bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of bubble shell nonlinearity on ultrasound nonlinear propagation through microbubble populations
Authors: Tang Meng-Xing , Loughran Jonathan , Stride Eleanor , Zhang Dong , Eckersley Robert J.
Published: March 2011

Nonlinear propagation of ultrasound through microbubble populations can generate artifacts and reduce contrast to tissue ratio in ultrasound imaging. The existing propagation model, which underestimates harmonic generation by an order of magnitude, was revised by incorporating a nonlinear constitutive equation for the coating into the description of the microbubble dynamics. Significantly better agreement with experiments was obtained, indicating that coating nonlinearity represents an important contribution to nonlinear propagation of ultrasound in microbubble populations. The results were found to be sensitive to the parameters characterizing the coating nonlinearity and thus accurate measurement of these parameters is required for accurate quantitative predictions.
On the detection of objects buried at a shallow depth using seismic wave reflections
Authors: Papandreou Ben , Brennan Michael J. , Rustighi Emiliano
Published: March 2011

This paper concerns the detection of shallow (of the order 1 m) buried objects using seismic excitation. Time-extended signals are used to generate a compressional wave using a shaker attached to the ground. The wave propagates through the ground, reflects off a buried object and is captured by an array of geophones on the surface. The envelopes of the cross-correlation functions between the measured ground velocities and the excitation signal are calculated and summed to generate a cross-sectional image of the ground. The wide cross-correlation peaks caused by high ground attenuation are partially compensated for by using the generalized cross-correlation function called the phase transform. Simple simulations are conducted to demonstrate the method, and some field experiments have been carried out aimed at the detection of a buried concrete pipe. In the experiments the pipe could be detected using the method proposed, with experimental and simulated data producing good agreement.
The Δ
F508
Mutation Causes CFTR Misprocessing and Cystic Fibrosis–Like Disease in Pigs
Authors: Ostedgaard Lynda S. , Meyerholz David K. , Chen Jeng-Haur , Pezzulo Alejandro A. , Karp Philip H. , Rokhlina Tatiana , Ernst Sarah E. , Hanfland Robert A. , Reznikov Leah R. , Ludwig Paula S. , Rogan Mark P. , Davis Greg J. , Dohrn Cassie L. , Wohlford-Lenane Christine , Taft Peter J. , Rector Michael V. , Hornick Emma , Nassar Boulos S. , Samuel Melissa , Zhang Yuping , Richter Sandra S. , Uc Aliye , Shilyansky Joel , Prather Randall S. , McCray Paul B. , Zabner Joseph , Welsh Michael J. , Stoltz David A.
Published: March 2011

A common mutation in human cystic fibrosis, CFTR-ΔF508, results in misprocessed CFTR and a cystic fibrosis–like clinical phenotype in pigs.
Electronic nicotine delivery systems: a research agenda
Authors: Etter Jean-François , Bullen Chris , Flouris Andreas D , Laugesen Murray , Eissenberg Thomas
Published: March 2011

Electronic nicotine delivery systems (ENDS, also called electronic cigarettes or e-cigarettes) are marketed to deliver nicotine and sometimes other substances by inhalation. Some tobacco smokers report that they used ENDS as a smoking cessation aid. Whether sold as tobacco products or drug delivery devices, these products need to be regulated, and thus far, across countries and states, there has been a wide range of regulatory responses ranging from no regulation to complete bans. The empirical basis for these regulatory decisions is uncertain, and more research on ENDS must be conducted in order to ensure that the decisions of regulators, health care providers and consumers are based on science. However, there is a dearth of scientific research on these products, including safety, abuse liability and efficacy for smoking cessation. The authors, who cover a broad range of scientific expertise, from basic science to public health, suggest research priorities for non-clinical, clinical and public health studies. They conclude that the first priority is to characterize the safety profile of these products, including in long-term users. If these products are demonstrated to be safe, their efficacy as smoking cessation aids should then be tested in appropriately designed trials. Until these studies are conducted, continued marketing constitutes an uncontrolled experiment and the primary outcome measure, poorly assessed, is user health. Potentially, this research effort, contributing to the safety and efficacy of new smoking cessation devices and to the withdrawal of dangerous products, could save many lives.
North Atlantic spreading axes terminate in the continental cul-de-sacs of Baffin Bay and the Laptev Sea
Authors: Pulvertaft T. Christopher R. , Dawes Peter R.
Published: March 2011

In conventional plate-tectonic models, an independent Greenland plate is supposed to have drifted in the Paleogene along a transform fault through Nares Strait that links the two branches of the North Atlantic spreading system. However, this postulated structure — widely known as the Wegener Fault — cannot be detected by any means in the southern part of the strait. The mapped geology flanking this part of the strait is identical, with no evidence whatsoever of any strike-slip displacement or compressional deformation, and geophysical data provide no support for the existence of such tectonism offshore. We analyse the serious drawback of having a major transform located within a Precambrian crustal block stable since the Paleozoic and emphasize that the extinct Labrador – Baffin Bay spreading axis is but a mirror image of the active North Atlantic – Gakkel Ridge that terminates in a continental cul-de-sac in the Laptev Sea. We conclude that, in the Baffin Bay – Nares Strait region, there is only one plate (North American) and that the extension required to absorb Labrador – Baffin Bay spreading is to be found in structures within the Canadian Arctic Islands.
Fractional order theory of a perfect conducting thermoelastic medium
Authors: Ezzat Magdy A. , El-Karamany Ahmed S.
Published: March 2011

