bluuebunny/crossref_metadata_2025 huggingface dataset:
GAMMA-RAYS FROM MILLISECOND PULSAR POPULATION IN THE GALACTIC CENTRE
Authors: BEDNAREK WLODEK , SOBCZAK TOMASZ
Published: March 2014

The central dense stellar cluster in the Galactic Center (GC) contains the mass of ~4 times larger than that of the central black hole. It is expected to be formed as a result of a merging process of several massive globular clusters which provided a large number of millisecond pulsars (MSPs). We propose that the GeV-TeV γ-ray emission observed from GC is in fact a cumulative effect of the emission from several globular clusters captured by the GC black hole. We calculate the expected TeV γ-ray emission produced by leptons, injected by pulsars, by the Inverse Compton Scattering process in the diffusive radiation field. It is shown that this emission can be responsible for the multi-TeV γ-rays observed by the Cherenkov telescopes from GC if about a thousand of MSPs are present in the central cluster in GC.
THE FSRQs 3C 279 AND PKS 1510-089: MAGIC LATEST RESULTS AND MULTIWAVELENGTH OBSERVATIONS
Authors:   (for the AGILE Collaboration)(for the MAGIC Collaboration)(for the Fermi-LAT Collaboration), DE CANEVA G. , BARRES DE ALMEIDA U. , LINDFORS E. , SAITO K. , SCHULTZ C. , SITAREK J. , TAVECCHIO F. , LUCARELLI F. , PITTORI C. , VERCELLONE S. , VERRECCHIA F. , BUSON S. , D'AMMANDO F. , HAYASHIDA M. , LAHTEENMAKI A. , TORNIKOSKI M. , HOVATTA T. , MUNDELL C. , STEELE I. , NILSSON K. , MARSCHER A. , JORSTAD S.
Published: March 2014

At very high energy (VHE, E> 100 GeV), we count only three blazars of the flat spectrum radio quasars (FSRQs) type to date. The MAGIC experiment detected all three of them; here we present MAGIC observations of 3C 279 and PKS 1510-089. 3C 279 was observed in 2011, without a significant detection, hence upper limits on the differential flux have been computed. The MAGIC observations of PKS 1510-089 in 2012 were triggered by alerts of high activity states and resulted in a significant detection. MAGIC observations are complemented with simultaneous multiwavelength observations in high energy γ rays, X-rays, optical and radio wavelengths and polarization measurements. With the study of the spectral features and the variability observed, we aim to identify the physical processes responsible for the behavior of this source class. In particular, we propose coherent scenarios, which take into account both the modeling of the spectral energy distribution and the constraints obtained from the lightcurves.
ON THE GAMMA-RAY EMISSION FROM THE CORE AND RADIO LOBES OF THE RADIO GALAXY CENTAURUS A
Authors: SAHAKYAN NAREK , RIEGER FRANK M. , AHARONIAN FELIX , YANG RUIZHI , DE ONA-WILHELMI EMMA
Published: March 2014

We summarize recent results based on an analysis of Fermi-LAT data for the lobes and the core of the nearby radio galaxy Centaurus A (Cen A). In the case of the core, high-energy (HE; > 100 MeV) γ-rays up to 50 GeV have been detected with a detection significance of about 44σ. The average gamma-ray spectrum of the core reveals interesting evidence for a possible deviation from a simple power-law. A likelihood analysis with a broken power-law model shows that the photon index becomes substantially harder above Eb ≃ 4 GeV, changing from Γ1 = 2.74 ± 0.03 below to Γ2 = 2.09 ± 0.20 above. It seems possible that this hardening marks the contribution of an additional high-energy component beyond the common synchrotron-self Compton jet emission.

In the case of the lobes, the high-energy gamma-ray emission extends up to 6 GeV, with a significance of more than 10 and 20 σ for the north and the south lobe, respectively. Based on a detailed spatial analysis and comparison with the associated radio lobes, a substantial extension of the HE γ-ray emission beyond the WMAP radio image for the northern lobe of Cen A is found. We provide a short discussion of the lobe's spectral energy distribution (SED) in the context of hadronic and time-dependent leptonic scenarios.
SUPERMASSIVE BLACK HOLE BINARIES AT HIGH ENERGIES
Authors: ROMERO GUSTAVO E. , PÉREZ DANIELA , VILA GABRIELA S.
Published: March 2014

An accretion disk around a supermassive black hole may be strongly perturbed by the presence of a secondary black hole. Recent simulations have shown that, under certain conditions, the tidal torques exerted by the secondary black hole may open an annular gap in the disk. In this regime, matter "overflows" across the secondary's orbit to accrete onto the primary and may feed a pair of relativistic jets.

