bluuebunny/crossref_metadata_2025 huggingface dataset:
SolarUV‐Bradiation and ethylene play a key role in modulating effective defenses againstAnticarsia gemmatalislarvae in field‐grown soybean
Authors: Dillon Francisco M. , Tejedor M. Daniela , Ilina Natalia , Chludil Hugo D. , Mithöfer Axel , Pagano Eduardo A. , Zavala Jorge A.
Published: November 2017

Solar UV‐B radiation has been reported to enhance plant defenses against herbivore insects in many species. However, the mechanism and traits involved in the UV‐B mediated increment of plant resistance are unknown in crops species, such as soybean. Here, we studied defense‐related responses in undamaged andAnticarsia gemmatalislarvae‐damaged leaves of two soybean cultivars grown under attenuated or full solar UV‐B radiation. We determined changes in jasmonates, ethylene (ET), salicylic acid, trypsin protease inhibitor activity, flavonoids, and mRNA expression of genes related with defenses. ET emission induced byAnticarsia gemmatalisdamage was synergistically increased in plants grown under solar UV‐B radiation and was positively correlated with malonyl genistin concentration, trypsin proteinase inhibitor activity and expression ofIFS2, and the pathogenesis proteinPR2, while was negatively correlated with leaf consumption. The precursor of ET, aminocyclopropane‐carboxylic acid, applied exogenously to soybean was sufficient to strongly induce leaf isoflavonoids. Our results showed that in field‐grown soybean isoflavonoids were regulated by both herbivory and solar UV‐B inducible ET, whereas flavonols were regulated by solar UV‐B radiation only and not by herbivory or ET. Our study suggests that, although ET can modulate UV‐B‐mediated priming of inducible plant defenses, some plant defenses, such as isoflavonoids, are regulated by ET alone.
Time, physics, and philosophy: It's all relative
Authors: Baron Sam
Published: November 2017

This article provides a non‐technical overview of the conflict between the special theory of relativity and the dynamic theories of time. The chief argument against dynamic theories of time from relativistic mechanics is presented. The space of current responses to that argument is subsequently mapped.
Elevated ozone concentration decreases whole‐plant hydraulic conductance and disturbs water use regulation in soybean plants
Authors: Zhang Wei‐Wei , Wang Miao , Wang Ai‐Ying , Yin Xiao‐Han , Feng Zhao‐Zhong , Hao Guang‐You
Published: November 2017

Elevated tropospheric ozone (O3) concentration has been shown to affect many aspects of plant performance including detrimental effects on leaf photosynthesis and plant growth. However, it is not known whether such changes are accompanied by concomitant responses in plant hydraulic architecture and water relations, which would have great implications for plant growth and survival in face of unfavorable water conditions. A soybean (Glycine max (L.) Merr.) cultivar commonly used in Northeast China was exposed to non‐filtered air (NF, averaged 24.0 nl l−1) and elevated O3 concentrations (eO3, 40 nl l−1 supplied with NF air) in six open‐top chambers for 50 days. The eO3 treatment resulted in a significant decrease in whole‐plant hydraulic conductance that is mainly attributable to the reduced hydraulic conductance of the root system and the leaflets, while stem and leaf petiole hydraulic conductance showed no significant response to eO3. Stomatal conductance of plants grown under eO3 was lower during mid‐morning but significantly higher at midday, which resulted in substantially more negative daily minimum water potentials. Moreover, excised leaves from the eO3 treated plants showed significantly higher rates of water loss, suggesting a lower ability to withhold water when water supply is impeded. Our results indicate that, besides the direct detrimental effects of eO3 on photosynthetic carbon assimilation, its influences on hydraulic architecture and water relations may also negatively affect O3‐sensitive crops by deteriorating the detrimental effects of unfavorable water conditions.
Microbial colonization of the periodontal pocket and its significance for periodontal therapy
Authors: Mombelli Andrea
Published: November 2017

The aim of this paper was to evaluate strategies for periodontal therapy from the perspective of periodontal disease being a consequence of microbial colonization of the periodontal pocket environment. In classic bacterial infections the diversity of the microbiota decreases as the disease develops. In most cases of periodontitis, however, the diversity of the flora increases. Most incriminating bacteria are thought to harm tissues significantly only if present in high numbers over prolonged periods of time. Clinical trials have repeatedly demonstrated that scaling and root planing, a procedure that aims to remove subgingival bacterial deposits by scraping on the tooth surface within the periodontal pocket, is effective. At present, for the therapy of any form of periodontal disease, there exists no protocol with proven superiority, in terms of efficiency or effectiveness, over scaling and root planing plus systemic amoxicillin and metronidazole. Some exponents advocate rationing these drugs for patients with a specific microbial profile. However, the evidence for any benefit of bacteriology‐assisted clinical protocols is unsatisfactory. Treated sites are subject to recolonization with a microbiota similar to that present before therapy. The degree and speed of recolonization depends on the treatment protocol, the distribution patterns of periodontal microorganisms elsewhere in the oral cavity and the quality of the patient's oral hygiene. To limit the use of antibiotics and to avoid accumulation of harmful effects by repeated therapy, further efforts must be made to optimize procedures addressing the microbial colonization and recolonization of the periodontal pocket.
Premature birth affects the degree of airway dysanapsis and mechanical ventilatory constraints
Authors: Duke Joseph W. , Gladstone Igor M. , Sheel A. William , Lovering Andrew T.
Published: November 2017

