bluuebunny/crossref_metadata_2025 huggingface dataset:
Horizontal transfers of LTR retrotransposons in seven species of Rosales
Authors: Hou Fei , Ma Bi , Xin Youchao , Kuang Lulu , He Ningjia
Published: June 2018

Horizontal transposable element transfer (HTT) events have occurred among a large number of species and play important roles in the composition and evolution of eukaryotic genomes. HTTs are also regarded as effective forces in promoting genomic variation and biological innovation. In the present study, HTT events were identified and analyzed in seven sequenced species of Rosales using bioinformatics methods by comparing sequence conservation and Ka/Ksvalue of reverse transcriptase (RT) with 20 conserved genes, estimating the dating of HTTs, and analyzing the phylogenetic relationships. Seven HTT events involving long terminal repeat (LTR) retrotransposons, two HTTs between Morus notabilis and Ziziphus jujuba, and five between Malus domestica and Pyrus bretschneideri were identified. Further analysis revealed that these LTR retrotransposons had functional structures, and the copy insertion times were lower than the dating of HTTs, particularly in Mn.Zj.1 and Md.Pb.3. Altogether, the results demonstrate that LTR retrotransposons still have potential transposition activity in host genomes. These results indicate that HTT events are another strategy for exchanging genetic material among species and are important for the evolution of genomes.
Online Graph Coloring Against a Randomized Adversary
Authors: Burjons Elisabet , Hromkovič Juraj , Královič Rastislav , Královič Richard , Muñoz Xavier , Unger Walter
Published: June 2018

We consider an online model where an adversary constructs a set of [Formula: see text] instances [Formula: see text] instead of one single instance. The algorithm knows [Formula: see text] and the adversary will choose one instance from [Formula: see text] at random to present to the algorithm. We further focus on adversaries that construct sets of [Formula: see text]-chromatic instances. In this setting, we provide upper and lower bounds on the competitive ratio for the online graph coloring problem as a function of the parameters in this model. Both bounds are linear in [Formula: see text] and matching upper and lower bound are given for a specific set of algorithms that we call “minimalistic online algorithms”.
Vacuum persistence amplitude and gravitational potential in f(R) gravity
Authors: Jahan A. , Heydarnezhad S.
Published: June 2018

The source theory provides a straightforward way to obtain the Newton’s potential upon establishing the vacuum-to-vacuum transition amplitude in quantized Einstein theory of gravity. Here, we use the same method to derive the gravitational potential of two static point masses in f(R) = R + aR2 gravity.
A new family of solutions to Einstein’s vacuum field equations with cosmological constant
Authors: Yang Feng , Sun Qing-You
Published: June 2018

In this paper, we construct a new time-periodic solution and a new time-machine solution according to the general form of the new family of solutions to the Einstein’s vacuum field equations with cosmological constant. The time-periodic solutions have some relations with the loop universe. The time-machine solutions are spacetime configurations including closed time-like curves (CTCs), and allowing physical observers to return to their own past. This problem has been of concern a lot recently. We expect the new solutions obtained in this paper can be applied in modern cosmology and general relativity.
Effect of optical lattice on rotating Bose–Einstein condensates in synthetic magnetic field
Authors: Hua Jingmin , Wang Bing , Fan Genwang , Lan Yu , Zhao Qiang
Published: June 2018

In this paper, we study the static and dynamic properties of vortices formation in a rotating Bose–Einstein condensate in synthetic magnetic field. The condensate is confined in a harmonic potential and an optical lattice potential. We numerically solve the time-dependent Gross–Pitaevskii equation in two dimensions and compare the vortices formation process with rotating frame method. We derive the two expressions about vortex number N[Formula: see text] and chemical potential [Formula: see text] as a function of rotational frequency [Formula: see text], which show that the number of vortices N[Formula: see text] increases linearly with [Formula: see text], while the chemical potential [Formula: see text] remains nearly unchanged with increasing [Formula: see text]. The analytical results are in qualitative agreement with the numerical ones. Moreover, we also investigate the vortex dynamics. Numerical results indicate that the time spent for the formation of steady state vortices is reduced drastically if the optical lattice is considered. Nevertheless, the synthetic magnetic field approach is still low efficient to generate more vortices.
First-principles study of electronic and sodium-ion transport properties of transition-metal dichalcogenides
Authors: Liu Zheng-Hai , Lin Ying , Cao Can , Zou Shu-Liang , Xiao Jian-Tian , Xiao Jin , Chen Ling-Na
Published: June 2018

Two-dimensional (2D) layered materials such as transition-metal dichalcogenides TS[Formula: see text]X[Formula: see text] (T = Mo, W; X = Se, Te) are available in mono and bilayers forms. The Rashba spin splitting is induced by the breaking of inversion symmetry in monolayer. The electronic structure of TS[Formula: see text]X[Formula: see text] is sensitive to an applied electric field. The perpendicular electric field can tune the energy gap. The semiconductor–metal transition appears under the critical electric field in the MoSSe/WSSe heterobilayer, and MoSTe/WSTe heterobilayer exhibits metal character due to spin–orbit coupling. Moreover, the results show that during sodiation/desodiation processes single-phase transition occurs with one one-dimensional (1D) transportation paths of sodium ions in MoS2, suggesting fast diffusion. Our results provide important insights into a wide range of applications of spin-polarized semiconductors and energy storage for transition-metal dichalcogenides TS[Formula: see text]X[Formula: see text].
Persistence of magicity in neutron-rich exotic 78Ni in ground as well as excited states
Authors: Aggarwal Mamta , Saxena G.
Published: June 2018