In this work we study the radiative properties of a binary system of supermassive black holes, assuming that a relativistic jet is launched from the primary and the migration of the secondary across the disk proceeds in the "overflowing" regime. The modified radiative spectrum of the disk is calculated accounting for strong gravitational effects in the innermost region. The jet emits non-thermal radiation all along the electromagnetic spectrum by interaction of locally accelerated electrons with the jet's magnetic field and internal and external radiation. In particular, we investigate whether the interaction of the relativistic electrons with the photons emitted by the accretion disk induces any signature in the spectral energy distribution of the jet that may reveal the presence of the secondary black hole.
FORMATION AND COLLIMATION OF RELATIVISTIC MHD JETS — SIMULATIONS AND RADIO MAPS
Authors: FENDT CHRISTIAN , PORTH OLIVER , SHEIKHNEZAMI SOMAYEH
Published: March 2014

We present results of magnetohydrodynamic (MHD) simulations of jet formation and propagation, discussing a variety of astrophysical setups. In the first approach we consider simulations of relativistic MHD jet formation, considering jets launched from the surface of a Keplerian disk, demonstrating numerically — for the first time — the self-collimating ability of relativistic MHD jets. We obtain Lorentz factors up to ≃ 10 while acquiring a high degree of collimation of about 1 degree. We then present synchrotron maps calculated from the intrinsic jet structure derived from the MHD jet formation simulation. We finally present (non-relativistic) MHD simulations of jet lauching, treating the transition between accretion and ejection. These setups include a physical magnetic diffusivity which is essential for loading the accretion material onto the outflow. We find relatively high mass fluxes in the outflow, of the order of 20-40% of the accretion rate.
COLLISIONLESS RELATIVISTIC SHOCKS: CURRENT DRIVEN TURBULENCE AND PARTICLE ACCELERATION
Authors: PELLETIER GUY , LEMOINE MARTIN , GREMILLET LAURENT , PLOTNIKOV ILLYA
Published: March 2014

The physics of collisionless relativistic shocks with a moderate magnetization is presented. Micro-physics is relevant to explain the most energetic radiative phenomena of Nature, namely that of the termination shock of Gamma Ray Bursts. A transition towards Fermi process occurs for decreasing magnetization around a critical value which turns out to be the condition for the scattering to break the mean field inhibition. Scattering is produced by magnetic micro-turbulence driven by the current carried by returning particles, which had not been considered till now, but turns out to be more intense than Weibel's one around the transition. The current is also responsible for a buffer effect on the motion of the incoming flow, on which the threshold for the onset of turbulence depends.
EVOLUTION OF THE RADIO OUTFLOW IN LS 5039
Authors: MOLDÓN J. , RIBÓ M. , PAREDES J. M.
Published: March 2014

Gamma-ray binaries allow us to study physical processes such as particle acceleration up to TeV energies as well as very high energy gamma-ray emission and absorption with changing geometrical configurations on a periodic basis. These sources produce outflows of radio-emitting particles whose structure can be imaged with very long baseline interferometry (VLBI). We observed the gamma-ray binary LS 5039 with the VLBA at 5 GHz during five consecutive days. We present the observed radio morphological changes, which display a periodic orbital modulation. Multifrequency and multiepoch VLBI observations conducted during the last decade confirm that the morphological periodicity is stable on timescales of years. Using a simple model we show that the observed behavior is compatible with the presence of a young non-accreting pulsar with an outflow behind it.
GENERAL RELATIVISTIC EQUILIBRIUM MODELS OF MAGNETIZED NEUTRON STARS
Authors: PILI A. G. , BUCCIANTINI N. , DEL ZANNA L.
Published: March 2014

Magnetic fields play a crucial role in many astrophysical scenarios and, in particular, are of paramount importance in the emission mechanism and evolution of Neutron Stars (NSs). To understand the role of the magnetic field in compact objects it is important to obtain, as a first step, accurate equilibrium models for magnetized NSs. Using the conformally flat approximation we solve the Einstein's equations together with the GRMHD equations in the case of a static axisymmetric NS taking into account different types of magnetic configuration. This allows us to investigate the effect of the magnetic field on global properties of NSs such as their deformation.
THE OPTICALLY THICK HOMOGENEOUS SSC MODEL: APPLICATION TO RADIO GALAXY NGC 1275
Authors: BANASIŃSKI PIOTR , BEDNAREK WLODEK
Published: March 2014

We consider the Synchrotron Self-Compton (SSC) model for jets in active galaxies in which produced γ-ray photons can be absorbed in collisions with the synchrotron radiation already at the emission region. In terms of such modified SSC model, we argue that the higher emission stages should be characterised by γ-ray spectra extending to lower energies due to the efficient absorption of the highest energy γ-rays. As an example, we show that different emission stages of the nearby radio galaxy NGC 1275 could be explained by such scenario.
NEUTRINO AND UHECR SPECTRA FROM MRK 421
Authors: PETROPOULOU MARIA , DIMITRAKOUDIS STAVROS , MASTICHIADIS APOSTOLOS
Published: March 2014

We present the neutrino and UHECR spectra obtained from a detailed fitting of the spectral energy distribution (SED) of Mrk 421 (March 2001) using two variations of the leptohadronic model. In particular, while the low-energy component (optical to X-rays) of the SED is fitted by synchrotron emission of primary electrons in both models, the high-energy one (GeV-TeV gamma-rays) is synchrotron emission attributed either to ultra-high energy protons (LHs model) or to secondary electrons produced by the decay of charged pions (LHπ model). In the LHπ case we find that the produced neutrino spectra are sharply peaked at Eν ~ 30 PeV with a peak flux slightly below the IC-40 sensitivity limit for Mrk 421. In the LHs model, on the other hand, the neutrino spectra fall well outside the PeV energy range, but the calculated E ~ 30 EeV — UHECR flux at earth is close to that observed by HiresI, Telescope Array and Pierre Augere experiments.
Seismic stratigraphic subdivision of the Triassic succession in the Central North Sea; integrating seismic reflection and well data
Authors: Jarsve Erlend M. , Maast Tom E. , Gabrielsen Roy H. , Faleide Jan I. , Nystuen Johan P. , Sassier Caroline
Published: March 2014