In this work, a new mathematical model of magneto-thermoelasticity theory is constructed in the context of a new consideration of heat conduction law with time-fractional order. This model is applied to a one-dimensional application for a perfect conducting half-space of elastic material, which is thermally shocked in the presence of magnetic field. Laplace transforms and state-space techniques (Ezzat. Can. J. Phys. 86, 1242, (2008)) will be used to obtain the general solution for any set of boundary conditions. According to numerical results and graphs, it is found that introducing a fractional derivative of order α has a significant effect on the temperature, stress, and heat flux distributions as well as the induced electric and magnetic fields; the curves are smoother in the case of 0 < α < 1 due to weak thermal conductivity. Some comparisons are made and shown in figures to estimate the effects of the fractional order parameter on all the studied fields.
Fluorescence from the A2Σ+state suggests a non-Franck–Condon N2O+•vibrational state population after keV collisional activation with helium
Authors: Lin Yawei , Mayer Paul M.
Published: March 2011

A commercial analytical mass spectrometer coupled with a spectrograph and charge-coupled device (CCD) detector was used to obtain the collision-induced emission (CIE) spectra (190–1020 nm) from ion–molecule collisions between N2O+•and He at laboratory frame collision energies of 4–8 keV. The observed emissions were from the A2Σ+ → X2Π+system of N2O+•, excited fragments of the parent molecule, and the target gas. The relative emission intensities of the N2O+•ions and their fragments were independent of the ion translational energy within the 4–8 keV range, confirming the curve-crossing mechanism for translational-to-internal energy transfer in this system. Band emission intensities of [Formula: see text] and [Formula: see text] relative to the [Formula: see text] band within the N2O+•(A → X) system have been measured and compared with reference data. The results indicated that the collisionally excited ion has a decidedly non-Franck–Condon vibrational state distribution.
Photochromic benzo[g]quinoxalines
Authors: Rakotomalala Muriel , Katz Michael , Voisin Emilie , Pace Tamara C. S. , Bohne Cornelia , Williams Vance E.
Published: March 2011

The photochromism of two 2,3-diarylbenzo[g]quinoxaline derivatives was explored. Irradiating 2,3-diphenylbenzo[g]quinoxaline with 350 nm light led to the formation of its photodimer, which could be reverted to its monomers either thermally or photochemically.The resulting photodimer absorbs at a longer wavelength than analogous dianthracene derivatives. 2,3-Dipyridylbenzo[g]quinoxaline was also observed to undergo photodimerization. The ability of these readily prepared benzoquinoxaline derivatives to undergo [4 + 4]-photocycloaddition reactions makes them attractive alternatives to anthracene derivatives.
Photoautoionization structure in the halogen systems Br2, I2, BrCl, ICl, and IBr
Authors: Yencha Andrew J. , Kaur Devinder
Published: March 2011

The photoabsorption ion-yield spectra of the titled molecules have been recorded in the threshold ionization region between the two spin-orbit components of the ground states of the molecular ions. All ion-yield spectra display rather simple autoionization structure superimposed on a smoothly rising continuum in the ionization energy region. The structure was analyzed in terms of autoionizing Rydberg states and their vibrational profiles simulated using Rydberg–Klein–Rees (RKR) derived potential energy curves and calculated Franck–Condon factors using Gaussian line-shape functions. All of the structure observed is attributed to spin-orbit autoionization. There seems to be a propensity for autoionization of sσ Rydberg states in all of the interhalogen molecules studied.
Density functional theory computational study on Diels–Alder reactions of cyclopentadiene with selected vinylsilanes and methylenecyclopropane
Authors: Werstiuk Nick Henry , Sokol Wojciech
Published: March 2011

Aimed at predicting relative reactivities, density functional theory (DFT) calculations were carried out on a series of Diels–Alder reactions involving silylvinyl derivatives reacting with cyclopentadiene as part of a synthetic research project. Using three reactions for which experimental rate data are available to calibrate our calculations, we computationally pinpointed the best synthetic route to bicyclo[2.2.1]hept-5-ene-2,2-diylbis(trimethylsilane) (1). The synthesis begins with the Diels–Alder reaction of cyclopentadiene (2) with commercially available (1-bromovinyl)trimethylsilane (6).
Modulation of metabolic and cardiac dysfunctions by insulin sensitizers and angiotensin receptor blocker in rat model of type 2 diabetes mellitus
Authors: Hussein Abd El-Aziz M. , Omar Nisereen M. , Sakr Hussein , Elsamanoudy Ayman Z. , Shaheen Dalia
Published: March 2011

The objective of this study was to investigate the modulation of metabolic dysfunctions, adiponectin levels, and cardiac dysfunctions of type 2 diabetes mellitus (T2DM) by a combination of the insulin sensitizer rosiglitazone and angiotensin receptor blocker telmisartan in an experimental rat model. Fifty male adult Sprague–Dawley rats were divided equally into 5 groups. Group I: fed normal chow; served as normal control group. Groups II–V: fed a high-fat diet (HFD) for 2 weeks, followed by injection of streptozotocin (STZ; 35 mg/kg) to create a model of T2DM. Group II: treated with vehicle. Group III: treated with rosiglitazone (4 mg/kg). Group IV: treated with telmisartan (5 mg/kg). Group V: treated with both agents. Untreated HFD-STZ rats showed elevated fasting blood glucose, insulin, homeostasis model assessment (HOMA) index, triglycerides (TGs), low-density lipoprotein cholesterol (LDL), and total serum cholesterol (TC), with a decrease in high-density lipoprotein cholesterol (HDL) and adiponectin levels (p < 0.001). Rosiglitazone exerted more improvement in all parameters than telmisartan did, and a combination of both did not augment the improvement further, except for TGs and adiponectin. For the isolated atrial study, a combination of rosiglitazone and telmisartan corrected the responses of the atria of HFD-STZ rats to the negative inotropic effect induced by adenosine better than either one did alone, whereas this combination, surprisingly, significantly attenuated the positive inotropic response to β-adrenoreceptor and α-adrenoreceptor agonists. In conclusion, rosiglitazone significantly improved the metabolic and cardiac dysfunctions in T2DM. Moreover, a combination of rosiglitazone and telmisartan offered more improvement in serum TGs and adiponectin, and restored the atrial inotropic response to adenosine. Surprisingly, this combination significantly attenuates the positive inotropic response to α1-adrenoreceptor and β-adrenoreceptor agonists.
Enalapril decreases cardiac mass and fetal gene expression without affecting the expression of endothelin-1, transforming growth factor β-1, or cardiotrophin-1 in the healthy normotensive rat
Authors: Mackovicova Katarina , Gazova Andrea , Kucerova Dana , Gajdacova Beata , Klimas Jan , Ochodnicky Peter , Goncalvesova Eva , Kyselovic Jan , Krenek Peter
Published: March 2011