Recent experimental observation of magicity in [Formula: see text]Ni has infused the interest to examine the persistence of the magic character across the [Formula: see text] shell gap in extremely neutron-rich exotic nucleus [Formula: see text]Ni in ground as well as excited states. A systematic study of Ni isotopes and [Formula: see text] isotones in ground state is performed within the microscopic framework of relativistic mean-field (RMF) theory and the triaxially deformed Nilsson–Strutinsky model (NSM). Ground state density distributions, charge form factors, radii, separation energies, pairing energies, single-particle energies and the shell corrections show strong magicity in [Formula: see text]Ni. Excited nuclei are treated within the statistical theory of hot rotating nuclei where the variations of level density parameter and entropy show significant magicity with a deep minima at [Formula: see text], which persists up to the temperatures [Formula: see text]1.5–2[Formula: see text]MeV and then slowly disappears with increasing temperature. Rotational states are evaluated and effect of rotation on [Formula: see text] ([Formula: see text]) isotones are studied. Our results agree very well with the available experimental data and few other theoretical calculations.
HETEROGENEITY IN RISK PREFERENCES LEADS TO STOCHASTIC VOLATILITY
Authors: LEISEN DIETMAR P. J.
Published: June 2018

This paper studies the price processes of a claim on terminal endowment and of a claim on firm book value when the underlying variables follow a bivariate geometric Brownian motion. If the state-price process is multiplicatively separable into time and endowment functions, our main result shows that firm (endowment) price volatility is stochastic (state-dependent) if, and only if, the endowment function is not a power function. In a pure exchange economy populated by two agents with constant relative risk aversion (CRRA) preferences we confirm the separability, and we show furthermore that firm (endowment) price volatility is stochastic (state-dependent) if, and only if, both agents are heterogeneous in risk-preferences.
A general renormalization procedure on the one-dimensional lattice and decay of correlations
Authors: Lopes Artur O.
Published: June 2018

We present a general form of renormalization operator [Formula: see text] acting on potentials [Formula: see text]. We exhibit the analytical expression of the fixed point potential [Formula: see text] for such operator [Formula: see text]. This potential can be expressed in a natural way in terms of a certain integral over the Hausdorff probability on a Cantor type set on the interval [0,1]. This result generalizes a previous one by Baraviera, Leplaideur and Lopes where the fixed point potential [Formula: see text] was of Hofbauer type.

For the potentials of Hofbauer type (a well-known case of phase transition) the decay is like [Formula: see text], [Formula: see text].

Among other things we present the estimation of the decay of correlation of the equilibrium probability associated to the fixed potential [Formula: see text] of our general renormalization procedure. In some cases we get polynomial decay like [Formula: see text], [Formula: see text], and in others a decay faster than [Formula: see text], when [Formula: see text].

The potentials [Formula: see text] we consider here are elements of the so-called family of Walters’ potentials on [Formula: see text] which generalizes a family of potentials considered initially by Hofbauer. For these potentials some explicit expressions for the eigenfunctions are known.

In a final section we also show that given any choice [Formula: see text] of real numbers varying with [Formula: see text] there exists a potential [Formula: see text] on the class defined by Walters which has a invariant probability with such numbers as the coefficients of correlation (for a certain explicit observable function).
On the existence and uniqueness of solution to a stochastic 2D Allen–Cahn–Navier–Stokes model
Authors: Medjo Theodore Tachim
Published: June 2018

We study, in this paper, a stochastic version of a coupled Allen–Cahn–Navier–Stokes model in a two-dimensional (2D) bounded domain. The model consists of the Navier–Stokes equations (NSEs) for the velocity, coupled with a Allen–Cahn model for the order (phase) parameter. We prove the existence and the uniqueness of a variational solution.
Occupation times of discrete-time fractional Brownian motion
Authors: Denker Manfred , Zheng Xiaofei
Published: June 2018

We prove a conditional local limit theorem for discrete-time fractional Brownian motions (dfBm) with Hurst parameter [Formula: see text]. Using results from infinite ergodic theory, it is then shown that the properly scaled occupation time of dfBm converges to a Mittag-Leffler distribution.
WBFQC: A new approach for compressing next-generation sequencing data splitting into homogeneous streams
Authors: Kumar Sanjeev , Agarwal Suneeta , Ranvijay
Published: June 2018