The Triassic sedimentary succession in the Central North Sea has been investigated to establish a broader understanding of the Triassic Period, from the combined interpretation of seismic reflection data and well data. The Triassic succession has been subdivided into four seismic units, where unit boundaries are characterized by regional seismic amplitude anomalies, reflecting changes in gross sedimentary facies or rock properties. A successful correlation between sedimentary facies, interpreted within the well sections and distinct seismic reflection patterns, allowed a thorough mapping of the gross palaeoenvironment throughout the Triassic. The method presented of subdividing a continental sedimentary succession into seismic units should be applicable elsewhere in other basins. The main source area during the Triassic was Scandinavia to the north, and sediment transportation was mainly along north–south- and NE–SW-trending lineaments, which are at present located onshore southern Norway, and in the Åsta Graben and the Varnes Graben offshore. An uplifted Skagerrak Graben area acted as source area in the Early and early Middle Triassic, with sediment dispersal to the south and SW. High relief existed for a longer period in western Scandinavia than in eastern Scandinavia, which supports an asymmetric shape of the Scandinavian mountains during the Triassic. Accommodation space in the Early Triassic was mainly controlled by the relief inherited from a Late Carboniferous–Permian rift phase. Although thermally induced regional subsidence continued in the Middle and Late Triassic, creation of local accommodation space was mainly limited to halokinesis, including redistribution and withdrawal of salt from the subsurface. The Upper Triassic succession is eroded across the western and central parts of the study area, although the Upper Triassic unit is preserved in synforms adjacent to salt structures. In the western part of the study area, dry, playa conditions prevailed during the Early Triassic, although fluvial systems supplied long-transported sandy detritus southeastwards in the late Early Triassic. More sandy detritus was transported into the sedimentary basin in the Middle and Late Triassic, concurrently with a gradually wetter climate.

Supplementary material:

Uninterpreted seismic sections are available at
www.geolsoc.org.uk/SUP18726
.
The Gondwana connections of northern Patagonia
Authors: Pankhurst R. J. , Rapela C. W. , López De Luchi M. G. , Rapalini A. E. , Fanning C. M. , Galindo C.
Published: March 2014

A multidisciplinary study (U–Pb sensitive high-resolution ion microprobe geochronology, Hf and O isotopes in zircon, Sr and Nd isotopes in whole-rocks, as well as major and trace element geochemistry) has been carried out on granitoid samples from the area west of Valcheta, North Patagonian Massif, Argentina. These confirm the Cambrian age of the Tardugno Granodiorite (528 ± 4 Ma) and the Late Permian age of granites in the central part of the Yaminué complex (250 Ma). Together with petrological and structural information for the area, we consider a previously suggested idea that the Cambrian and Ordovician granites of northeastern Patagonia represent continuation of the Pampean and Famatinian orogenic belts of the Sierras Pampeanas, respectively. Our interpretation does not support the hypothesis that Patagonia was accreted in Late Palaeozoic times as a far-travelled terrane, originating in the Central Transantarctic Mountains, and the arguments for and against this idea are reviewed. A parautochthonous origin is preferred with no major ocean closure between the North Patagonian Massif and the Sierra de la Ventana fold belt.

Supplementary material:

U–Pb SHRIMP analytical data, geochemical analyses and sample global positioning system locations are available at
www.geolsoc.org.uk/SUP18722
.
Deformation structures and processes within the continental crust: an introduction
Authors: Llana-Fúnez Sergio , Marcos Alberto , Bastida Fernando
Published: March 2014

The collection of research papers in this volume provides an overview of current trends in the study of deformation structures and deformation processes in rocks from the continental crust. The volume has been divided into three sections to reflect the current interest in structures and processes: shear zones and folds; the interactions between magmatism and structure; and the relationship between microstructure and rheology. The range of topics includes the geometry of natural structures from field observations, the detailed analysis of the microstructure of deformed rocks, the timing of deformation by various geochronological techniques, the modelling of deformation processes to constrain the development of structures in rocks, and the use of laboratory experimentation to reproduce deformation fabrics in rocks. The mixture of techniques and methods treated illustrate the broad and multidisciplinary approach to the study of rock deformation in the continental crust.
Coral reefs in the Anthropocene: persistence or the end of the line?
Authors: Hoegh-Guldberg O.
Published: March 2014

Tropical coastal ecosystems such as coral reefs have provided food, income and resources to humans for millennia. The first interactions that people had with coral reef ecosystems left little signature or impact, most probably due to the restricted access, as well as the challenges and ephemeral technologies that people used to exploit these important ecosystems. As human populations expanded along tropical coastal areas, however, the influence of coastal people on coral reefs grew rapidly. Deforestation and coastal agriculture reduced coastal water quality, with many fringing coral reefs disappearing as impacts grew. Increasing numbers of fishers with increasingly advanced technologies exploited tropical coastal fisheries so that many marine species declined dramatically. These activities have removed some functional groups to the point where ecological transformations away from coral-dominated communities increasingly occurred. Shipping and marine pollution, as well as ocean warming and acidification from the burning of fossil fuels, have added further stress on tropical marine ecosystems. The latter represents a major threat with even small amounts of change potentially driving the ecological extinction of coral reefs and other marine ecosystems. Given inaction on the core drivers of these changes, the future does not look bright for coral reef ecosystems as we move into the critical phase of the Anthropocene Epoch.
Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids
Authors: Wu Jiaxi , Chen Zhijian J.
Published: March 2014