New Findings

What is the central question of this study?

Adult survivors of preterm birth without (PRE) and with bronchopulmonary dysplasia (BPD) have airflow obstruction at rest and significant mechanical ventilatory constraints during exercise compared with those born at full term (CON). Do PRE/BPD have smaller airways, indexed via the dysanapsis ratio, than CON?

What is the main finding and its importance?

The dysanapsis ratio was significantly smaller in BPD and PRE compared with CON, with BPD having the smallest dysanapsis ratio. These data suggest that airflow obstruction in PRE and BPD might be because of smaller airways than CON.

Adult survivors of very preterm birth (≤32 weeks gestational age) without (PRE) and with bronchopulmonary dysplasia (BPD) have obstructive lung disease as evidenced by reduced expiratory airflow at rest and have significant mechanical ventilatory constraints during exercise. Airflow obstruction, in any conditions, could be attributable to several factors, including small airways. PRE and/or BPD could have smaller airways than their counterparts born at full term (CON) owing to a greater degree of dysanaptic airway development during the pre‐ and/or postnatal period. Thus, the purpose of the present study was to compare the dysanapsis ratio (DR), as an index of airway size, between PRE, BPD and CON. To do so, we calculated DR in PRE (n = 21), BPD (n = 14) and CON (n = 34) individuals and examined flow–volume loops at rest and during submaximal exercise. The DR, using multiple estimates of static recoil pressure, was significantly smaller in PRE and BPD (0.16 ± 0.05 and 0.10 ± 0.03 a.u.) compared with CON (0.22 ± 0.04 a.u.; both P < 0.001) and smallest in BPD (P < 0.001). The DR was significantly correlated with peak expiratory airflow at rest (r = 0.42; P < 0.001) and the extent of expiratory flow limitation during exercise (r = 0.60; P < 0.001). Our findings suggest that PRE/BPD might have anatomically smaller airways than CON, which might help to explain their lower expiratory airflow rate at rest and during exercise and further our understanding of the consequences of preterm birth and neonatal O2 therapy.
Parallel Multi-Cycle LES of an Optical Pent-Roof DISI Engine Under Motored Operating Conditions
Authors: Van Dam Noah , Zeng Wei , Sjöberg Magnus , Som Sibendu
Published: November 2017

The use of Large-eddy Simulations (LES) has increased due to their ability to resolve the turbulent fluctuations of engine flows and capture the resulting cycle-to-cycle variability. One drawback of LES, however, is the requirement to run multiple engine cycles to obtain the necessary cycle statistics for full validation. The standard method to obtain the cycles by running a single simulation through many engine cycles sequentially can take a long time to complete. Recently, a new strategy has been proposed by our research group to reduce the amount of time necessary to simulate the many engine cycles by running individual engine cycle simulations in parallel. With modern large computing systems this has the potential to reduce the amount of time necessary for a full set of simulated engine cycles to finish by up to an order of magnitude. In this paper, the Parallel Perturbation Methodology (PPM) is used to simulate up to 35 engine cycles of an optically accessible, pent-roof Direct-injection Spark-ignition (DISI) engine at two different motored engine operating conditions, one throttled and one un-throttled. Comparisons are made against corresponding sequential-cycle simulations to verify the similarity of results using either methodology. Mean results from the PPM approach are very similar to sequential-cycle results with less than 0.5% difference in pressure and a magnitude structure index (MSI) of 0.95. Differences in cycle-to-cycle variability (CCV) predictions are larger, but close to the statistical uncertainty in the measurement for the number of cycles simulated. PPM LES results were also compared against experimental data. Mean quantities such as pressure or mean velocities were typically matched to within 5–10%. Pressure CCVs were under-predicted, mostly due to the lack of any perturbations in the pressure boundary conditions between cycles. Velocity CCVs for the simulations had the same average magnitude as experiments, but the experimental data showed greater spatial variation in the root-mean-square (RMS). Conversely, circular standard deviation results showed greater repeatability of the flow directionality and swirl vortex positioning than the simulations.
Operation of a Two-Stroke, Spark-Ignition Engine on a Non-Conventional Lubricant
Authors: Ahles Jacob , Price Kyle , Eggart Brian , Miers Scott A. , Wiegand Andrew , Kowalski Darin , Biske Andrew
Published: November 2017