Genomic data nowadays is playing a vital role in number of fields such as personalized medicine, forensic, drug discovery, sequence alignment and agriculture, etc. With the advancements and reduction in the cost of next-generation sequencing (NGS) technology, these data are growing exponentially. NGS data are being generated more rapidly than they could be significantly analyzed. Thus, there is much scope for developing novel data compression algorithms to facilitate data analysis along with data transfer and storage directly. An innovative compression technique is proposed here to address the problem of transmission and storage of large NGS data. This paper presents a lossless non-reference-based FastQ file compression approach, segregating the data into three different streams and then applying appropriate and efficient compression algorithms on each. Experiments show that the proposed approach (WBFQC) outperforms other state-of-the-art approaches for compressing NGS data in terms of compression ratio (CR), and compression and decompression time. It also has random access capability over compressed genomic data. An open source FastQ compression tool is also provided here ( http://www.algorithm-skg.com/wbfqc/home.html ).
Large-time behavior of strong solutions to the compressible magnetohydrodynamic system in the critical framework
Authors: Shi Weixuan , Xu Jiang
Published: June 2018

We study the compressible viscous magnetohydrodynamic (MHD) system and investigate the large-time behavior of strong solutions near constant equilibrium (away from vacuum). In the 80s, Umeda et al. considered the dissipative mechanisms for a rather general class of symmetric hyperbolic–parabolic systems, which is given by [Formula: see text] Here, [Formula: see text] denotes the characteristic root of linearized equations. From the point of view of dissipativity, Kawashima in his doctoral dissertation established the optimal time-decay estimates of [Formula: see text]-[Formula: see text]) type for solutions to the MHD system. Now, by using Fourier analysis techniques, we present more precise description for the large-time asymptotic behavior of solutions, not only in extra Lebesgue spaces but also in a full family of Besov norms with the negative regularity index. Precisely, we show that the [Formula: see text] norm (the slightly stronger [Formula: see text] norm in fact) of global solutions with the critical regularity, decays like [Formula: see text] as [Formula: see text]. Our decay results hold in case of large highly oscillating initial velocity and magnetic fields, which improve Kawashima’s classical efforts.
Preparation and electrochemical properties of cobalt-phthalocyanine-decorated Fe3O4 nanoparticles
Authors: Hong Sun-Mi , Son Hoseung , Park Jong S.
Published: June 2018

Phthalocyanines (Pcs) have been known for excellent electron transfer properties owing to their extended [Formula: see text]-conjugated structures. In addition, functionalized iron oxide nanoparticles (Fe[Formula: see text]O[Formula: see text] NPs) have attracted considerable interest owing to their unique spectral and electronic properties. Hence, it can be reasonably expected that Fe[Formula: see text]O[Formula: see text] NPs decorated with Pc molecules could provide a useful electrocatalytic system. Herein, we present the preparation and electrochemical properties of cobalt-phthalocyanine (CoPc)-decorated Fe[Formula: see text]O[Formula: see text] NPs (CoPc@Fe[Formula: see text]O[Formula: see text]. The Fe[Formula: see text]O[Formula: see text] NPs were first coated with a silica layer to produce SiO[Formula: see text]@Fe[Formula: see text]O[Formula: see text]. Subsequently, CoPc with a siloxane end group (CoPc-TEOS) was anchored to the outer surface of the SiO[Formula: see text]@Fe[Formula: see text]O[Formula: see text]. The CoPc@Fe[Formula: see text]O[Formula: see text] thus prepared was fully analyzed using various characterization methods. Distinctive electrochemical responses of CoPc and CoPc@Fe[Formula: see text]O[Formula: see text] in the presence of picric acid were observed, demonstrating the potential application of the current approach to electrochemical catalysis.
Photoluminescence behavior and thermal stability of Eu-doped SiAlON thin films prepared by RF magnetron co-sputtering of SiAlON and Eu2O3 targets
Authors: Hou Shaoke , Liu Qian , Ni Jia , Liu Guanghui , Wan Dongyun
Published: June 2018

Eu-doped SiAlON thin films were successfully prepared by co-sputtering method using [Formula: see text]-SiAlON and Eu2O3 ceramic target. The photoluminescence behaviors of the films are investigated as a function of Eu ions concentration and temperature. The doping concentration of Eu ions in films can be effectively controlled by adjusting the sputtering power of Eu2O3 target. XRD analysis and SEM morphology images illustrate that the Eu-doped SiAlON thin films are amorphous, dense, and smooth, no matter they experienced high temperature heat-treatment or not after co-sputtering deposition. An intense and broad blue emission band peaking at 416–450[Formula: see text]nm was exhibited when the films upon excitation at 275[Formula: see text]nm, proving a typical Eu[Formula: see text] emission. The divalent state of Eu ions in films was further identified. As the sputtering power of Eu2O3 target increases, the emission peak of Eu[Formula: see text] shows a red-shift. The prepared thin films possess a better resistant property of thermal quenching and the relative fluorescence intensity at 100∘C can remain about 86% of its initial value at room temperature.
Optimal Execution in a Multiplayer Model of Transient Price Impact
Authors: Strehle Elias
Published: June 2018