The innate immune system utilizes pattern-recognition receptors (PRRs) to detect the invasion of pathogens and initiate host antimicrobial responses such as the production of type I interferons and proinflammatory cytokines. Nucleic acids, which are essential genetic information carriers for all living organisms including viral, bacterial, and eukaryotic pathogens, are major structures detected by the innate immune system. However, inappropriate detection of self nucleic acids can result in autoimmune diseases. PRRs that recognize nucleic acids in cells include several endosomal members of the Toll-like receptor family and several cytosolic sensors for DNA and RNA. Here, we review the recent advances in understanding the mechanism of nucleic acid sensing and signaling in the cytosol of mammalian cells as well as the emerging role of cytosolic nucleic acids in autoimmunity.
Malaria Immunity in Man and Mosquito: Insights into Unsolved Mysteries of a Deadly Infectious Disease
Authors: Crompton Peter D. , Moebius Jacqueline , Portugal Silvia , Waisberg Michael , Hart Geoffrey , Garver Lindsey S. , Miller Louis H. , Barillas-Mury Carolina , Pierce Susan K.
Published: March 2014

Malaria is a mosquito-borne disease caused by parasites of the obligate intracellular Apicomplexa phylum the most deadly of which, Plasmodium falciparum, prevails in Africa. Malaria imposes a huge health burden on the world's most vulnerable populations, claiming the lives of nearly one million children and pregnant women each year. Although there is keen interest in eradicating malaria, we do not yet have the necessary tools to meet this challenge, including an effective malaria vaccine and adequate vector control strategies. Here we review what is known about the mechanisms at play in immune resistance to malaria in both the human and mosquito hosts at each step in the parasite's complex life cycle with a view toward developing the tools that will contribute to the prevention of disease and death and, ultimately, to the goal of malaria eradication. In so doing, we hope to inspire immunologists to participate in defeating this devastating disease.
Immunology of Psoriasis
Authors: Lowes Michelle A. , Suárez-Fariñas Mayte , Krueger James G.
Published: March 2014

The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The association between comorbidities and psoriasis is reviewed by correlating the skin transcriptome and serum proteins. Psoriasis-related cytokine-response pathways are considered in the context of the transcriptome of different mouse models. This approach offers a model for other inflammatory skin and autoimmune diseases.
Metabolic Regulation of Immune Responses
Authors: Ganeshan Kirthana , Chawla Ajay
Published: March 2014

The immune system defends against pathogens and maintains tissue homeostasis for the life of the organism. These diverse functions are bioenergetically expensive, requiring precise control of cellular metabolic pathways. Although initial observations in this area were made almost a century ago, studies over the past decade have elucidated the molecular basis for how extracellular signals control the uptake and catabolism of nutrients in quiescent and activated immune cells. Collectively, these studies have revealed that the metabolic pathways of oxidative metabolism, glycolysis, and glutaminolysis preferentially fuel the cell fate decisions and effector functions of immune cells. Here, we discuss these findings and provide a general framework for understanding how metabolism fuels and regulates the maturation of immune responses. A better understanding of the metabolic checkpoints that control these transitions might provide new insights for modulating immunity in infection, cancer, or inflammatory disorders.
Compassion at Work
Authors: Dutton Jane E. , Workman Kristina M. , Hardin Ashley E.
Published: March 2014

Compassion is an interpersonal process involving the noticing, feeling, sensemaking, and acting that alleviates the suffering of another person. This process has recently received substantial attention by organizational researchers and practitioners alike. This article reviews what researchers currently know about compassion as it unfolds in dyadic interactions in work organizations. We begin by reviewing what we know about the benefits of compassion for the person who is suffering, for the provider of compassion, and for third parties who witness or hear about compassion at work. The heart of the article focuses on what research tells us about embedding compassion in the personal, relational, and organizational contexts in which compassion takes place. We conclude by discussing implications for practice and for the future research agenda regarding this vital interpersonal process.
Intercultural Competence
Authors: Leung Kwok , Ang Soon , Tan Mei Ling
Published: March 2014

We review recent theoretical and empirical developments in the intercultural competencies literature, highlighting contemporary models and empirical research in organizational contexts. We survey the current conceptualizations of intercultural competencies and propose that intercultural competencies can be classified based on traits, attitudes and worldviews, capabilities, or a combination of these dimensions. We identify key psychological, behavioral, and performance outcomes associated with these models. We review empirical studies of intercultural competencies at the group level and discuss emerging models of dyad-level, firm-level, and multilevel intercultural competencies. We evaluate the current measurement of intercultural competencies and suggest alternative approaches. Finally, we examine research on selection, training, and development of intercultural competencies. We end each section by identifying future research foci, and we offer an integration of the literature at the end of the review.
Constructively Managing Conflicts in Organizations
Authors: Tjosvold Dean , Wong Alfred S.H. , Feng Chen Nancy Yi
Published: March 2014

Researchers have used various concepts to understand the conditions and dynamics by which conflict can be managed constructively. This review proposes that the variety of terms obscures consistent findings that open-minded discussions in which protagonists freely express their own views, listen and understand opposing ones, and then integrate them promote constructive conflict. Studies from several traditions also suggest that mutual benefit relationships are critical antecedents for open-minded discussion. This integration of research findings identifies the skills and relationships that can help managers and employees deal with their increasingly complex conflicts. Research is needed to deepen our understanding of the dynamics of open-minded discussion and the conditions that promote it as well as when open-mindedness is inappropriate. Training studies can test and show how the model of open-minded discussion supported by mutual benefit relationships can be applied in cross-cultural and other challenging settings.
ACTN3genotype and modulation of skeletal muscle response to exercise in human subjects
Authors: Norman Barbara , Esbjörnsson Mona , Rundqvist Håkan , Österlund Ted , Glenmark Birgitta , Jansson Eva
Published: March 2014