Two-stroke engines are capable of providing very high power density levels in a cost effective, easy-to-maintain package. They are, however, typically susceptible to higher levels of hydrocarbon emissions, lower durability, and a shorter lifecycle when compared to four-stroke engines. These detriments are easily overlooked in some military applications where power density is paramount, but most commercial two-stroke engines require specialized consumable lubricant. Typical military applications strive to minimize their logistics “trails,” which includes minimizing the variety of fluids they require. As a result, there has been very limited success in fielding small two-stroke engines for military use.

As a preliminary study, MIL-PRF-2104K Single Common Powertrain Lubricant (SCPL, a four-stroke heavy diesel engine oil) was utilized as the consumable lubricant (in place of conventional two-stroke oil) in a liquid-cooled, semi-direct fuel injected, spark-ignition, two-stroke engine. Empirical data was collected to study the impact of the oil on deposit build-up, power, wear, combustion stability, and fuel conversion efficiency. Over 147 hours of operation were logged and analyzed.

The performance of the engine on SCPL was consistent with conventional two-stroke oil and showed no degradation over the test duration. Brake specific fuel consumption was not negatively impacted with SCPL. Increased deposit build-up in the exhaust ports and on the spark plugs were the primary negative impacts of the SCPL oil. Spark plugs with hotter classifications and modification of the oiling rate resulted in a reduction of soot accumulation and spark plug fouling.
Waste Heat Recovery for Heavy-Duty Diesel Engines: A Review of Mechanical Turbocompounding
Authors: Jääskeläinen Hannu , Majewski W. Addy
Published: November 2017

Heat rejected with the exhaust gas, EGR, engine coolant and other engine components is a major source of efficiency loss in internal combustion engines. One important technology to recover some of this “wasted” heat is turbocompounding. The US Environmental Protection Agency (EPA) estimates that turbocompounding provides a 1.8% efficiency improvement, is already a commercial technology and a penetration rate of 10% is estimated by 2027. Line haul sleeper cab applications are the most likely to see the highest market penetration rates.

This paper presents an overview of mechanical turbocompounding for heavy-duty truck engines. For these applications, series turbocompounding is the most suitable configuration and a number of applications have used it since the early 1990s. Unlike other WHR technologies, turbocompounding interacts significantly with the engine through a higher exhaust backpressure. EGR makes it more challenging to realize an efficiency benefit from turbocompounding. It also makes emission control using aftertreatment technology more challenging due to a lower exhaust temperature.
Mesocrystalline calcium silicate hydrate: A bioinspired route toward elastic concrete materials
Authors: Picker Andreas , Nicoleau Luc , Burghard Zaklina , Bill Joachim , Zlotnikov Igor , Labbez Christophe , Nonat André , Cölfen Helmut
Published: November 2017

Controlled aggregation of polymer-stabilized calcium silicate hydrate nanoparticles leads to elastic cementitious materials.
Origami lattices with free-form surface ornaments
Authors: Janbaz Shahram , Noordzij Niels , Widyaratih Dwisetya S. , Hagen Cornelis W. , Fratila-Apachitei Lidy E. , Zadpoor Amir A.
Published: November 2017

We introduce folding strategies to fabricate lattice structures with arbitrarily complex surface (nano-) ornaments.
Stitching h-BN by atomic layer deposition of LiF as a stable interface for lithium metal anode
Authors: Xie Jin , Liao Lei , Gong Yongji , Li Yanbin , Shi Feifei , Pei Allen , Sun Jie , Zhang Rufan , Kong Biao , Subbaraman Ram , Christensen Jake , Cui Yi
Published: November 2017

Selective atomic layer deposition of LiF on h-BN as an interfacial layer enables stable cycling of Li metal anodes.
Political chill reverses thaw in U.S.-Cuban science
Authors: Stone Richard
Published: November 2017

Blows to research collaborations are collateral damage of the Trump administration's moves to cool relations
Host DNases prevent vascular occlusion by neutrophil extracellular traps
Authors: Jiménez-Alcázar Miguel , Rangaswamy Chandini , Panda Rachita , Bitterling Josephine , Simsek Yashin J. , Long Andy T. , Bilyy Rostyslav , Krenn Veit , Renné Christoph , Renné Thomas , Kluge Stefan , Panzer Ulf , Mizuta Ryushin , Mannherz Hans Georg , Kitamura Daisuke , Herrmann Martin , Napirei Markus , Fuchs Tobias A.
Published: November 2017

Blood DNases hack the NET

Neutrophil extracellular traps (NETs) are lattices of processed chromatin decorated with select secreted and cytoplasmic proteins that trap and neutralize microbes. However, their inappropriate release may do more harm than good by promoting inflammation and thrombosis. Jiménez-Alcázar
et al.
report that two deoxyribonucleases (DNases), DNASE1 and DNASE1L3, have partially redundant roles in degrading NETs in the circulation (see the Perspective by Gunzer). Knockout mice lacking these enzymes were unable to tolerate chronic neutrophilia, quickly dying after blood vessels were occluded by NET clots. Furthermore, the damage unleashed by clots during septicemia was enhanced when these DNases were absent.