Trading algorithms that execute large orders are susceptible to exploitation by order anticipation strategies. This paper studies the influence of order anticipation strategies in a multi-investor model of optimal execution under transient price impact. Existence and uniqueness of a Nash equilibrium is established under the assumption that trading incurs quadratic transaction costs. A closed-form representation of the Nash equilibrium is derived for exponential decay kernels. With this representation, it is shown that while order anticipation strategies raise the execution costs of a large order significantly, they typically do not cause price overshooting in the sense of Brunnermeier and Pedersen.
Alternative characterization of volatility of short-term interest rate
Authors: Bhar Ramaprasad , Lee Damien
Published: June 2018

Most reported stochastic volatility (SV) model for interest rates only deals with an AR specification for the latent factor process. We show in this paper the technical details for specifying the SV model for interest rates that includes an ARMA structure, a jump component and additional exogenous variables for the latent factor process. We demonstrate the efficacy of this approach with an application to the US short-term interest rate data. We find that the elasticity parameter of the variance is closer to 0.5, i.e., similar to that of the Cox–Ingersoll–Ross (1985) model of interest rates. This is quite a contrast to the finding Chan et al. [Chan, KC, GA Karolyi, F Longstaff and A Sanders (1992). The volatility of short-term interest rates: An empirical comparison of alternative models of term structure of interest rates, Journal of Finance, 47, 1209–1227]. who found the elasticity to be close to 1.5.
VIX derivatives valuation and estimation based on closed-form series expansions
Authors: Zhao Zhe , Cui Zhenyu , Florescu Ionuţ
Published: June 2018

We propose a new methodology to evaluate VIX derivatives. The approach is based on a closed-form Hermite series expansion, and can be applied to general stochastic volatility models. We exemplify the proposed method using the Heston model, the mean-reverting CEV model and the 3/2 model. Numerical results show that the proposed method is accurate and efficient.
The role of septic tanks in the dissolved phosphorus budget of the Upper River Nar and possible implications for other catchments
Authors: Speed C. D. , Fretwell B. A. , Davison P. S.
Published: June 2018

In rural areas of the UK, properties are often served by septic tanks, which discharge sewage effluent to ground close to the property served. Dissolved phosphorus as orthophosphate (OP) is present in the raw sewage and the discharge. This study investigated whether OP from sewage effluent discharges to ground from septic tanks is a significant OP source within the Upper River Nar at the catchment scale. An approach involving multiple strands of evidence was used: first, a high-level source apportionment apportioned only 0.9–1.0% of the catchment phosphorus to septic tanks compared with 40% agricultural sources and 9.9% urban (Mileham village); second, a bulk phosphate dilution assessment, based on diluting the total OP from septic tank discharges by potential recharge (excluding attenuation) predicted diluted effluent concentrations that were insufficient to affect surface water; third, an individual septic tank assessment using a groundwater fate and transport model showed that septic tank OP for the majority of properties is attenuated to concentrations below 0.001 mg P l
−1
before the effluent reaches surface water. Consideration is given to higher rural population densities, septic tanks clustered proximal to surface water and where greater fracture flow in the Chalk reduces the aquifer's ability to attenuate the OP.
Liberation of selenium from alteration of the Bowland Shale Formation: evidence from the Mam Tor landslide
Authors: Parnell John , Bullock Liam , Armstrong Joseph , Perez Magali
Published: June 2018

The Bowland Shale Formation is anomalously rich in selenium (Se) at levels an order of magnitude greater than other black shales. The Mam Tor landslide, Derbyshire, England, offers an opportunity to measure whether the Se anomaly is conferred to the alteration products formed by oxidative water flow through the shale. Selenium in the shale is concentrated in diagenetic pyrite. Alteration of the shale causes decomposition of the pyrite to iron oxyhydroxide, which is carried in colloidal form (ochre) by springs draining the landslide. The iron oxyhydroxide contains anomalously high Se, and anomalously high Se was measured in water ponded where the ochre precipitated, although not in flowing groundwater. Other trace elements including cadmium and thallium also occur at concentrations higher than in other ochres. Given the widespread nature of the Se anomaly in the Bowland Shale Formation and equivalents across Britain and Ireland, any alteration products derived from workings through the shale should be disposed of with care.
Harmonium
Authors: Pannuto Pat , Kempke Benjamin , Chuo Li-Xuan , Blaauw David , Dutta Prabal
Published: June 2018

We introduce
Harmonium
, a novel ultra wideband (UWB) RF localization architecture that achieves decimeter-scale accuracy indoors. Harmonium strikes a balance between tag simplicity and processing complexity to provide fast and accurate indoor location estimates. Harmonium uses only commodity components and consists of a small, inexpensive, lightweight, and FCC-compliant UWB transmitter or
tag
, fixed infrastructure
anchors
with known locations, and centralized processing that calculates the tag’s position. Anchors employ a new frequency-stepped narrowband receiver architecture that rejects narrowband interferers and extracts high-resolution timing information without the cost or complexity of traditional UWB approaches. In a complex indoor environment, 90% of position estimates obtained with Harmonium exhibit less than 31 cm of error with an average of 9 cm of inter-sample noise. In non-line-of-sight conditions (i.e., through-wall), 90% of position error is less than 42 cm. The tag draws 75 mW when actively transmitting, or 3.9 mJ per location fix at the 19 Hz update rate. Tags weigh 3 g and cost $4.50 USD at modest volumes. Furthermore, VLSI-based design concepts are identified for a simple, low-power realization of the Harmonium tag to offer a roadmap for the realization of Harmonium concepts in future integrated systems. Harmonium introduces a new design point for indoor localization and enables localization of small, fast objects such as micro quadrotors, devices previously restricted to expensive optical motion capture systems.
Plant-Parasitic Nematodes and Food Security in Sub-Saharan Africa
Authors: Coyne Danny L. , Cortada Laura , Dalzell Johnathan J. , Claudius-Cole Abiodun O. , Haukeland Solveig , Luambano Nessie , Talwana Herbert
Published: June 2018