Angiotensin II can induce cardiac hypertrophy by stimulating the release of growth factors. ACE inhibitors reduce angiotensin II levels and cardiac hypertrophy, but their effects on the healthy heart are largely unexplored. We hypothesized that ACE inhibition decreases left ventricular mass in normotensive animals and that this is associated with altered expression of cardiac fetal genes, growth factors, and endothelial nitric oxide synthase (eNOS). Wistar rats (n = 7 per group) were orally administered with enalapril twice daily for a total daily dose of 5 mg·kg–1·d–1(ENAP5) or 15 mg·kg–1·d–1(ENAP15) or vehicle. Systolic blood pressure was measured by the tail-cuff method. Left ventricular expression of cardiac myosin heavy chain-α (MYH6) and -β (MYH7), atrial natriuretic peptide (ANP), endothelin-1 (ET-1), transforming growth factor β-1 (TGFβ-1), cardiotrophin-1 (CT-1), and renal renin were examined by real-time PCR, and eNOS using Western blot. Blood pressure was decreased only in ENAP15 animals (p < 0.05 vs. Control), whereas left ventricular mass decreased after both doses of enalapril (p < 0.05 vs. Control). MYH7 and ANP were reduced in ENAP15, while no changes in ET-1, TGFβ-1, CT-1, and MYH6 mRNA or eNOS protein were observed. Renal renin dose-dependently increased after enalapril treatment. Enalapril significantly decreased left ventricular mass even after 1 week treatment in the normotensive rat. This was associated with a decreased expression of the fetal genes MYH7 and ANP, but not expression of ET-1, CT-1, or TGFβ-1.
Maturation increases superoxide radical production without increasing oxidative damage in the skeletal muscle of hooded seals (Cystophora cristata)
Authors: Vázquez-Medina J. P. , Olguín-Monroy N. O. , Maldonado P. D. , Santamaría A. , Königsberg M. , Elsner R. , Hammill M. O. , Burns J. M. , Zenteno-Savín T.
Published: March 2011

Diving vertebrates represent unique models for the study of the physiological responses to reactive oxygen species (ROS) production and oxidative stress because of their adaptability to cope with dive-derived ROS production. We hypothesized that in the skeletal muscle of a diving mammal, the hooded seal ( Cystophora cristata (Erxleben, 1777)), ROS production increases with maturation but the accumulation of oxidative damage does not. To test this, we analyzed the tissue capacity to produce ROS, the accumulation of oxidative damage, and the activity and protein content of the cooper, zinc, and manganese dependent superoxide dismutases (Cu,ZnSOD, MnSOD) in skeletal muscle from neonates, weaned pups, and adult hooded seals. Our results showed higher tissue capacity to produce ROS, higher Cu,ZnSOD and MnSOD activities, and higher MnSOD protein content in adult seals than in pups. No differences in oxidative damage to lipids, proteins, or DNA were detected among groups. Results suggest that increased SOD activity likely counters the oxidative damage commonly associated with increased ROS production. These findings highlight the unusual tolerance of skeletal muscle of seals to increased ROS production.
Heterosis and outbreeding depression between strains of young-of-the-year brook trout (Salvelinus fontinalis)
Authors: Granier S. , Audet C. , Bernatchez L.
Published: March 2011

Brook trout ( Salvelinus fontinalis (Mitchill, 1814)) supports a lucrative fish aquaculture industry in Quebec and production of this species is mainly oriented to stock enhancement supporting sport fisheries. The aim of this study was to verify the expression of interstrain heterosis, i.e., increased performance of first generation hybrid progeny, during the first stages of development in brook trout. Two wild populations that were recently introduced to fish production in Quebec, the Laval (L) and the Rupert (R) strains, and a domestic strain (D) that is present in most Quebec fish farms were used in this study. The growth of 72 full-sibling families, representing three pure (♀D × ♂D, ♀L × ♂L, ♀R × ♂R) and five hybrid (♀D × ♂L, ♀D × ♂R, ♀L × ♂D, ♀L × ♂R, ♀R × ♂L) cross types, were surveyed from hatching to 2136 degree-days. Both heterosis and outbreeding depression were observed, depending on the hybrid cross type. The occurrence of heterosis was dependent on the developmental stage, and growth advantage at a very early developmental stage did not necessarily translate into bigger size later on. Outbreeding depression in growth (mass or length) was much less common than heterosis, and when occurring, it varied from 9.2% to 33.3% compared with 9.0% to 88.2% improvement in growth traits for heterosis. The results indicate that in early development, there was higher occurrence of heterosis relative to fish mass than to fish length and that, overall, the occurrence of heterosis was unpredictable.
FLOW IMPROVEMENT BY PROVIDING PARTIAL TRAFFIC INFORMATION FOR ROAD USERS
Authors: SUN XIAO-YAN , HAO QING-YI , LIU MU-REN , WANG BING-HONG
Published: March 2011