Science
, this issue p.
1202
; see also p.
1126
Egg accumulation with 3D embryos provides insight into the life history of a pterosaur
Authors: Wang Xiaolin , Kellner Alexander W. A. , Jiang Shunxing , Cheng Xin , Wang Qiang , Ma Yingxia , Paidoula Yahefujiang , Rodrigues Taissa , Chen He , Sayão Juliana M. , Li Ning , Zhang Jialiang , Bantim Renan A. M. , Meng Xi , Zhang Xinjun , Qiu Rui , Zhou Zhonghe
Published: November 2017

Even more like birds

Ecological convergence between pterosaurs and birds is often invoked, but to what degree the two groups share behavior is debated. Wang
et al.
describe a site with more than 100 fossilized pterosaur eggs that reveals that hatchling pterosaurs were likely not as precocial as previously thought (see the Perspective by Deeming). Furthermore, the overlaying of multiple clutches suggests that the pterosaurs may have exhibited breeding site fidelity, similar to rookery-breeding seabirds. Thus, the similarity between these two groups goes beyond wings.

Science
, this issue p.
1197
; see also p.
1124
Benzene submits to main-group power
Authors: Mulvey Robert Emmet
Published: November 2017

Calcium hydride reagents allow benzene to react with electron-rich reagents
Biohybrid actuators for robotics: A review of devices actuated by living cells
Authors: Ricotti Leonardo , Trimmer Barry , Feinberg Adam W. , Raman Ritu , Parker Kevin K. , Bashir Rashid , Sitti Metin , Martel Sylvain , Dario Paolo , Menciassi Arianna
Published: November 2017

Biohybrid systems exploit the unique features of living cells or tissues for actuating artificial devices.
Atrial fibrillation prevention: an appraisal of current evidence
Authors: Boriani Giuseppe , Proietti Marco
Published: November 2017

Atrial fibrillation (AF), which is the most diagnosed arrhythmia, is becoming a significant issue for health policy-makers. In particular, more and more attention is being devoted to AF prevention. Indeed, several studies recently published point out how targeted interventions could be useful in reducing the risk of AF occurrence (or recurrence). In this review, we briefly summarised the role of the major risk factors associated with the incidence of AF, as well as the effectiveness of interventions aimed at controlling these risk factors. Several general risk factors, such as alcohol consumption, physical activity, smoking habit, as well as specific cardiovascular risk factors as diabetes mellitus, hypertension and obesity have a relevant impact in determining the occurrence of AF, along with a strong clinical evidence of a dose–effect response mechanism for most of the factors examined. Specific interventions aimed at controlling risk factors have been showed to clearly reduce the risk of AF in several cohorts. Even more importantly, integrated programmes aimed at controlling for multiple risk factors would be more efficient in terms of reducing risk of AF, in particular whena stricter control is observed. AF prevention requires a series of initiatives focused on the many risk factors that we reviewed, as well as a more integrated approach, which should involve many stakeholders at different levels. In this light and also considering the constantly changing epidemiology, AF prevention may constitute a future ‘win–win’ strategy for all the stakeholders.
Mineralogy and genesis of the Ni–Co lateritic regolith deposit of the Çaldağ area (Manisa, western Anatolia), Turkey
Authors: Helvacı Cahit , Oyman Tolga , Gündoğan İbrahim , Sözbilir Hasan , Parlak Osman , Kadir Selahattin , Güven Necip
Published: November 2017