Sub-Saharan Africa (SSA) is a region beset with challenges, not least its ability to feed itself. Low agricultural productivity, exploding populations, and escalating urbanization have led to declining per capita food availability. In order to reverse this trend, crop production systems must intensify, which brings with it an elevated threat from pests and diseases, including plant-parasitic nematodes. A holistic systems approach to pest management recognizes disciplinary integration. However, a critical under-representation of nematology expertise is a pivotal shortcoming, especially given the magnitude of the threat nematodes pose under more intensified systems. With more volatile climates, efficient use of water by healthy root systems is especially crucial. Within SSA, smallholder farming systems dominate the agricultural landscape, where a limited understanding of nematode problems prevails. This review provides a synopsis of current nematode challenges facing SSA and presents the opportunities to overcome current shortcomings, including a means to increase nematology capacity.
Multifaceted Impacts of Bacteriophages in the Plant Microbiome
Authors: Koskella Britt , Taylor Tiffany B.
Published: June 2018

Plant-associated bacteria face multiple selection pressures within their environments and have evolved countless adaptations that both depend on and shape bacterial phenotype and their interaction with plant hosts. Explaining bacterial adaptation and evolution therefore requires considering each of these forces independently as well as their interactions. In this review, we examine how bacteriophage viruses (phages) can alter the ecology and evolution of plant-associated bacterial populations and communities. This includes influencing a bacterial population's response to both abiotic and biotic selection pressures and altering ecological interactions within the microbiome and between the bacteria and host plant. We outline specific ways in which phages can alter bacterial phenotype and discuss when and how this might impact plant-microbe interactions, including for plant pathogens. Finally, we highlight key open questions in phage-bacteria-plant research and offer suggestions for future study.
Antifibrotic cardioprotection of berberine via downregulating myocardial IGF-1 receptor-regulated MMP-2/MMP-9 expression in diabetic rats
Authors: Li Guohua , Xing Wenjuan , Zhang Min , Geng Fenghao , Yang Hongyan , Zhang Haifeng , Zhang Xing , Li Jia , Dong Ling , Gao Feng
Published: June 2018

Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Our previous studies have shown that berberine, a natural alkaloid, attenuates cardiac ischemia-reperfusion injury in diabetic rats. The aim of present study was to investigate the effects of long-term berberine treatment on cardiac remodeling in diabetic rats and the underlying mechanisms. Diabetic rats induced by low-dose streptozotocin injection combined with 8 wk of high-fat diet displayed significant cardiac matrix collagen deposition and dysfunction, whereas berberine administration (200 mg·kg−1·day−1, gavage 4 wk) significantly ameliorated cardiac fibrosis and dysfunction and reduced cardiac IGF-1 receptor (IGF-1R) expression in diabetic rats. Interestingly, IGF-1R expression was upregulated in cardiac fibroblasts isolated from diabetic hearts or cultured in high-glucose conditions (30 mM). High glucose treatment or IGF-1R overexpression increased matrix metalloproteinase (MMP)-2/MMP-9 expression, α-smooth muscle actin (α-SMA), and collagen type I expression in cardiac fibroblasts. In contrast, berberine treatment significantly inhibited IGF-1R expression and exerted an antifibrotic effect in high glucose-cultured cardiac fibroblasts, as manifested by decreased MMP-2/MMP-9, α-SMA, and collagen type I expression, whereas IGF-1R siRNA plus berberine treatment did not further enhance this antifibrotic effect compared with berberine treatment alone. Taken together, long-term berberine treatment ameliorates cardiac fibrosis and dysfunction by downregulating IGF-1R expression in cardiac fibroblasts and subsequently reducing MMP-2/MMP-9, α-SMA, and collagen type I expression in diabetic hearts. The findings suggest the therapeutic potential of berberine for diabetic cardiomyopathy associated with cardiac fibrosis.