In this paper, we investigate two two-route traffic models, i.e. asymmetric and symmetric two-route traffic models, with mean velocity information feedback strategy. The simulation results show that, for asymmetric two-route model, average flux can be significantly improved if only partial road information is provided for road users. However, for symmetric two-route model, average flux of the two routes adopting information feedback cannot outweigh the flux of two routes chosen completely at random. We explain the results by studying the vehicle number on two routes. We hope the study may provide a good suggestion to the design of Advanced Traveler Information Systems.
PARALLEL 3D FINITE-DIFFERENCE TIME-DOMAIN METHOD ON MULTI-GPU SYSTEMS
Authors: DU LIU-GE , LI KANG , KONG FAN-MIN , HU YUAN
Published: March 2011

Finite-difference time-domain (FDTD) is a popular but computational intensive method to solve Maxwell's equations for electrical and optical devices simulation. This paper presents implementations of three-dimensional FDTD with convolutional perfect match layer (CPML) absorbing boundary conditions on graphics processing unit (GPU). Electromagnetic fields in Yee cells are calculated in parallel millions of threads arranged as a grid of blocks with compute unified device architecture (CUDA) programming model and considerable speedup factors are obtained versus sequential CPU code. We extend the parallel algorithm to multiple GPUs in order to solve electrically large structures. Asynchronous memory copy scheme is used in data exchange procedure to improve the computation efficiency. We successfully use this technique to simulate pointwise source radiation and validate the result by comparison to high precision computation, which shows favorable agreements. With four commodity GTX295 graphics cards on a single personal computer, more than 4000 million Yee cells can be updated in one second, which is hundreds of times faster than traditional CPU computation.
JUSTIFICATION OF POINT ELECTRODE MODELS IN ELECTRICAL IMPEDANCE TOMOGRAPHY
Authors: HANKE MARTIN , HARRACH BASTIAN , HYVÖNEN NUUTTI
Published: March 2011

The most accurate model for real-life electrical impedance tomography is the complete electrode model, which takes into account electrode shapes and (usually unknown) contact impedances at electrode-object interfaces. When the electrodes are small, however, it is tempting to formally replace them by point sources. This simplifies the model considerably and completely eliminates the effect of contact impedance.

In this work we rigorously justify such a point electrode model for the important case of having difference measurements ("relative data") as data for the reconstruction problem. We do this by deriving the asymptotic limit of the complete model for vanishing electrode size. This is supplemented by an analogous result for the case that the distance between two adjacent electrodes also tends to zero, thus providing a physical interpretation and justification of the so-called backscattering data introduced by two of the authors.
SYNTHESIS, MECHANICAL AND ELECTRICAL PROPERTIES OF CARBON MICROCOILS AND NANOCOILS
Authors: BI HUI , KOU KAICHANG , YIN YONGBAI , OSTRIKOV KOSTYA (KEN) , LIU ZONGWEN
Published: March 2011

The results on the synthesis, mechanical and electrical properties of carbon microcoils and nanocoils (CMCs, CNCs) synthesized using catalytic CVD and Ni–P and Co–P catalyst alloys, respectively, are reported. SEM analysis reveals that the CMCs and CNCs have unique helical morphologies, and diameters of 5.0–9.0 μm and 450–550 nm, respectively. Moreover, CMCs with flat cross-section can be stretched to 3 times their original coil lengths. Current–voltage characteristics of a single microcoil have also been obtained. It is found that the CMCs have the electrical conductivity between 100 and 160 S/cm, whereas the electrical resistance increases by about 20% during the coil extension. Besides, the microcoils can produce light in vacuum when the test voltage reaches 10 V. The emission intensity increases as the voltage increases. The mechanical and electrical properties of CMCs and CNC make them potentially useful in many applications in micromagnetic sensors, mechanical microsprings and optoelectronics.
HIGHLY EFFICIENT SIZE REDUCTION OF NANOPARTICLES BY THE SHOCK WAVE METHOD
Authors: WANG WEI , ZHANG QI , LIU ZHENGXUN , LIBOR ZSUZSANNA
Published: March 2011

A highly efficient method for size reduction of nanoparticles has been reported. Ferroelectric lead zirconate titanate (PZT) particles were used as an example to indicate the working principle. The typical average particle size of PZT particles prepared by hydrothermal method is between 500 and 1000 nm. Through the application of high intensity focused ultrasound (HIFU) to the particles, the average size of the particles is reduced to as small as 10–20 nm. The crystalline structure of the treated particles remains according to the X-ray diffraction (XRD) profiles. Transmission electron microscopy (TEM) shows that the treated particles have identical morphology and size. The nonlinear effects of shock wave introduced by HIFU were studied, and the size reduction results were compared with those by ultrasonic cavitations. Finally, the possible reasons for less damage caused by shock wave were discussed.
Effective Transport Properties of LiMn2O4 Electrode via Particle-Scale Modeling
Authors: Gupta Amit , Seo Jeong Hun , Zhang Xiangchun , Du Wenbo , Sastry Ann Marie , Shyy Wei
Published: March 2011