The Çaldağ Ni–Co deposit is characterized by a reddish brown oxide lateritic regolith, containing residual Ni deposit formed by the intense tropical weathering of peridotites. Nickel–Co ore is associated with transported ferricrete during the late Paleocene – middle Eocene, represented by colloform Fe oxides and residual lateritization during the Oligocene. The lateritic regoliths are developed over dunitic ultramafic rocks and consist mainly of smectite, berthierine, kaolinite, gypsum, pyrite, takovite, and pecoraite. These units were examined using polarized-light microscopy, X-ray diffraction, scanning and transmission electron microscopy, and geochemical methods. Mineralogical zonation from the base of the profile upwards has the following zones: ultramafic bedrocks, serpentinized ultramafic rocks (saprock), saprolite, carbonate- and sulfide-bearing zone, ferruginous saprolite zone, and silcrete. In addition, Fe oxides, smectite and opal-CT, and quartz increase towards the surface, whereas olivine, pyroxene, and serpentine decrease upwards in response to chemical weathering. Nickel–Co mineralization associated with Fe oxides and smectitic clays formed under wet and dry conditions, respectively, as a result of an increased Fe2O3+ Al2O3+ Ni + Co/MgO ratio. Field observations and mineralogical and geochemical analyses reveal that the smectite formed under basic conditions was controlled by multistage chemical weathering of ultramafic and volcanic rocks and by the concentrations of Si, Al, Fe, and Mg. Locally, concentrations of S in conjunction with Fe and Ca resulted in precipitation of goethite–hematite, gypsum, and pyrite in dissolution voids in association with smectite under acidic conditions that developed in a well-drained system.
PARALLEL STUDIES OF COMPLEMENT AND COAGULATION II. THE RELATIVE EFFECTS OF DICUMAROL
Authors: Boulanger Paul , Rice Christine E.
Published: November 2017

A marked increase was produced in the prothrombin time values of plasma of guinea pigs through the administration of dicumarol, without any accompanying change in the whole complement titer of the serum or in its relative concentration in the four major complement components.
DIGITAL TRANSFORMATION OF BUSINESS MODELS — BEST PRACTICE, ENABLERS, AND ROADMAP
Authors: SCHALLMO DANIEL , WILLIAMS CHRISTOPHER A. , BOARDMAN LUKE
Published: November 2017

The purpose of this paper is to clarify the definition of digital transformation (DT) and to introduce a structured approach with phases, activities and results. Our research is based on a literature review which provides insight into the basic understanding of DT. Examples complete the research and show the practical application of DT. The main findings are that although DT is a widely known concept, an approach for the structured DT of business models is missing. The paper offers a clear definition of the DT of business models and phases for the DT of business models. Moreover, the paper offers examples of enablers and DT.
Design Experiences in Minimalistic Flying Sensor Node Platform through SensorFly
Authors: Chen Xinlei , Purohit Aveek , Pan Shijia , Ruiz Carlos , Han Jun , Sun Zheng , Mokaya Frank , Tague Patric , Zhang Pei
Published: November 2017

Indoor emergency response situations, such as urban fire, are characterized by dangerous constantly changing operating environments with little access to situational information for first responders.
In situ
information about the conditions, such as the extent and evolution of an indoor fire, can augment rescue efforts and reduce risk to emergency personnel. Static sensor networks that are pre-deployed or manually deployed have been proposed but are less practical due to need for large infrastructure, lack of adaptivity, and limited coverage. Controlled-mobility in sensor networks, that is, the capability of nodes to move as per network needs can provide the desired autonomy to overcome these limitations.

In this article, we present SensorFly, a controlled-mobile aerial sensor network platform for indoor emergency response application. The miniature, low-cost sensor platform has capabilities to self deploy, achieve three-dimensional sensing, and adapt to node and network disruptions in harsh environments. We describe hardware design trade-offs, the software architecture, and the implementation that enables limited-capability nodes to collectively achieve application goals. Through the indoor fire monitoring application scenario, we validate that the platform can achieve coverage and sensing accuracy that matches or exceeds static sensor networks and provide higher adaptability and autonomy.
Quality of Information in Mobile Crowdsensing
Authors: Restuccia Francesco , Ghosh Nirnay , Bhattacharjee Shameek , Das Sajal K. , Melodia Tommaso
Published: November 2017

Smartphones have become the most pervasive devices in people’s lives and are clearly transforming the way we live and perceive technology. Today’s smartphones benefit from almost ubiquitous Internet connectivity and come equipped with a plethora of inexpensive yet powerful embedded sensors, such as an accelerometer, a gyroscope, a microphone, and a camera. This unique combination has enabled revolutionary applications based on the mobile crowdsensing paradigm, such as real-time road traffic monitoring, air and noise pollution, crime control, and wildlife monitoring, just to name a few. Differently from prior sensing paradigms, humans are now the primary actors of the sensing process, since they become fundamental in retrieving reliable and up-to-date information about the event being monitored. As humans may behave unreliably or maliciously, assessing and guaranteeing Quality of Information (QoI) becomes more important than ever. In this article, we provide a new framework for defining and enforcing the QoI in mobile crowdsensing and analyze in depth the current state of the art on the topic. We also outline novel research challenges, along with possible directions of future work.
Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation
Authors: Gehrke Nadine , Nagel Michael , Straub Beate K. , Wörns Marcus A. , Schuchmann Marcus , Galle Peter R. , Schattenberg Jörn M.
Published: November 2017

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP−/−) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68+ macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP−/− mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP−/− mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury.

NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.
β-PIX plays an important role in regulation of intestinal epithelial restitution by interacting with GIT1 and Rac1 after wounding
Authors: Rathor Navneeta , Chung Hee Kyoung , Wang Shelley R. , Qian Michael , Turner Douglas J. , Wang Jian-Ying , Rao Jaladanki N.
Published: November 2017

Early gut mucosal restitution is a process by which intestinal epithelial cells (IECs) migrate over the wounded area, and its defective regulation occurs commonly in various critical pathological conditions. This rapid reepithelialization is mediated by different activating small GTP-binding proteins, but the exact mechanism underlying this process remains largely unknown. Recently, it has been reported that interaction between p21-activated kinase-interacting exchange factor (β-PIX) and G protein-coupled receptor kinase-interacting protein 1 (GIT1) activates small GTPases and plays an important role in the regulation of cell motility. Here, we show that induced association of β-PIX with GIT1 is essential for the stimulation of IEC migration after wounding by activating Rac1. Levels of β-PIX and GIT1 proteins and their association in differentiated IECs (line of IEC-Cdx2L1) were much higher than those observed in undifferentiated IECs (line of IEC-6), which was associated with an increase in IEC migration after wounding. Decreased levels of endogenous β-PIX by its gene-silencing destabilized β-PIX/GIT1 complexes, repressed Rac1 activity and inhibited cell migration over the wounded area. In contrast, ectopic overexpression of β-PIX increased the levels of β-PIX/GIT1 complexes, stimulated Rac1 activity, and enhanced intestinal epithelial restitution. Increased levels of cellular polyamines also stimulated β-PIX/GIT1 association, increased Rac1 activity, and promoted the epithelial restitution. Moreover, polyamine depletion decreased cellular abundances of β-PIX/GIT1 complex and repressed IEC migration after wounding, which was rescued by ectopic overexpression of β-PIX or GIT1. These results indicate that β-PIX/GIT1/Rac1 association is necessary for stimulation of IEC migration after wounding and that this signaling pathway is tightly regulated by cellular polyamines.

NEW & NOTEWORTHY Our current study demonstrates that induced association of β-PIX with GIT1 is essential for the stimulation of intestinal epithelial restitution by activating Rac1, and this signaling pathway is tightly regulated by cellular polyamines.
Prior automatic posture and activity identification improves physical activity energy expenditure prediction from hip-worn triaxial accelerometry
Authors: Garnotel M. , Bastian T. , Romero-Ugalde H. M. , Maire A. , Dugas J. , Zahariev A. , Doron M. , Jallon P. , Charpentier G. , Franc S. , Blanc S. , Bonnet S. , Simon C.
Published: November 2017

Accelerometry is increasingly used to quantify physical activity (PA) and related energy expenditure (EE). Linear regression models designed to derive PAEE from accelerometry-counts have shown their limits, mostly due to the lack of consideration of the nature of activities performed. Here we tested whether a model coupling an automatic activity/posture recognition (AAR) algorithm with an activity-specific count-based model, developed in 61 subjects in laboratory conditions, improved PAEE and total EE (TEE) predictions from a hip-worn triaxial-accelerometer (ActigraphGT3X+) in free-living conditions. Data from two independent subject groups of varying body mass index and age were considered: 20 subjects engaged in a 3-h urban-circuit, with activity-by-activity reference PAEE from combined heart-rate and accelerometry monitoring (Actiheart); and 56 subjects involved in a 14-day trial, with PAEE and TEE measured using the doubly-labeled water method. PAEE was estimated from accelerometry using the activity-specific model coupled to the AAR algorithm (AAR model), a simple linear model (SLM), and equations provided by the companion-software of used activity-devices (Freedson and Actiheart models). AAR-model predictions were in closer agreement with selected references than those from other count-based models, both for PAEE during the urban-circuit (RMSE = 6.19 vs 7.90 for SLM and 9.62 kJ/min for Freedson) and for EE over the 14-day trial, reaching Actiheart performances in the latter (PAEE: RMSE = 0.93 vs. 1.53 for SLM, 1.43 for Freedson, 0.91 MJ/day for Actiheart; TEE: RMSE = 1.05 vs. 1.57 for SLM, 1.70 for Freedson, 0.95 MJ/day for Actiheart). Overall, the AAR model resulted in a 43% increase of daily PAEE variance explained by accelerometry predictions.