α-Actinin-3 is a Z-disc protein expressed only in type II muscle fibers. A polymorphism in the ACTN3 gene (R577X) results in lack of α-actinin-3 in XX genotype. The prevalence of the mutated X-allele is lower among power/sprint oriented athletes compared with controls, indicating that the lack of α-actinin-3 is detrimental in these sports, but a mechanistic link has not been established. Results from Actn3-knockout (KO) mouse model suggest that α-actinin-3 may affect muscle mass and muscle glycogen levels. In the present investigation we examined muscle fiber type composition, cross-sectional fiber area (CSA), and muscle glycogen levels at baseline in 143 human subjects with different ACTN3 genotypes. In addition, hypertrophy signaling and glycogen utilization in response to sprint exercise were studied in a subset of subjects. Glycogen utilization was analyzed in separate pools of type I and type II fibers. No differences in fiber type composition, CSA, or muscle glycogen levels were observed at baseline across the ACTN3 genotypes. However, the sprint exercise-induced increase in phosphorylation of mTOR and p70S6k was smaller in XX than in RR+RX ( P = 0.03 and P = 0.01, respectively), indicating a less pronounced activation of hypertrophy signaling in XX. Glycogen utilization during sprint exercise varied across ACTN3 genotypes in type II fibers ( P = 0.03) but not in type I fibers ( P = 0.38). The present results are in accordance with findings from the KO mice and reinforce the hypothesis that ACTN3 genotype-associated differences in muscle mass and glycogen utilization provide a mechanistic explanation for the modulation of human performance by the ACTN3 genotype.
The “second wind” in McArdle's disease patients during a second bout of constant work rate submaximal exercise
Authors: Porcelli Simone , Marzorati Mauro , Belletti Michele , Bellistri Giuseppe , Morandi Lucia , Grassi Bruno
Published: March 2014

Patients with McArdle's disease (McA) typically show the “second-wind” phenomenon, a sudden decrease in heart rate (HR) and an improved exercise tolerance occurring after a few minutes of exercise. In the present study, we investigated whether in McA a first bout of exercise determines a second wind during a second bout, separated by the first by a few minutes of recovery. Eight McA (44 ± 4 yr) and a control group of six mitochondrial myopathy patients (51 ± 6 yr) performed two repetitions (CWR1 and CWR2) of 6-min constant work rate exercise (∼50% of peak work rate) separated by 6-min (SHORT) or 18-min (LONG) recovery. Pulmonary O2uptake (V̇o2), HR, cardiac output, rates of perceived exertion, vastus lateralis oxygenation {changes in deoxygenated Hb and myoglobin Mb concentrations, Δ[deoxy(Hb+Mb)], by near-infrared spectroscopy} were determined. In McA, V̇o2(0.86 ± 0.2 vs. 0.95 ± 0.1 l/min), HR (113 ± 10 vs. 150 ± 13 beats/min), cardiac output (11.6 ± 0.6 vs. 15.0 ± 0.8 l/min), and rates of perceived exertion (11 ± 2 vs. 14 ± 3) were lower, whereas Δ[deoxy(Hb+Mb)] was higher (14.7 ± 2.3 vs. −0.1 ± 4.6%) in CWR2-SHORT vs. CWR1; the “overshoot” of Δ[deoxy(Hb+Mb)] and the “slow component” of V̇o2kinetics disappeared in CWR2-SHORT. No differences (vs. CWR1) were observed in McA during CWR2-LONG, or in mitochondrial myopathy patients during both CWR2-SHORT and -LONG. A second-wind phenomenon was observed in McA during the second of two consecutive 6-min constant-work rate submaximal exercises. The second wind was associated with changes of physiological variables, suggesting an enhanced skeletal muscle oxidative metabolism. The second wind was not described after a longer (18-min) recovery period.
Ca++-sensitizing mutations in troponin, Pi, and 2-deoxyATP alter the depressive effect of acidosis on regulated thin-filament velocity
Authors: Longyear Thomas J. , Turner Matthew A. , Davis Jonathan P. , Lopez Joseph , Biesiadecki Brandon , Debold Edward P.
Published: March 2014

Repeated, intense contractile activity compromises the ability of skeletal muscle to generate force and velocity, resulting in fatigue. The decrease in velocity is thought to be due, in part, to the intracellular build-up of acidosis inhibiting the function of the contractile proteins myosin and troponin; however, the underlying molecular basis of this process remains poorly understood. We sought to gain novel insight into the decrease in velocity by determining whether the depressive effect of acidosis could be altered by 1) introducing Ca++-sensitizing mutations into troponin (Tn) or 2) by agents that directly affect myosin function, including inorganic phosphate (Pi) and 2-deoxy-ATP (dATP) in an in vitro motility assay. Acidosis reduced regulated thin-filament velocity ( VRTF) at both maximal and submaximal Ca++levels in a pH-dependent manner. A truncated construct of the inhibitory subunit of Tn (TnI) and a Ca++-sensitizing mutation in the Ca++-binding subunit of Tn (TnC) increased VRTFat submaximal Ca++under acidic conditions but had no effect on VRTFat maximal Ca++levels. In contrast, both Piand replacement of ATP with dATP reversed much of the acidosis-induced depression of VRTFat saturating Ca++. Interestingly, despite producing similar magnitude increases in VRTF, the combined effects of Piand dATP were additive, suggesting different underlying mechanisms of action. These findings suggest that acidosis depresses velocity by slowing the detachment rate from actin but also by possibly slowing the attachment rate.
Involvement of brain cytokines in zymosan-induced febrile response
Authors: Bastos-Pereira Amanda L. , Fraga Daniel , Ott Daniela , Simm Björn , Murgott Jolanta , Roth Joachim , Zampronio Aleksander R.
Published: March 2014