The extension of Li-ion batteries, from portable electronics to hybrid and electric vehicles, is significant. Developing a better understanding of the role of material properties and manipulating the morphology of the particle clusters comprising Li-ion electrodes could lead to potential opportunities for attaining higher performance goals, for which the effect of both material properties and morphology needs to be considered in a physics-based model. In this work, different particle packing arrangements are analyzed for the calculation of effective transport properties and reaction density that appear in the porous-electrode formulation due to the volume-averaging process. Surrogate-based analysis is used to systematically construct and validate reduced-order models for species transport at the particle-electrolyte interface. The low effective solid transport predicted through microscale modeling indicates the effect of packing arrangement and tortuosity, an aspect not captured by the Bruggeman’s relation. Particle cluster simulations reveal a Li-ion flux quantitatively different than that predicted by the porous-electrode model due to the variation of overpotential at the microscale. The present study offers a first-step towards integration of the effect of microstructure into a macroscale simulation.
Skeletal muscle protein synthesis and the abundance of the mRNA translation initiation repressor PDCD4 are inversely regulated by fasting and refeeding in rats
Authors: Zargar Sana , Moreira Tracy S. , Samimi-Seisan Helena , Jeganathan Senthure , Kakade Dhanshri , Islam Nushaba , Campbell Jonathan , Adegoke Olasunkanmi A. J.
Published: March 2011

Optimal skeletal muscle mass is vital to human health, because defects in muscle protein metabolism underlie or exacerbate human diseases. The mammalian target of rapamycin complex 1 is critical in the regulation of mRNA translation and protein synthesis. These functions are mediated in part by the ribosomal protein S6 kinase 1 (S6K1) through mechanisms that are poorly understood. The tumor suppressor programmed cell death 4 (PDCD4) has been identified as a novel substrate of S6K1. Here, we examined 1) the expression of PDCD4 in skeletal muscle and 2) its regulation by feed deprivation (FD) and refeeding. Male rats (∼100 g; n = 6) were subjected to FD for 48 h; some rats were refed for 2 h. FD suppressed muscle fractional rates of protein synthesis and Ser67phosphorylation of PDCD4 (−50%) but increased PDCD4 abundance ( P < 0.05); refeeding reversed these changes ( P < 0.05). Consistent with these effects being regulated by S6K1, activation of this kinase was suppressed by FD (−91%, P < 0.05) but was increased by refeeding. Gavaging rats subjected to FD with a mixture of amino acids partially restored muscle fractional rates of protein synthesis and reduced PDCD4 abundance relative to FD. Finally, when myoblasts were grown in amino acid- and serum-free medium, phenylalanine incorporation into proteins in cells depleted of PDCD4 more than doubled the values in cells with a normal level of PDCD4 ( P < 0.0001). Thus feeding stimulates fractional protein synthesis in skeletal muscle in parallel with the reduction of the abundance of this mRNA translation inhibitor.
Themes in fibrosis and gastrointestinal inflammation
Authors: Fiocchi Claudio , Lund P. Kay
Published: March 2011

Wound healing is an appropriate response to inflammation and tissue injury in the gastrointestinal tract. If wound healing responses are excessive, perpetuated, or prolonged, they lead to fibrosis, distortion of tissue architecture, and loss of function. This introductory editorial and the minireviews or reviews in this themes series highlight the diversity in severity and location of fibrosis in response to gastrointestinal inflammation. The multiplicity of cellular and molecular mediators and new players, including stem cells or extracellular matrix-producing cells derived from nonmesenchymal cell types, is reviewed. Comparisons of inflammation-induced fibrosis across organ systems and the need for integrated and systems-based molecular approaches, new imaging modalities, well-characterized animal models, cell culture models, and improved diagnostic or predictive markers are reviewed. To date, intestinal fibrosis has received much less attention than inflammation in terms of defining mechanisms and underlying causes. This themes series aims to illustrate the importance of research in this area in gastrointestinal health and disease.
Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions
Authors: Arduini Alessandro , Serviddio Gaetano , Escobar Javier , Tormos Ana M. , Bellanti Francesco , Viña José , Monsalve María , Sastre Juan
Published: March 2011

Chronic cholestasis is characterized by mitochondrial dysfunction, associated with loss of mitochondrial membrane potential, decreased activities of respiratory chain complexes, and ATP production. Our aim was to determine the molecular mechanisms that link long-term cholestasis to mitochondrial dysfunction. We studied a model of chronic cholestasis induced by bile duct ligation in rats. Key sensors and regulators of the energetic state and mitochondrial biogenesis, mitochondrial DNA (mtDNA)-to-nuclear DNA (nDNA) ratio (mtDNA/nDNA) relative copy number, mtDNA deletions, and indexes of apoptosis (BAX, BCL-2, and cleaved caspase 3) and cell proliferation (PCNA) were evaluated. Our results show that long-term cholestasis is associated with absence of activation of key sensors of the energetic state, evidenced by decreased SIRT1 and pyruvate dehydrogenase kinase levels and lack of AMPK activation. Key mitochondrial biogenesis regulators (PGC-1α and GABP-α) decreased and NRF-1 was not transcriptionally active. Mitochondrial transcription factor A (TFAM) protein levels increased transiently in liver mitochondria at 2 wk after bile duct ligation, but they dramatically decreased at 4 wk. Reduced TFAM levels at this stage were mirrored by a marked decrease (65%) in mtDNA/nDNA relative copy number. The blockade of mitochondrial biogenesis should not be ascribed to activation of apoptosis or inhibition of cell proliferation. Impaired mitochondrial turnover and loss of the DNA stabilizing effect of TFAM are likely the causative event involved in the genetic instability evidenced by accumulation of mtDNA deletions. In conclusion, the lack of stimulation of mitochondrial biogenesis leads to mtDNA severe depletion and deletions in long-term cholestasis. Hence, long-term cholestasis should be considered a secondary mitochondrial hepatopathy.
Caveolin-1 and force regulation in porcine airway smooth muscle
Authors: Sathish Venkatachalem , Yang Binxia , Meuchel Lucas W. , VanOosten Sarah K. , Ryu Alexander J. , Thompson Michael A. , Prakash Y. S. , Pabelick Christina M.
Published: March 2011