NEW & NOTEWORTHY Although triaxial accelerometry is widely used in free-living conditions to assess the impact of physical activity energy expenditure (PAEE) on health, its precision and accuracy are often debated. Here we developed and validated an activity-specific model which, coupled with an automatic activity-recognition algorithm, improved the variance explained by the predictions from accelerometry counts by 43% of daily PAEE compared with models relying on a simple relationship between accelerometry counts and EE.
Peripheral Neuropathy Induced by Microtubule-Targeted Chemotherapies: Insights into Acute Injury and Long-term Recovery
Authors: Wozniak Krystyna M. , Vornov James J. , Wu Ying , Liu Ying , Carozzi Valentina A. , Rodriguez-Menendez Virginia , Ballarini Elisa , Alberti Paola , Pozzi Eleonora , Semperboni Sara , Cook Brett M. , Littlefield Bruce A. , Nomoto Kenichi , Condon Krista , Eckley Sean , DesJardins Christopher , Wilson Leslie , Jordan Mary A. , Feinstein Stuart C. , Cavaletti Guido , Polydefkis Michael , Slusher Barbara S.
Published: November 2017

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3–6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.

Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. Cancer Res; 78(3); 817–29. ©2017 AACR.
Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study
Authors: Norquist Barbara M. , Brady Mark F. , Harrell Maria I. , Walsh Tom , Lee Ming K. , Gulsuner Suleyman , Bernards Sarah S. , Casadei Silvia , Burger Robert A. , Tewari Krishnansu S. , Backes Floor , Mannel Robert S. , Glaser Gretchen , Bailey Cheryl , Rubin Stephen , Soper John , Lankes Heather A. , Ramirez Nilsa C. , King Mary Claire , Birrer Michael J. , Swisher Elizabeth M.
Published: November 2017

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab.

Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS).

Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57–0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50–0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66–0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59–0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40–0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25–0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.

Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777–83. ©2017 AACR.
Whole-Exome Sequencing of Cell-Free DNA Reveals Temporo-spatial Heterogeneity and Identifies Treatment-Resistant Clones in Neuroblastoma
Authors: Chicard Mathieu , Colmet-Daage Leo , Clement Nathalie , Danzon Adrien , Bohec Mylène , Bernard Virginie , Baulande Sylvain , Bellini Angela , Deveau Paul , Pierron Gaëlle , Lapouble Eve , Janoueix-Lerosey Isabelle , Peuchmaur Michel , Corradini Nadège , Defachelles Anne Sophie , Valteau-Couanet Dominique , Michon Jean , Combaret Valérie , Delattre Olivier , Schleiermacher Gudrun
Published: November 2017

Purpose: Neuroblastoma displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression.

Experimental Design: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole-exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 neuroblastoma patients.

Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of single-nucleotide variants (SNV) and copy number alterations, with 41% and 93% of all detected alterations common to the primary neuroblastoma and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate time points during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2.

Conclusions: Modelization of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating toward tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies. Clin Cancer Res; 24(4); 939–49. ©2017 AACR.
Surviving Ovarian Cancer: An Affair between Defective DNA Repair and RB1
Authors: Peng Guang , Mills Gordon B.
Published: November 2017

Detailed clinical and molecular evaluation of large cohorts of exceptional survivors provides an unprecedented opportunity to identify mechanisms underlying long-term survival that can drive future therapeutic approaches and biomarker development. Exceptional survivors of high-grade serous ovarian cancer demonstrate concurrent disruption of homologous recombination DNA repair and retinoblastoma protein. Clin Cancer Res; 24(3); 508–10. ©2017 AACR.

See related article by Garsed et al., p. 569
Assessment of Bronchial Obstruction Using Lateral Pressure Measurement during Bronchoscopy
Authors: Nishine Hiroki , Hiramoto Takehiko , Inoue Takeo , Furuya Naoki , Kida Hirotaka , Handa Hiroshi , Nobuyama Seiichi , Mineshita Masamichi , Miyazawa Teruomi
Published: November 2017

Background: In patients with bronchial obstruction estimating the location of the maximal obstruction is crucial for guiding interventional bronchoscopy. However, flow-volume curves cannot discriminate between the right and left lungs. Objectives: The aim of this study was to physiologically evaluate bronchial obstruction during interventional bronchoscopy. Methods: We prospectively measured lateral airway pressure (Plat) at either side of the obstruction using a double-lumen catheter (pressure-pressure [P-P] curve) simultaneously to assess the degree of bronchial obstruction in 22 patients. The shape of the P-P curve was assessed to confirm the site of maximal obstruction. Results: In the experimental study, Plat was uniform between both bronchi in the normal model. For the unilateral and bilateral obstruction models, a phase shift was only seen for the more obstructed side. In healthy subjects, the angle of the P-P curve was close to 45° and linear in shape. In patients with bronchial obstruction, the angle was much smaller but approached 45° after the bronchoscopic procedure. The degree of bronchial obstruction was significantly correlated with the angle of the P-P curve (r = –0.51, p < 0.01). Dyspnea significantly increased when the airway lumen was obstructed by more than 60% (p < 0.0001), and when the P-P curve appeared loop-shaped (p < 0.01). Conclusions: The shape of the P-P curve could be used to detect the site of maximal obstruction for the optimal positioning of the stent and assess the need for additional procedures in real time in patients with bronchial obstruction.
Classifying Apnea of Prematurity by Transcutaneous Electromyography of the Diaphragm
Authors: Kraaijenga Juliette V. , Hutten Gerard J. , de Waal Cornelia G. , de Jongh Frans H. , Onland Wes , van Kaam Anton H.
Published: November 2017