This study compared the involvement of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) within the central nervous system (CNS) in the febrile response induced by zymosan (zym) and lipopolysaccharide (LPS). In addition, we investigated whether zym could activate important regions related to fever; namely, the vascular organ of the laminae terminalis (OVLT) and the median preoptic nucleus (MnPO). Intraperitoneal injection of zym (1, 3, and 10 mg/kg) induced a dose-related increase in core temperature. Zym (3 mg/kg) also reduced tail skin temperature, suggesting the activation of heat conservation mechanisms, as expected, during fever. LPS increased plasma levels of TNF-α measured at 1 h, IL-1β measured at 2 h, and IL-6 measured at 3 h after injection. Zym increased circulating levels of IL-6 but not those of TNF-α or IL-1β at the same time points. In addition, an intracerebroventricular injection of antibodies against TNF-α (2.5 μg) and IL-6 (10 μg) or the IL-1 receptor antagonist (160 ng) reduced the febrile response induced by zym and LPS. Zym (100 μg/ml) also increased intracellular calcium concentration in the OVLT and MnPO from rat primary neuroglial cultures and increased release of TNF-α and IL-6 into the supernatants of these cultures. Together, these results suggest that TNF-α, IL-1β, and IL-6 within the CNS participate in the febrile response induced by zym. However, the time course of release of these cytokines may be different from that of LPS. In addition, zym can directly activate the brain areas related to fever.
A Meta-analysis of Lung Cancer Gene Expression Identifies PTK7 as a Survival Gene in Lung Adenocarcinoma
Authors: Chen Ron , Khatri Purvesh , Mazur Pawel K. , Polin Melanie , Zheng Yanyan , Vaka Dedeepya , Hoang Chuong D. , Shrager Joseph , Xu Yue , Vicent Silvestre , Butte Atul J. , Sweet-Cordero E. Alejandro
Published: March 2014

Lung cancer remains the most common cause of cancer-related death worldwide and it continues to lack effective treatment. The increasingly large and diverse public databases of lung cancer gene expression constitute a rich source of candidate oncogenic drivers and therapeutic targets. To define novel targets for lung adenocarcinoma, we conducted a large-scale meta-analysis of genes specifically overexpressed in adenocarcinoma. We identified an 11-gene signature that was overexpressed consistently in adenocarcinoma specimens relative to normal lung tissue. Six genes in this signature were specifically overexpressed in adenocarcinoma relative to other subtypes of non–small cell lung cancer (NSCLC). Among these genes was the little studied protein tyrosine kinase PTK7. Immunohistochemical analysis confirmed that PTK7 is highly expressed in primary adenocarcinoma patient samples. RNA interference–mediated attenuation of PTK7 decreased cell viability and increased apoptosis in a subset of adenocarcinoma cell lines. Further, loss of PTK7 activated the MKK7–JNK stress response pathway and impaired tumor growth in xenotransplantation assays. Our work defines PTK7 as a highly and specifically expressed gene in adenocarcinoma and a potential therapeutic target in this subset of NSCLC. Cancer Res; 74(10); 2892–902. ©2014 AACR.
Stress-Induced CXCR4 Promotes Migration and Invasion of Ewing Sarcoma
Authors: Krook Melanie A. , Nicholls Lauren A. , Scannell Christopher A. , Chugh Rashmi , Thomas Dafydd G. , Lawlor Elizabeth R.
Published: March 2014

Ewing sarcoma is the second most common bone cancer in pediatric patients. Although the primary cause of death in Ewing sarcoma is metastasis, the mechanism underlying tumor spread needs to be elucidated. To this end, the role of the CXCR4/SDF-1a chemokine axis as a mediator of Ewing sarcoma metastasis was investigated. CXCR4 expression status was measured in primary tumor specimens by immunohistochemical staining and in multiple cell lines by quantitative reverse transcriptase PCR and flow cytometry. Migration and invasion of CXCR4-positive Ewing sarcoma cells toward CXCL12/SDF-1a were also determined. Interestingly, while CXCR4 status was disparate among Ewing sarcoma cells, ranging from absent to high-level expression, its expression was found to be highly dynamic and responsive to changes in the microenvironment. In particular, upregulation of CXCR4 occurred in cells that were subjected to growth factor deprivation, hypoxia, and space constraints. This upregulation of CXCR4 was rapidly reversed upon removal of the offending cellular stress conditions. Functionally, CXCR4-positive cells migrated and invaded toward an SDF-1a gradient and these aggressive properties were impeded by both the CXCR4 small-molecule inhibitor AMD3100, and by knockdown of CXCR4. In addition, CXCR4-dependent migration and invasion were inhibited by small-molecule inhibitors of Cdc42 and Rac1, mechanistically implicating these Rho-GTPases as downstream mediators of the CXCR4-dependent phenotype.