Caveolae are specialized membrane microdomains expressing the scaffolding protein caveolin-1. We recently demonstrated the presence of caveolae in human airway smooth muscle (ASM) and the contribution of caveolin-1 to intracellular calcium ([Ca2+]i) regulation. In the present study, we tested the hypothesis that caveolin-1 regulates ASM contractility. We examined the role of caveolins in force regulation of porcine ASM under control conditions as well as TNF-α-induced airway inflammation. In porcine ASM strips, exposure to 10 mM methyl-β-cyclodextrin (CD) or 5 μM of the caveolin-1 specific scaffolding domain inhibitor peptide (CSD) resulted in time-dependent decrease in force responses to 1 μM ACh. Overnight exposure to the cytokine TNF-α (50 ng/ml) accelerated and increased caveolin-1 expression and enhanced force responses to ACh. Suppression of caveolin-1 with small interfering RNA mimicked the effects of CD or CSD. Regarding mechanisms by which caveolae contribute to contractile changes, inhibition of MAP kinase with 10 μM PD98059 did not alter control or TNF-α-induced increases in force responses to ACh. However, inhibiting RhoA with 100 μM fasudil or 10 μM Y27632 resulted in significant decreases in force responses, with lesser effects in TNF-α exposed samples. Furthermore, Ca2+ sensitivity for force generation was substantially reduced by fasudil or Y27632, an effect even more enhanced in the absence of caveolin-1 signaling. Overall, these results indicate that caveolin-1 is a critical player in enhanced ASM contractility with airway inflammation.
PDH activation during in vitro muscle contractions in PDH kinase 2 knockout mice: effect of PDH kinase 1 compensation
Authors: Dunford Emily C. , Herbst Eric A. , Jeoung Nam Ho , Gittings William , Greig Inglis J. , Vandenboom Rene , LeBlanc Paul J. , Harris Robert A. , Peters Sandra J.
Published: March 2011

Pyruvate dehydrogenase (PDH) plays an important role in regulating carbohydrate oxidation in skeletal muscle. PDH is deactivated by a set of PDH kinases (PDK1, PDK2, PDK3, PDK4), with PDK2 and PDK4 being the most predominant isoforms in skeletal muscle. Although PDK2 is the most abundant isoform, few studies have examined its physiological role. The role of PDK2 on PDH activation (PDHa) at rest and during muscle stimulation at 10 and 40 Hz (eliciting low- and moderate-intensity muscle contractions, respectively) in isolated extensor digitorum longus muscles was studied in PDK2 knockout (PDK2KO) and wild-type (WT) mice ( n = 5 per group). PDHa activity was unexpectedly 35 and 77% lower in PDK2KO than WT muscle ( P = 0.043), while total PDK activity was nearly fourfold lower in PDK2KO muscle ( P = 0.006). During 40-Hz contractions, initial force was lower in PDK2KO than WT muscle ( P < 0.001) but fatigued similarly to ∼75% of initial force by 3 min. There were no differences in initial force or rate of fatigue during 10-Hz contractions. PDK1 compensated for the lack of PDK2 and was 1.8-fold higher in PDK2KO than WT muscle ( P = 0.019). This likely contributed to ensuring that resting PDHa activity was similar between the groups and accounts for the lower PDH activation during muscle contraction, as PDK1 is a very potent inhibitor of the PDH complex. Increased PDK1 expression appears to be regulated by hypoxia inducible factor-1α, which was 3.5-fold higher in PDK2KO muscle. It is clear that PDK2 activity is essential, even at rest, in regulation of carbohydrate oxidation and production of reducing equivalents for the electron transport chain. In addition, these results underscore the importance of the overall kinetics of the PDK isoform population, rather than total PDK activity, in determining transformation of the PDH complex and PDHa activity during muscle contraction.
Differences in serotoninergic metabolism possibly contribute to differences in breathing phenotype of FVB/N and C57BL/6J mice
Authors: Menuet Clément , Kourdougli Nazim , Hilaire Gérard , Voituron Nicolas
Published: March 2011

Mouse readiness for gene manipulation allowed the production of mutants with breathing defects reminiscent of breathing syndromes. As C57BL/6J and FVB/N inbred strains were often used as background strains for producing mutants, we compared their breathing pattern from birth onwards. At birth, in vivo and in vitro approaches revealed robust respiratory rhythm in FVB/N, but not C57BL/6J, neonates. With aging, rhythm robustness difference persisted, and interstrain differences in tidal volume, minute ventilation, breathing regulations, and blood-gas parameters were observed. As serotonin affected maturation and function of the medullary respiratory network, we examined the serotoninergic metabolism in the medulla of C57BL/6J and FVB/N neonates and aged mice. Interstrain differences in serotoninergic metabolism were observed at both ages. We conclude that differences in serotoninergic metabolism possibly contribute to differences in breathing phenotype of FVB/N and C57BL/6J mice.
Evening exposure to a light-emitting diodes (LED)-backlit computer screen affects circadian physiology and cognitive performance
Authors: Cajochen Christian , Frey Sylvia , Anders Doreen , Späti Jakub , Bues Matthias , Pross Achim , Mager Ralph , Wirz-Justice Anna , Stefani Oliver
Published: March 2011