Background: Treatment of apnea is highly dependent on the type of apnea. Chest impedance (CI) has inaccuracies in monitoring respiration, which compromises accurate apnea classification. Electrical activity of the diaphragm measured by transcutaneous electromyography (EMG) is feasible in preterm infants and might improve the accuracy of apnea classification. Objectives: To compare the accuracy of apnea classification based on diaphragmatic EMG (dEMG) and CI tracings in preterm infants. Methods: Fifteen cases of central apnea, 5 of obstructive apnea, and 10 of mixed apnea were selected from recordings containing synchronized continuous tracings of respiratory inductive plethysmography (RIP), airway flow, heart rate (HR), oxygen saturation (SpO2), and breathing activity measured by dEMG and CI. Twenty-two assessors (neonatologists, pediatricians-in-training, and nurses) classified each apnea twice; once based on dEMG, HR, and SpO2 tracings, and once based on CI, HR, and SpO2. The assessors were blinded to the type of respiratory tracing (dEMG or CI) and to the RIP and flow tracings. Results: In total 1,320 assessments were performed, and in 71.1% the apnea was classified correctly. Subgroup analysis based on respiratory tracing showed that 74.8% of the dEMG tracings were classified correctly compared to 67.3% of the CI tracings (p < 0.001). This improved apnea classification based on dEMG was present for central (86.7 vs. 80.3%, p < 0.02) and obstructive (56.4 vs. 32.7%, p < 0.001) apnea. The improved apnea classification based on dEMG tracing was independent of the type of assessor. Conclusion: Transcutaneous dEMG improves the accuracy of apnea classification when compared to CI in preterm infants, making this technique a promising candidate for future monitoring systems.
Cord Blood Biomarkers of Cardiac Dysfunction and Damage in Term Growth-Restricted Fetuses Classified by Severity Criteria
Authors: Perez-Cruz Míriam , Crispi Fàtima , Fernández María Teresa , Parra Johanna Alexandra , Valls Anna , Gomez Roig María Dolores , Gratacós Eduard
Published: November 2017

Objective: To assess cardiovascular function and damage in term small-for-gestational-age (SGA) and intrauterine growth-restricted (IUGR) fetuses by echocardiography and biomarkers in cord blood. Methods: This was a cohort study including 60 normal fetuses and 47 term small fetuses subclassified as small for gestational age (SGA) with estimated fetal weight (EFW) between the 3rd and 9th centiles and normal fetoplacental Doppler (n = 14) or intrauterine growth restriction (IUGR, n = 33) if EFW <3rd centile or EFW <10th centile together with cerebroplacental ratio <5th and/or mean uterine artery pulsatility index >95th centile. Fetal echocardiography included left myocardial performance index (MPI) and annular plane systolic excursion. Fetal B-type natriuretic peptide (BNP), troponin-I, heart-type fatty acid-binding proteins (H-FABP), and homocysteine concentrations were measured in cord blood collected at delivery. Results: Both SGA and IUGR cases presented echocardiographic signs of systolic and diastolic dysfunction with increased MPI (mean controls 0.43 [SD 0.12], SGA 0.47 [0.03], and IUGR 0.57 [0.08], p < 0.01) and decreased mitral annular plane systolic excursion (controls 6.0 mm [1.0], SGA 5.5 mm [0.6], and IUGR 4.9 mm [0.8], p = 0 01). IUGR fetuses presented increased levels of cord blood BNP (controls 17.2 pg/mL [11.5], SGA 22.4 pg/mL [10.7], and IUGR 31.2 pg/mL [26.8], p < 0.01). Troponin I was increased in both SGA and IUGR cases (controls 0.004 ng/mL [0.007], SGA 0.012 ng/mL [0.02], and IUGR 0.018 ng/mL [0.05], p < 0.01). H-FABP and homocysteine showed similar values among groups. Conclusions: Cardiac dysfunction and cell damage is a common feature of term SGA and IUGR fetuses despite of the severity criteria for perinatal outcome. Further research is needed to evaluate the potential long-term consequences on their cardiovascular system.