Implications: This study reveals the highly plastic and dynamic nature of CXCR4 expression in Ewing sarcoma and supports a model in which stress-induced upregulation of CXCR4 contributes to tumor metastasis to lung and bone marrow, which express high levels of SDF-1a. Mol Cancer Res; 12(6); 953–64. ©2014 AACR.
Bone Morphogenetic Protein-12 Induces Tenogenic Differentiation of Mesenchymal Stem Cells Derived from Equine Amniotic Fluid
Authors: Gulati Baldev R. , Kumar Rajesh , Mohanty Niharika , Kumar Pawan , Somasundaram Rajesh K. , Yadav Prem S.
Published: March 2014

Tendon injuries are common in race horses, and mesenchymal stem cells (MSCs) isolated from adult and foetal tissue have been used for tendon regeneration. In the present study, we evaluated equine amniotic fluid (AF) as a source of MSCs and standardised methodology and markers for their in vitro tenogenic differentiation. Plastic-adherent colonies were isolated from 12 of 20 AF samples by day 6 after seeding and 70-80% cell confluency was reached by day 17. These cells expressed mesenchymal surface markers [cluster of differentiation (CD)73, CD90 and CD105] by reverse transcription (RT)-polymerase chain reaction (PCR) and immunocytochemistry, but did not express haematopoietic markers (CD34, CD45 and CD14). In flow cytometry, the expression of CD29, CD44, CD73 and CD90 was observed in 68.83 ± 1.27, 93.66 ± 1.80, 96.96 ± 0.44 and 93.7 ± 1.89% of AF-MSCs, respectively. Osteogenic, chondrogenic and adipogenic differentiation of MSCs was confirmed by von Kossa and Alizarin red S, Alcian blue and oil red O staining, respectively. Upon supplementation of MSC growth media with 50 ng/ml bone morphogenetic protein (BMP)-12, AF-MSCs differentiated to tenocytes within 14 days. The differentiated cells were more slender, elongated and spindle shaped with thinner and longer cytoplasmic processes and showed expression of tenomodulin and decorin by RT-PCR and immunocytochemistry. In flow cytometry, 96.7 ± 1.90 and 80.9 ± 6.4% of differentiated cells expressed tenomodulin and decorin in comparison to 1.6 and 3.1% in undifferentiated control cells, respectively. Our results suggest that AF is an easily accessible and effective source of MSCs. On BMP-12 supplementation, AF-MSCs can be differentiated to tenocytes, which could be exploited for regeneration of ruptured or damaged tendon in race horses.
Assessment with Unenhanced MRI Techniques of Renal Morphology and Hemodynamic Changes during Acute Kidney Injury and Chronic Kidney Disease in Mice
Authors: Milman Zohar , Axelrod Jonathan H. , Heyman Samuel N. , Nachmansson Nathalie , Abramovitch Rinat
Published: March 2014

Background/Aims: Changes in renal oxygenation and perfusion have been identified as common pathways to the development and progression of renal disease. Recently, the sensitivity of hemodynamic response imaging (HRI) was demonstrated; this is a functional magnetic resonance imaging (MRI) method combined with transient hypercapnia and hyperoxia for the evaluation of renal perfusion and vascular reactivity. The aim of this study was to utilize HRI for the noninvasive evaluation of changes in renal hemodynamics and morphology during acute, chronic and acute-on-chronic renal failures. Methods: Renal-HRI maps and true fast imaging with steady-state precession (True-FISP) images were used to evaluate renal perfusion, morphology and corticomedullary differentiation (CMD). MR images were acquired on two mouse models of kidney injury: adenine-induced chronic kidney disease (CKD) and rhabdomyolysis-induced acute kidney injury (AKI). Serum urea was measured from these mice in order to determine renal function. Results: Renal-HRI maps revealed a blunted response to hypercapnia and hyperoxia with evolving kidney dysfunction in both models, reflecting hampered renal vascular reactivity and perfusion. True-FISP images showed a high sensitivity to renal morphological changes, with different patterns characterizing each model. Calculated data obtained from HRI and True-FISP during the evolution of renal failure and upon recovery, with and without protective intervention, closely correlated with the degree of renal impairment. Conclusions: This study suggests the potential combined usage of two noninvasive MRI methods, HRI and True-FISP, for the assessment of renal dysfunction without the potential risk associated with contrast-agents administration. HRI may also serve as a research tool in experimental settings, revealing the hemodynamic changes associated with kidney dysfunction.
Non-vitamin K antagonist oral anticoagulants (NOACs): No longer new or novel
Authors: de Caterina Raffaele , Andreotti Felicita , Arnesen Harald , Bachmann Fedor , Huber Kurt , Jespersen Jørgen , Kristensen Steen Dalby , Lip Gregory Y. H. , Morais Joao , Rasmussen Lars H. , Siegbahn Agneta , Storey Robert F. , Weitz Jeffrey I. , Husted Steen ,   the ESC Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease
Published: March 2014

Note: The editorial process for this paper was fully handled by Prof Christian Weber, Editor in Chief.
Macrophage Inflammatory Markers Are Associated With Subclinical Carotid Artery Disease in Women With Human Immunodeficiency Virus or Hepatitis C Virus Infection
Authors: Shaked Iftach , Hanna David B. , Gleißner Christian , Marsh Brenda , Plants Jill , Tracy Daniel , Anastos Kathryn , Cohen Mardge , Golub Elizabeth T. , Karim Roksana , Lazar Jason , Prasad Vinayaka , Tien Phyllis C. , Young Mary A. , Landay Alan L. , Kaplan Robert C. , Ley Klaus
Published: March 2014

Objective—

Infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV) may be associated with atherosclerosis and vascular disease. Macrophages are a major component of atherosclerotic plaque, and classically activated (M1) macrophages contribute to plaque instability. Our goal was to identify plasma biomarkers that reflect macrophage inflammation and are associated with subclinical atherosclerosis.

