. They identified three modules and showed large-scale structural changes upon firing. T6SSs are organized in multibarrel gun-like arrays and may contribute to the survival of bacteria inside their host.

Science
, this issue p.
713
Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration
Authors: Yaspan Brian L. , Williams David F. , Holz Frank G. , Regillo Carl D. , Li Zhengrong , Dressen Amy , van Lookeren Campagne Menno , Le Kha N. , Graham Robert R. , Beres Tatiana , Bhangale Tushar R. , Honigberg Lee A. , Smith Ashley , Henry Erin C. , Ho Carole , Strauss Erich C. ,   for the MAHALO Study Investigators
Published: August 2017

The phase 2 MAHALO clinical trial shows that lampalizumab reduces geographic atrophy secondary to age-related macular degeneration and implicates complement dysregulation in disease pathogenesis.
The long noncoding RNAWispercontrols cardiac fibrosis and remodeling
Authors: Micheletti Rudi , Plaisance Isabelle , Abraham Brian J. , Sarre Alexandre , Ting Ching-Chia , Alexanian Michael , Maric Daniel , Maison Damien , Nemir Mohamed , Young Richard A. , Schroen Blanche , González Arantxa , Ounzain Samir , Pedrazzini Thierry
Published: August 2017

A super-enhancer–associated long noncoding RNA,Wisper, controls cardiac fibrosis and pathological remodeling in the damaged heart.
Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts
Authors: Miller Miles A. , Chandra Ravi , Cuccarese Michael F. , Pfirschke Christina , Engblom Camilla , Stapleton Shawn , Adhikary Utsarga , Kohler Rainer H. , Mohan James F. , Pittet Mikael J. , Weissleder Ralph
Published: August 2017

Radiation therapy enhances nanotherapeutic drug delivery in a tumor-associated macrophage–dependent fashion.
Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief
Authors: Jensen Dane D. , Lieu TinaMarie , Halls Michelle L. , Veldhuis Nicholas A. , Imlach Wendy L. , Mai Quynh N. , Poole Daniel P. , Quach Tim , Aurelio Luigi , Conner Joshua , Herenbrink Carmen Klein , Barlow Nicholas , Simpson Jamie S. , Scanlon Martin J. , Graham Bimbil , McCluskey Adam , Robinson Phillip J. , Escriou Virginie , Nassini Romina , Materazzi Serena , Geppetti Pierangelo , Hicks Gareth A. , Christie Macdonald J. , Porter Christopher J. H. , Canals Meritxell , Bunnett Nigel W.
Published: August 2017

Therapeutic targeting of the neurokinin 1 receptor in endosomes provides efficacious and prolonged pain relief.
Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in
RAS
mutant cancers
Authors: Sun Chaoyang , Fang Yong , Yin Jun , Chen Jian , Ju Zhenlin , Zhang Dong , Chen Xiaohua , Vellano Christopher P. , Jeong Kang Jin , Ng Patrick Kwok-Shing , Eterovic Agda Karina B. , Bhola Neil H. , Lu Yiling , Westin Shannon N. , Grandis Jennifer R. , Lin Shiaw-Yih , Scott Kenneth L. , Peng Guang , Brugge Joan , Mills Gordon B.
Published: August 2017

Mutant
RAS
has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple
RAS
mutant tumor models across tumor lineages where
RAS
mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of
BRCA1/2
and
p53
mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in
RAS
mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor–induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant
RAS
to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in
RAS
mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with
RAS
mutant tumors where there are few effective therapeutic options.
Rapamycin keeps the reproductive clock ticking
Authors: Hine Christopher
Published: August 2017

Two weeks of rapamycin administration in young and old female mice leads to long-term improvements in ovarian function and reproductive longevity.
Driver mutations take the wheel in invasive yet nonmalignant disease
Authors: Miller Miles A.
Published: August 2017

Despite their low risk for malignant transformation, infiltrating endometriotic lesions harbor cancer-associated mutations.
Zoonotic Risk, Pathogenesis, and Transmission of Avian-Origin H3N2 Canine Influenza Virus
Authors: Sun Hailiang , Blackmon Sherry , Yang Guohua , Waters Kaitlyn , Li Tao , Tangwangvivat Ratanaporn , Xu Yifei , Shyu Daniel , Wen Feng , Cooley Jim , Senter Lucy , Lin Xiaoxu , Jarman Richard , Hanson Larry , Webby Richard , Wan Xiu-Feng
Published: August 2017