Many people spend an increasing amount of time in front of computer screens equipped with light-emitting diodes (LED) with a short wavelength (blue range). Thus we investigated the repercussions on melatonin (a marker of the circadian clock), alertness, and cognitive performance levels in 13 young male volunteers under controlled laboratory conditions in a balanced crossover design. A 5-h evening exposure to a white LED-backlit screen with more than twice as much 464 nm light emission {irradiance of 0,241 Watt/(steradian × m2) [W/(sr × m2)], 2.1 × 1013photons/(cm2× s), in the wavelength range of 454 and 474 nm} than a white non-LED-backlit screen [irradiance of 0,099 W/(sr × m2), 0.7 × 1013photons/(cm2× s), in the wavelength range of 454 and 474 nm] elicited a significant suppression of the evening rise in endogenous melatonin and subjective as well as objective sleepiness, as indexed by a reduced incidence of slow eye movements and EEG low-frequency activity (1–7 Hz) in frontal brain regions. Concomitantly, sustained attention, as determined by the GO/NOGO task; working memory/attention, as assessed by “explicit timing”; and declarative memory performance in a word-learning paradigm were significantly enhanced in the LED-backlit screen compared with the non-LED condition. Screen quality and visual comfort were rated the same in both screen conditions, whereas the non-LED screen tended to be considered brighter. Our data indicate that the spectral profile of light emitted by computer screens impacts on circadian physiology, alertness, and cognitive performance levels. The challenge will be to design a computer screen with a spectral profile that can be individually programmed to add timed, essential light information to the circadian system in humans.
Pulmonary O2uptake kinetics as a determinant of high-intensity exercise tolerance in humans
Authors: Murgatroyd Scott R. , Ferguson Carrie , Ward Susan A. , Whipp Brian J. , Rossiter Harry B.
Published: March 2011

Tolerance to high-intensity constant-power (P) exercise is well described by a hyperbola with two parameters: a curvature constant (W′) and power asymptote termed “critical power” (CP). Since the ability to sustain exercise is closely related to the ability to meet the ATP demand in a steady state, we reasoned that pulmonary O2uptake (V̇o2) kinetics would relate to the P-tolerable duration (tlim) parameters. We hypothesized that 1) the fundamental time constant (τV̇o2) would relate inversely to CP; and 2) the slow-component magnitude (ΔV̇o2sc) would relate directly to W′. Fourteen healthy men performed cycle ergometry protocols to the limit of tolerance: 1) an incremental ramp test; 2) a series of constant-P tests to determine V̇o2max, CP, and W′; and 3) repeated constant-P tests (WR6) normalized to a 6 min tlimfor τV̇o2and ΔV̇o2scestimation. The WR6tlimaveraged 365 ± 16 s, and V̇o2max(4.18 ± 0.49 l/min) was achieved in every case. CP (range: 171–294 W) was inversely correlated with τV̇o2(18–38 s; R2= 0.90), and W′ (12.8–29.9 kJ) was directly correlated with ΔV̇o2sc(0.42–0.96 l/min; R2= 0.76). These findings support the notions that 1) rapid V̇o2adaptation at exercise onset allows a steady state to be achieved at higher work rates compared with when V̇o2kinetics are slower; and 2) exercise exceeding this limit initiates a “fatigue cascade” linking W′ to a progressive increase in the O2cost of power production (V̇o2sc), which, if continued, results in attainment of V̇o2maxand exercise intolerance. Collectively, these data implicate V̇o2kinetics as a key determinant of high-intensity exercise tolerance in humans.
Association between Abdominal Fat (DXA) and Its Subcomponents (CT Scan) before and after Weight Loss in Obese Postmenopausal Women: A MONET Study
Authors: Doyon Caroline Y. , Brochu Martin , Messier Virginie , Lavoie Marie-Ève , Faraj May , Doucet Éric , Rabasa-Lhoret Rémi , Dionne Isabelle J.
Published: March 2011

Introduction. Subcutaneous fat (ScF) and visceral fat (VF) measurements using CT scan are expensive and may imply significant radiation doses. Cross-sectional studies using CT scan showed that ScF and VF are significantly correlated with abdominal fat measured by DXA (AF-DXA). The association has not been studied after a weight loss.Objective. To determine (1) the associations between AF-DXA and ScF and VF before and after weight loss and (2) the associations between their changes.Methods. 137 overweight/obese postmenopausal women were divided in two groups (1-caloric restriction or 2-caloric restriction + resistance training). AF was assessed using DXA and CT scan.Results. Correlations between AF-DXA and ScF (before:r=0.87, after;r=0.87;P<.01) and, AF-DXA and VF (before:r=0.61, after;r=0.69;P<.01) are not different before and after the weight loss. Correlations between delta AF-DXA and delta ScF (r=0.72;P<.01) or delta VF (r=0.51;P<.01) were found.Conclusion. The use of AF-DXA as a surrogate for VF after weight loss is questionable, but may be interesting for ScF.
A Review of the Impact of Occupational Contact Dermatitis on Quality of Life
Authors: Lau Melisa Yi Zhi , Burgess John Anthony , Nixon Rosemary , Dharmage Shyamali C. , Matheson Melanie Claire
Published: March 2011

Occupational contact dermatitis (OCD) is the most common occupational skin disease in many countries. We reviewed the current evidence on how OCD impacts on quality of life (QoL). The three commonly used QoL questionnaires in OCD were the Short-Form Health Survey (SF-36), the Dermatology Life Quality Index (DLQI), and the Skindex. Despite the availability of a variety of validated QoL instruments, none of them is specific to OCD or entirely adequate in capturing the impact of OCD on QoL. Nonetheless, the results of this paper do suggest a significant impact. Use of QoL measures in clinical settings will provide patients with an opportunity to express their concerns and assist clinicians to evaluate the effectiveness of management beyond the clinical outcomes. This paper also highlights the lack of a disease-specific QOL instrument and the importance of developing a validated measure to assess QOL in OCD, enabling comparison across countries and occupational groups.
A Simple Approach to Cancer Therapy Afforded by Multivalent Pseudopeptides That Target Cell-Surface Nucleoproteins
Authors: Destouches Damien , Page Nicolas , Hamma-Kourbali Yamina , Machi Valérie , Chaloin Olivier , Frechault Sophie , Birmpas Charalampos , Katsoris Panagiotis , Beyrath Julien , Albanese Patricia , Maurer Marie , Carpentier Gilles , Strub Jean-Marc , Van Dorsselaer Alain , Muller Sylviane , Bagnard Dominique , Briand Jean Paul , Courty José
Published: March 2011