NEW & NOTEWORTHY Berberine downregulated IGF-1 receptor expression and matrix metalloproteinase-2/matrix metalloproteinase-9 levels in cardiac fibroblasts and thus inhibited fibroblast differentiation and collagen overproduction in diabetic hearts, suggesting a novel mechanism for antifibrotic cardioprotection of berberine in type 2 diabetes.
A mini review: Proteomics approaches to understand disused vs. exercised human skeletal muscle
Authors: Cho Yoshitake , Ross Robert S.
Published: June 2018

Immobilization, bed rest, or denervation leads to muscle disuse and subsequent skeletal muscle atrophy. Muscle atrophy can also occur as a component of various chronic diseases such as cancer, AIDS, sepsis, diabetes, and chronic heart failure or as a direct result of genetic muscle disorders. In addition to this atrophic loss of muscle mass, metabolic deregulation of muscle also occurs. In contrast, physical exercise plays a beneficial role in counteracting disuse-induced atrophy by increasing muscle mass and strength. Along with this, exercise can also reduce mitochondrial dysfunction and metabolic deregulation. Still, while exercise causes valuable metabolic and functional adaptations in skeletal muscle, the mechanisms and effectors that lead to these changes such as increased mitochondria content or enhanced protein synthesis are not fully understood. Therefore, mechanistic insights may ultimately provide novel ways to treat disuse induced atrophy and metabolic deregulation. Mass spectrometry (MS)-based proteomics offers enormous promise for investigating the molecular mechanisms underlying disuse and exercise-induced changes in skeletal muscle. This review will focus on initial findings uncovered by using proteomics approaches with human skeletal muscle specimens and discuss their potential for the future study.
Dual Src and MEK Inhibition Decreases Ovarian Cancer Growth and Targets Tumor Initiating Stem-Like Cells
Authors: Simpkins Fiona , Jang Kibeom , Yoon Hyunho , Hew Karina E. , Kim Minsoon , Azzam Diana J. , Sun Jun , Zhao Dekuang , Ince Tan A. , Liu Wenbin , Guo Wei , Wei Zhi , Zhang Gao , Mills Gordon B. , Slingerland Joyce M.
Published: June 2018

Purpose: Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition.

Experimental Design: MEK and Src activation was assayed in primary HGSOC from The Cancer Genome Atlas (TGGA). Effects of dual kinase inhibition were assayed on cell-cycle, apoptosis, gene, and proteomic analysis; cancer stem cells; and xenografts.

Results: Both Src and MAPK are coactivated in 31% of HGSOC, and this associates with worse overall survival on multivariate analysis. Frequent dual kinase activation in HGSOC led us to assay the efficacy of combined Src and MEK inhibition. Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell-cycle arrest in vitro, and tumor inhibition in xenografts. Gene expression and proteomic analysis confirmed cell-cycle inhibition and autophagy. Dual therapy also potently inhibited tumor-initiating cells. Src and MAPK were both activated in tumor-initiating populations. Combination treatment followed by drug washout decreased sphere formation and ALDH1+ cells. In vivo, tumors dissociated after dual therapy showed a marked decrease in ALDH1 staining, sphere formation, and loss of tumor-initiating cells upon serial xenografting.

Conclusions: Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2–mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating ovarian cancer populations, supporting further evaluation of combined Src–MEK inhibition in clinical trials. Clin Cancer Res; 24(19); 4874–86. ©2018 AACR.
Functional Parameters Derived from Magnetic Resonance Imaging Reflect Vascular Morphology in Preclinical Tumors and in Human Liver Metastases
Authors: Kannan Pavitra , Kretzschmar Warren W. , Winter Helen , Warren Daniel , Bates Russell , Allen Philip D. , Syed Nigar , Irving Benjamin , Papiez Bartlomiej W. , Kaeppler Jakob , Markelc Bosjtan , Kinchesh Paul , Gilchrist Stuart , Smart Sean , Schnabel Julia A. , Maughan Tim , Harris Adrian L. , Muschel Ruth J. , Partridge Mike , Sharma Ricky A. , Kersemans Veerle
Published: June 2018

Purpose: Tumor vessels influence the growth and response of tumors to therapy. Imaging vascular changes in vivo using dynamic contrast-enhanced MRI (DCE-MRI) has shown potential to guide clinical decision making for treatment. However, quantitative MR imaging biomarkers of vascular function have not been widely adopted, partly because their relationship to structural changes in vessels remains unclear. We aimed to elucidate the relationships between vessel function and morphology in vivo.

Experimental Design: Untreated preclinical tumors with different levels of vascularization were imaged sequentially using DCE-MRI and CT. Relationships between functional parameters from MR (iAUC, Ktrans, and BATfrac) and structural parameters from CT (vessel volume, radius, and tortuosity) were assessed using linear models. Tumors treated with anti-VEGFR2 antibody were then imaged to determine whether antiangiogenic therapy altered these relationships. Finally, functional–structural relationships were measured in 10 patients with liver metastases from colorectal cancer.

Results: Functional parameters iAUC and Ktrans primarily reflected vessel volume in untreated preclinical tumors. The relationships varied spatially and with tumor vascularity, and were altered by antiangiogenic treatment. In human liver metastases, all three structural parameters were linearly correlated with iAUC and Ktrans. For iAUC, structural parameters also modified each other's effect.