Two subtypes of influenza A virus (IAV), avian-origin canine influenza virus (CIV) H3N2 (CIV-H3N2) and equine-origin CIV H3N8 (CIV-H3N8), are enzootic in the canine population. Dogs have been demonstrated to seroconvert in response to diverse IAVs, and naturally occurring reassortants of CIV-H3N2 and the 2009 H1N1 pandemic virus (pdmH1N1) have been isolated. We conducted a thorough phenotypic evaluation of CIV-H3N2 in order to assess its threat to human health. Using ferret-generated antiserum, we determined that CIV-H3N2 is antigenically distinct from contemporary human H3N2 IAVs, suggesting that there may be minimal herd immunity in humans. We assessed the public health risk of CIV-H3N2 × pandemic H1N1 (pdmH1N1) reassortants by characterizing their
in vitro
genetic compatibility and
in vivo
pathogenicity and transmissibility. Using a luciferase minigenome assay, we quantified the polymerase activity of all possible 16 ribonucleoprotein (RNP) complexes (PB2, PB1, PA, NP) between CIV-H3N2 and pdmH1N1, identifying some combinations that were more active than either parental virus complex. Using reverse genetics and fixing the CIV-H3N2 hemagglutinin (HA), we found that 51 of the 127 possible reassortant viruses were viable and able to be rescued. Nineteen of these reassortant viruses had high-growth phenotypes
in vitro
, and 13 of these replicated in mouse lungs. A single reassortant with the NP and HA gene segments from CIV-H3N2 was selected for characterization in ferrets. The reassortant was efficiently transmitted by contact but not by the airborne route and was pathogenic in ferrets. Our results suggest that CIV-H3N2 reassortants may pose a moderate risk to public health and that the canine host should be monitored for emerging IAVs.

IMPORTANCE
IAV pandemics are caused by the introduction of novel viruses that are capable of efficient and sustained transmission into a human population with limited herd immunity. Dogs are a a potential mixing vessel for avian and mammalian IAVs and represent a human health concern due to their susceptibility to infection, large global population, and close physical contact with humans. Our results suggest that humans are likely to have limited preexisting immunity to CIV-H3N2 and that CIV-H3N2 × pdmH1N1 reassortants have moderate genetic compatibility and are transmissible by direct contact in ferrets. Our study contributes to the increasing evidence that surveillance of the canine population for IAVs is an important component of pandemic preparedness.
Screening of FDA-Approved Drugs for Inhibitors of Japanese Encephalitis Virus Infection
Authors: Wang Shaobo , Liu Yang , Guo Jiao , Wang Peilin , Zhang Leike , Xiao Gengfu , Wang Wei
Published: August 2017

Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. No approved drug is available for the specific treatment of JEV infections, and the available vaccines are not effective against all clinical JEV isolates. In the study described here, a high-throughput screening of an FDA-approved drug library for inhibitors of JEV was performed. Five hit drugs that inhibited JEV infection with a selective index of >10 were identified. The antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors that confirmed that calcium is essential for JEV infection, most likely during viral replication, were utilized. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the nonstructural NS4B protein, which is relatively conserved in flaviviruses, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca
2+
channel (VGCC) inhibitor, without an apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing the viral load in the brain, while it abrogated the histopathological changes associated with JEV infection. This study provides five antiflavivirus candidates and identifies cytoplasmic calcium to be a novel antiviral target for the treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flaviviruses.

IMPORTANCE
No approved therapy for the treatment of Japanese encephalitis virus infection is currently available. Repurposing of approved drugs would accelerate the development of a therapeutic stratagem. In this study, we screened a library of FDA-approved drugs and identified five hit drugs, especially calcium inhibitors, exerting antiflavivirus activity that blocked viral replication. The
in vivo
efficacy and toxicity of manidipine were investigated with a mouse model of JEV infection, and the viral target was identified by generating an adaptive mutant.
Epistatic Interactions within the Influenza A Virus Polymerase Complex Mediate Mutagen Resistance and Replication Fidelity
Authors: Pauly Matthew D. , Lyons Daniel M. , Fitzsimmons William J. , Lauring Adam S.
Published: August 2017