Recent studies have implicated the involvement of cell surface forms of nucleolin in tumor growth. In this study, we investigated whether a synthetic ligand of cell-surface nucleolin known as N6L could exert antitumor activity. We found that N6L inhibits the anchorage-dependent and independent growth of tumor cell lines and that it also hampers angiogenesis. Additionally, we found that N6L is a proapoptotic molecule that increases Annexin V staining and caspase-3/7 activity in vitro and DNA fragmentation in vivo. Through affinity isolation experiments and mass-spectrometry analysis, we also identified nucleophosmin as a new N6L target. Notably, in mouse xenograft models, N6L administration inhibited human tumor growth. Biodistribution studies carried out in tumor-bearing mice indicated that following administration N6L rapidly localizes to tumor tissue, consistent with its observed antitumor effects. Our findings define N6L as a novel anticancer drug candidate warranting further investigation. Cancer Res; 71(9); 3296–305. ©2011 AACR.
Aberrant Expression of OX1 Receptors for Orexins in Colon Cancers and Liver Metastases: an Openable Gate to Apoptosis
Authors: Voisin Thierry , El Firar Aadil , Fasseu Magali , Rouyer-Fessard Christiane , Descatoire Véronique , Walker Francine , Paradis Valérie , Bedossa Pierre , Henin Dominique , Lehy Thérèse , Laburthe Marc
Published: March 2011

Resistance to apoptosis is a recurrent theme in colon cancer. We have shown previously that the 7-transmembrane spanning receptor OX1R for orexins promotes robust apoptosis in the human colon cancer cell line HT29 through an entirely novel mechanism involving phosphorylation of tyrosine-based motifs in OX1R. Here, we investigated the status of OX1R in a large series of human colorectal tumors and hepatic metastases. All primary colorectal tumors regardless of their localization and Duke's stages and all hepatic metastases tested expressed OX1R mRNA and/or protein. In sharp contrast, adjacent normal colonocytes or hepatocytes as well as control normal tissues were negative. Next, we showed that nine human colon cancer cell lines established from primary tumors or metastases expressed OX1R mRNA and underwent important apoptosis on orexin-A challenge. Most interestingly, orexin-A also promoted robust apoptosis in cells that are resistant to the most commonly used drug in colon cancer chemotherapy, 5-fluorouracil. When human colon cancer cells were xenografted in nude mice, orexin-A administered at day 0 strongly slowed the tumor growth and even reversed the development of established tumors when administered 7 days after cell inoculation. Orexin-A also acts by promoting tumor apoptosis in vivo because caspase-3 is activated in tumors on orexin treatment of nude mice. These findings support that OX1R is an Achilles heel of colon cancers, even after metastasis or chemoresistance. They suggest that OX1R agonists might be novel candidates for colon cancer therapy. Cancer Res; 71(9); 3341–51. ©2011 AACR.
Effects of mTOR Inhibitor Everolimus (RAD001) on Bladder Cancer Cells
Authors: Chiong Edmund , Lee I-Ling , Dadbin Ali , Sabichi Anita L. , Harris Loleta , Urbauer Diana , McConkey David J. , Dickstein Rian J. , Cheng Tiewei , Grossman H. Barton
Published: March 2011

Purpose: We investigated the effect of the mTOR inhibitor RAD001 (everolimus) on human bladder cancer (BC) cells in vitro and in vivo.

Experimental Design: The effect of RAD001 on the growth of UM-UC-3, UM-UC-6, UM-UC-9, and UM-UC-14 BC cells were assessed by crystal violet and [3H]thymidine incorporation assays. Flow cytometric cell-cycle analyses were done to measure the apoptotic cell fraction. Protein synthesis was measured using tritium-labeled leucine incorporation assays. The effects of RAD001 on the mTOR pathway were analyzed by Western blotting. To test the effects of RAD001 in vivo, UM-UC-3, UM-UC-6, and UM-UC-9 cells were subcutaneously implanted into nude mice. Tumor-bearing mice were treated orally with RAD001 or placebo. Tumors were harvested for immunohistochemical analysis.

Results: In vitro, RAD001 transiently inhibited BC cell growth in a dose-dependent manner. This effect was augmented by re-treatment of cells after 3 days. UM-UC-14 cells were the most sensitive to RAD001, whereas UM-UC-9 cells were the least sensitive. After re-treatment with RAD001, only sensitive cell lines showed G1-phase arrest, with no evidence of apoptosis. RAD001 significantly inhibited the growth of tumors that were subcutaneously implanted in mice. Inhibition of protein synthesis through the S6K and 4EBP1 pathways seems to be the main mechanism for the RAD001-induced growth inhibition. However, inhibition of angiogenesis was the predominant mechanism of the effect of RAD001 on UM-UC-9 cells.

Conclusions: The mTOR inhibitor RAD001 inhibits growth of BC cells in vitro. RAD001 is effective in treating BC tumors in an in vivo nude mouse model despite the heterogeneity of in vitro responses. Clin Cancer Res; 17(9); 2863–73. ©2011 AACR.