Conclusions: Our findings suggest that MR imaging biomarkers of vascular function are linked to structural changes in tumor vessels and that antiangiogenic therapy can affect this link. Our work also demonstrates the feasibility of three-dimensional functional–structural validation of MR biomarkers in vivo to improve their biological interpretation and clinical utility. Clin Cancer Res; 24(19); 4694–704. ©2018 AACR.
Cancer-Stimulated CAFs Enhance Monocyte Differentiation and Protumoral TAM Activation via IL6 and GM-CSF Secretion
Authors: Cho Haaglim , Seo Youngha , Loke Kin Man , Kim Seon-Wook , Oh Seong-Min , Kim Jun-Hyeong , Soh Jihee , Kim Hyoen Sik , Lee Hyunju , Kim Jin , Min Jung-Joon , Jung Da-Woon , Williams Darren Reece
Published: June 2018

Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network.

Experimental Design: Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database.

Results: Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell–activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data.

Conclusions: Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the “henchmen” for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. Clin Cancer Res; 24(21); 5407–21. ©2018 AACR.
Arsenic Trioxide and Sorafenib Induce Synthetic Lethality of FLT3-ITD Acute Myeloid Leukemia Cells
Authors: Wang Rui , Li Ying , Gong Ping , Gabrilove Janice , Waxman Samuel , Jing Yongkui
Published: June 2018

Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity, produces an impressive but short-lived remission in FLT3-ITD AML patients. The second, arsenic trioxide (ATO), at therapeutically achievable concentrations, reduces the level of FLT3-ITD and Mcl-1 proteins, and induces apoptosis in leukemic cell lines and in primary cells expressing FLT3-ITD. We linked this relative sensitivity to ATO to low levels of reduced glutathione. While producing proapoptotic effects, ATO treatment also has an unwanted effect whereby it causes the accumulation of the phosphorylated (inactive) form of glycogen synthase kinase 3β (GSK3β), a kinase necessary for apoptosis. When ATO is combined with Sorafenib, GSK3β is activated, Mcl-1 is further reduced, and proapoptotic proteins Bak and Bax are activated. Mice xenografted with FLT3-ITD MOLM13 cell line treated with the Sorafenib/ATO combination have significantly improved survival. This combination has potential to improve the therapeutic outcome of FLT3-ITD–targeted therapy of AML patients. Mol Cancer Ther; 17(9); 1871–80. ©2018 AACR.
Targeting Notch1 and IKKα Enhanced NF-κB Activation in CD133+ Skin Cancer Stem Cells
Authors: Quan Xin Xin , Hawk Nga Voong , Chen Weiping , Coupar Jamie , Lee Steven K. , Petersen David W. , Meltzer Paul S. , Montemarano Andrew , Braun Martin , Chen Zhong , Van Waes Carter
Published: June 2018

Cancer stem–like cells are hypothesized to be the major tumor-initiating cell population of human cutaneous squamous cell carcinoma (cSCC), but the landscape of molecular alterations underpinning their signaling and cellular phenotypes as drug targets remains undefined. In this study, we developed an experimental pipeline to isolate a highly enriched CD133+CD31−CD45−CD61−CD24− (CD133+) cell population from primary cSCC specimens by flow cytometry. The CD133+ cells show enhanced stem–like phenotypes, which were verified by spheroid and colony formation in vitro and tumor generation in vivo. Gene expression profiling of CD133+/− cells was compared and validated, and differentially expressed gene signatures and top pathways were identified. CD133+ cells expressed a repertoire of stemness and cancer-related genes, including NOTCH and NOTCH1-mediated NF-κB pathway signaling. Other cancer-related genes from WNT, growth factor receptors, PI3K/mTOR, STAT pathways, and chromatin modifiers were also identified. Pharmacologic and genetic targeting of NOTCH1, IKKα, RELA, and RELB modulated NF-κB transactivation, the CD133+ population, and cellular and stemness phenotypes. Immunofluorescent staining confirmed colocalization of CD133+ and IKKα expression in SCC tumor specimens. Our functional, genetic, and pharmacologic studies uncovered a novel linkage between NOTCH1, IKKα, and NF-κB pathway activation in maintaining the CD133+ stem SCC phenotypes. Studies investigating markers of activation and modulators of NOTCH, IKK/NF-κB, and other pathways regulating these cancer stem gene signatures could further accelerate the development of effective therapeutic strategies to treat cSCC recurrence and metastasis. Mol Cancer Ther; 17(9); 2034–48. ©2018 AACR.
A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy
Authors: Manara Maria Cristina , Valente Sergio , Cristalli Camilla , Nicoletti Giordano , Landuzzi Lorena , Zwergel Clemens , Mazzone Roberta , Stazi Giulia , Arimondo Paola B. , Pasello Michela , Guerzoni Clara , Picci Piero , Nanni Patrizia , Lollini Pier-Luigi , Mai Antonello , Scotlandi Katia
Published: June 2018