RNA viruses exist as genetically diverse populations. This standing genetic diversity gives them the potential to adapt rapidly, evolve resistance to antiviral therapeutics, and evade immune responses. Viral mutants with altered mutation rates or mutational tolerance have provided insights into how genetic diversity arises and how it affects the behavior of RNA viruses. To this end, we identified variants within the polymerase complex of influenza virus that are able tolerate drug-mediated increases in viral mutation rates. We find that drug resistance is highly dependent on interactions among mutations in the polymerase complex. In contrast to other viruses, influenza virus counters the effect of higher mutation rates primarily by maintaining high levels of genome replication. These findings suggest the importance of maintaining large population sizes for viruses with high mutation rates and show that multiple proteins can affect both mutation rate and genome synthesis.
Portal hypertension and its management in children
Authors: Grammatikopoulos Tassos , McKiernan Patrick James , Dhawan Anil
Published: August 2017

Portal hypertension (PHT), defined as raised intravascular pressure in the portal system, is a complication of chronic liver disease or liver vascular occlusion. Advances in our ability to diagnose and monitor the condition but also predict the risk of gastrointestinal bleeding have enabled us to optimise the management of children with PHT either at a surveillance or at a postbleeding stage. A consensus among paediatric centres in the classification of varices can be beneficial in streamlining future paediatric studies. New invasive (endoscopic and surgical procedures) and non-invasive (pharmacotherapy) techniques are currently used enabling clinicians to reduce mortality and morbidity in children with PHT.
Amblyopia and strabismus: trends in prevalence and risk factors among young adults in Israel
Authors: Shapira Yinon , Machluf Yossy , Mimouni Michael , Chaiter Yoram , Mezer Eedy
Published: August 2017

Aims

To estimate the prevalence of amblyopia, present strabismus and amblyopia risk factors (ARFs) among young adults in Israel and to analyse trends over time of prevalence rates.

Methods

We conducted a cross-sectional study including 107 608 pre-enlistees aged 17.4±0.6 years born between 1971 and 1994. Across the birth years, the following trends of prevalence rates among young adults were analysed: prevalence of amblyopia, prevalence of strabismus, severity of amblyopia and prevalence of ARFs (strabismsus, anisometropia and isoametropia). Unilateral amblyopia was defined as best corrected visual acuity (BCVA) of <0.67 (6/9) in either eye or as an interocular difference of two lines or more. Bilateral amblyopia was defined as BCVA of <0.67 (6/9) in both eyes. The severity of amblyopia was classified as mild (BCVA ≥0.5 [6/12]), moderate (BCVA <0.5 [6/12] and ≥0.25 [6/24]) or severe (BCVA <0.25 [6/24]).

Results

The prevalence of young adulthood amblyopia declined by 33%, from 1.2% to 0.8% (R2=0.87, p<0.001) across 24 birth years. This decline may be due to a drop in unilateral amblyopia from 1% to 0.6% (R2=0.93, p<0.001), while the prevalence of bilateral amblyopia remained stable (0.2%, p=0.12). The decline in amblyopia was apparent in mild and moderate amblyopia, but not in severe amblyopia. Strabismus and anisometropia were detected in 6–12% and 11–20% of subjects with unilateral amblyopia, respectively, without significant trends. Strabismic amblyopia remained constant in the entire population across years. Isoametropia was detected in 46–59% of subjects with bilateral amblyopia without a significant trend across birth years. Prevalence of strabismus in the study population decreased by 50%, from 1.2% to 0.6% (R2=0.75, p<0.001). In subjects with present strabismus, the prevalence of mild unilateral amblyopia increased, while moderate or severe unilateral amblyopia remained relatively stable.

Conclusion

Among young adults, the prevalence of unilateral amblyopia, as well as the prevalence of present strabismus, decreased significantly over a period of a generation. The prevalence of strabismic, bilateral or severe (both unilateral and bilateral) amblyopia remained stable. The establishment of the national screening programme for children and the improved utility of treatment for amblyopia and strabismus coincide with these trends. Thus, it is possible that these early interventions resulted in modification of the ‘natural history’ of these conditions and their prevalence in adolescence.
Optical coherence tomography angiography enhances the detection of optic nerve damage in multiple sclerosis
Authors: Spain Rebecca I , Liu Liang , Zhang Xinbo , Jia Yali , Tan Ou , Bourdette Dennis , Huang David
Published: August 2017

Background

Quantitative assessment of optic nerve damage is important in the evaluation of optic neuritis (ON) and multiple sclerosis (MS).