Approach and Results—

We tested whether M1 macrophages produce galectin-3–binding protein in vitro. Then, we measured galectin-3–binding protein and the soluble macrophage biomarkers soluble cluster of differentiation (CD) 163 and soluble CD14 in 264 participants in the Women’s Interagency HIV Study. Women were positive for HIV, HCV, both, or neither (66 in each group, matched for age, race/ethnicity, and smoking status). Carotid artery disease was assessed by ultrasound measurement of right distal common carotid artery intima-media thickness, distensibility, and presence of atherosclerotic lesions (intima-media thickness >1.5 mm). Plasma galectin-3–binding protein was higher in HCV+ than HCV− women (
P
<0.01) but did not differ by HIV status. The 3 inflammatory macrophage markers were significantly correlated with each other and negatively correlated with CD4+ counts in HIV-infected women. We defined a macrophage score as 1, 2, or 3 biomarkers elevated above the median. In models adjusted for traditional risk factors, higher macrophage scores were significantly associated with increased atherosclerotic lesions and lower carotid distensibility. Receiver-operator curve analysis of lesions revealed that the markers added predictive value beyond traditional risk factors and C-reactive protein.

Conclusions—

The macrophage inflammatory markers galectin-3–binding protein, soluble CD163, and soluble CD14 are significantly associated with carotid artery disease in the setting of HIV and HCV infection.
Cardiogenic Genes Expressed in Cardiac Fibroblasts Contribute to Heart Development and Repair
Authors: Furtado Milena B. , Costa Mauro W. , Pranoto Edward A. , Salimova Ekaterina , Pinto Alexander R. , Lam Nicholas T. , Park Anthony , Snider Paige , Chandran Anjana , Harvey Richard P. , Boyd Richard , Conway Simon J. , Pearson James , Kaye David M. , Rosenthal Nadia A.
Published: March 2014

Rationale:

Cardiac fibroblasts are critical to proper heart function through multiple interactions with the myocardial compartment, but appreciation of their contribution has suffered from incomplete characterization and lack of cell-specific markers.

Objective:

To generate an unbiased comparative gene expression profile of the cardiac fibroblast pool, identify and characterize the role of key genes in cardiac fibroblast function, and determine their contribution to myocardial development and regeneration.

Methods and Results:

High-throughput cell surface and intracellular profiling of cardiac and tail fibroblasts identified canonical mesenchymal stem cell and a surprising number of cardiogenic genes, some expressed at higher levels than in whole heart. While genetically marked fibroblasts contributed heterogeneously to interstitial but not cardiomyocyte compartments in infarcted hearts, fibroblast-restricted depletion of one highly expressed cardiogenic marker, T-box 20, caused marked myocardial dysmorphology and perturbations in scar formation on myocardial infarction.

Conclusions:

The surprising transcriptional identity of cardiac fibroblasts, the adoption of cardiogenic gene programs, and direct contribution to cardiac development and repair provoke alternative interpretations for studies on more specialized cardiac progenitors, offering a novel perspective for reinterpreting cardiac regenerative therapies.
Is the Long-Term Prognosis of Transient Ischemic Attack or Minor Ischemic Stroke Affected by the Occurrence of Nonfocal Symptoms?
Authors: Compter Annette , van der Worp H. Bart , van Gijn Jan , Kappelle L. Jaap , Koudstaal Peter J. , Algra Ale
Published: March 2014

Background and Purpose—

In patients with a transient ischemic attack or ischemic stroke, nonfocal neurological symptoms, such as confusion and nonrotatory dizziness, may be associated with a higher risk of vascular events. We assessed the relationship between nonfocal symptoms and the long-term risk of vascular events or death in patients with a transient ischemic attack or minor ischemic stroke.

Methods—

We related initial symptoms with outcome events in 2409 patients with a transient ischemic attack (n=723) or minor ischemic stroke (n=1686), included in the Life Long After Cerebral ischemia cohort. All patients underwent a standardized interview on the occurrence of focal and nonfocal neurological symptoms during the qualifying event. The primary outcome was the composite of any stroke, myocardial infarction, or vascular death. Secondary outcomes were all-cause death, vascular death, cardiac death, myocardial infarction, and stroke. Hazard ratios were calculated with Cox regression.

Results—

Focal symptoms were accompanied by nonfocal symptoms in 739 (31%) patients. During a mean follow-up of 10.1 years, the primary outcome occurred in 1313 (55%) patients. There was no difference in the risk of the primary outcome between patients with both focal and nonfocal symptoms and patients with focal symptoms alone (adjusted hazard ratio, 0.97; 95% confidence interval, 0.86–1.09;
P
=0.60). The risk of each of the secondary outcomes was also similar in both groups.

Conclusions—

About one third of the patients with a transient ischemic attack or minor ischemic stroke has both focal and nonfocal neurological symptoms. Nonfocal symptoms are not associated with an increased long-term risk of vascular events or death.

Clinical Trial Registration—

This trial was not registered because enrollment began before July 1, 2005.