The identification of new therapeutic strategies against osteosarcoma, the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. Osteosarcoma originates from the transformation of mesenchymal stem cells (MSC) and/or osteoblast progenitors, and the loss of differentiation is a common biological osteosarcoma feature, which has strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking osteosarcoma cells in G1 or G2–M phases and induced osteoblastic differentiation through the specific reexpression of genes regulating this physiologic process. Although MC3343 has a similar antiproliferative effect as 5azadC, the conventional FDA-approved nucleoside inhibitor of DNA methylation, its effects on cell differentiation are distinct. Induction of the mature osteoblast phenotype coupled with a sustained cytostatic response was also confirmed in vivo when MC3343 was used against a patient-derived xenograft (PDX). In addition, MC3343 displayed synergistic effects with doxorubicin and cisplatin (CDDP), two major chemotherapeutic agents used to treat osteosarcoma. Specifically, MC3343 increased stable doxorubicin bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this nonnucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for patients with osteosarcoma who respond poorly to preadjuvant chemotherapy. Mol Cancer Ther; 17(9); 1881–92. ©2018 AACR.
Prevention Models of Childhood Obesity in Sweden
Authors: Flodmark Carl-Erik
Published: June 2018

The impact of childhood obesity on the Swedish Health Care system is described. Childhood Obesity and Diabetes Type 2 is increasing for the last 10 years, but not Diabetes Type 1. Thus, prevention is needed. How to define prevention of obesity? Could treatment of childhood obesity be regarded as prevention of adult obesity? Of course it could, but we are lacking a long term follow-up from childhood to adulthood. However, we know that childhood obesity is a risk factor for adult disease. But we need long-lasting results in children to being able to state that we have prevented adult obesity. What about treatment of children with overweight, i.e. defined as the less severe level of an increased body weight as opposed to obesity? There are few if any studies restricting the treatment only to overweight children. Normally, obese children are treated, and some overweight children are added usually to increase the study sample. Then of course promotion of a healthy lifestyle could be of major interest. Finally, the traditional concept of primary prevention seems to be the only solution that is realistic according to many. However, there is no clear pattern when primary prevention works.
MRI Changes in the Thalamus and Basal Ganglia of Full-Term Neonates with Perinatal Asphyxia
Authors: Imai Ken , de Vries Linda S. , Alderliesten Thomas , Wagenaar Nienke , van der Aa Niek E. , Lequin Maarten H. , Benders Manon J.N.L. , van Haastert Ingrid C. , Groenendaal Floris
Published: June 2018

Background: Magnetic resonance imaging (MRI) is the standard neuroimaging technique to assess perinatal asphyxia-associated brain injury in full-term infants. Diffusion-weighted imaging (DWI) is most informative when assessed during the first week after the insult. Objectives: To study the DWI abnormalities of the thalamus and basal ganglia in full-term infants with perinatal asphyxia. Methods: Fifty-five (near) term infants (normothermia n = 23; hypothermia n = 32) with thalamus and/or basal ganglia injury were included. MRI findings were assessed visually and quantitatively calculating apparent diffusion coefficient (ADC) values. Thalamus/basal ganglia ADC ratios were calculated to analyze the differences between these areas. Infants with an early MRI (days 1–3) or later MRI (days 4–7) were compared. Results: Isolated extensive thalamic injury was seen early, and focal thalamic and basal ganglia injury was seen later. On the early MRI, visual assessment underestimated abnormalities in the basal ganglia (59% abnormal vs. 90% abnormal on quantitative assessment; p = 0.015), suggesting the need for quantitative assessment. In infants treated with hypothermia, the thalamus/basal ganglia ADC ratio was lower. Conclusions: Both visual analysis and quantitative evaluation of cerebral MRI after perinatal asphyxia are needed, especially during the first few days after birth. Timing of ADC changes is influenced by therapeutic hypothermia.
Churg-Strauss Syndrome or Eosinophilic Granulomatosis with Polyangiitis: Exuberant Classic Clinical Picture of a Rare Disease
Authors: Mukamal Luana Vieira , Sodré Celso Tavares , Prata Lara Beatriz , Nakasato Fernanda , Cuzzi Tullia , Ramos-e-Silva Marcia
Published: June 2018

The authors present a classic case of Churg-Strauss syndrome with an exuberant clinical picture in a 34-year-old woman. She showed the following diagnostic criteria: asthma, polyneuropathy, rhinopathy, marked eosinophilia, positive p-ANCA with a perinuclear pattern, and skin histopathology results suggestive of vasculitis with eosinophils. There was a good response to prednisone, dexamethasone pulse therapy, and cyclophosphamide.
Case Report: Primary Orbital Squamous Cell Carcinoma
Authors: Blandford Alexander D. , Bellerive Claudine , Tom Martin , Koyfman Shlomo , Adelstein David J. , Plesec Thomas P. , Perry Julian D. , Singh Arun D.
Published: June 2018

Squamous cell carcinoma (SCC) of the orbit is almost uniformly the result of local invasion from a cutaneous primary, extension by perineural invasion, or the result of metastasis. This is owed to the lack of native squamous epithelium in the orbit. After review of the literature, to date, only 6 reports of 8 patients with primary orbital SCC exist. Of those cases, only 2 reported non-apical orbital SCC. There are 2 reports of orbital SCC after retina surgery with proposed transplanted conjunctival epithelium and subsequent malignant transformation of a conjunctival cyst. The initial signs and symptoms can be vague and lead to delay in diagnosis. We present a case of primary orbital SCC and discuss the workup, imaging, and multidisciplinary management of this rare condition.