Objective

To detect optic nerve damage using optical coherence tomography (OCT) and OCT angiography in MS.

Methods

Peripapillary retinal nerve fibre layer (NFL) thickness, macular ganglion cell complex (GCC) thickness and Optic Nerve Head Flow Index (ONH-FI) were measured. The ONH-FI was defined as flow signal averaged over the optic disc. Diagnostic accuracy was evaluated by the area under the receiver-operating characteristics curve (AROC).

Results

Sixty-eight eyes of 45 MS participants and 55 eyes of 32 healthy controls (HCs) were analysed. Of MS eyes, 25 had a history of ON (MS+ON) and 43 didn’t (MS−ON). MS−ON and MS+ON eyes had reductions in ONH-FI (p=0.031 and p=0.001, respectively), GCC thickness (p=0.245 and p<0.001, respectively), and NFL thickness (p=0.003 and p=0.024, respectively), compared with HCs. The highest AROC (0.940) was achieved by the logistic regression combination of all three variables, which was significantly higher than other variables (p=0.018).

Conclusion

MS produces both retinal structural loss and decreased ONH perfusion in MS eyes with and without history of ON. The combination of perfusion and structural measurements enhances detection of optic nerve damage in MS. OCT angiography may be a useful additional retinal marker in evaluation of ON in MS.
Petrography and phase equilibria modeling of mid-pressure aluminous gneisses derived from hydrothermally altered protoliths, Grenville Province, Canada
Authors: Patrick Mackenzie , Indares Aphrodite
Published: August 2017

A large portion of the hinterland of the central Grenville Province is characterized by mid-pressure granulite-facies metamorphic rocks. In the Manicouagan – Lac du Milieu region of Quebec, aluminous gneisses derived from hydrothermally altered felsic protoliths provide a record of anatectic processes and of the pressure–temperature (P–T) evolution during orogenesis. Samples collected in areas separated by several tens of kilometres consist of garnet + biotite + quartz + K-feldspar ± plagioclase ± sillimanite, with retrograde cordierite in some, and most display microstructural evidence of partial melting. However, they have a wide range of bulk compositions and textures, and may be grouped into two types: sillimanite-rich rocks, with a high alumina index and sillimanite-poor rocks with low alumina index and in which sillimanite is not part of the peak assemblage. Phase equilibria modeling with THERMOCALC software constrained the P–T field of the peak mineral assemblage(s) at 800–900 °C and 6–11 kbar (1 kbar = 100 MPa), with melt solidification in the range of 800–865 °C and 6–8 kbar. The presence of sillimanite inclusions in garnet, and the scarcity of retrograde cordierite are consistent with moderate dP/dT gradient “hairpin” P–T paths. The data suggest that this part of the mid-P hinterland in the central Grenville experienced a rather uniform high-temperature metamorphic evolution, with large temperature variations relative to pressure. This is consistent with the thermal evolution of middle crust beneath an orogenic plateau.
Neoglacial history of Robson Glacier, British Columbia
Authors: Luckman B.H. , Masiokas M.H. , Nicolussi K.
Published: August 2017

As glaciers in the Canadian Rockies recede, glacier forefields continue to yield subfossil wood from sites overridden by these glaciers during the Holocene. Robson Glacier in British Columbia formerly extended below tree line, and recession over the last century has progressively revealed a number of buried forest sites that are providing one of the more complete records of glacier history in the Canadian Rockies during the latter half of the Holocene. The glacier was advancing ca. 5.5 km upvalley of the Little Ice Age terminus ca. 5.26 cal ka BP, at sites ca. 2 km upvalley ca. 4.02 cal ka BP and ca. 3.55 cal ka BP, and 0.5–1 km upvalley between 1140 and 1350 A.D. There is also limited evidence based on detrital wood of an additional period of glacier advance ca. 3.24 cal ka BP. This record is more similar to glacier histories further west in British Columbia than elsewhere in the Rockies and provides the first evidence for a post-Hypsithermal glacier advance at ca. 5.26 cal ka BP in the Rockies. The utilization of the wiggle-matching approach using multiple 14C dates from sample locations determined by dendrochronological analyses enabled the recognition of 14C outliers and an increase in the precision and accuracy of the dating of glacier advances.