bluuebunny/crossref_metadata_2025 huggingface dataset:
Age- and sex-related morphological and physiological differences influence escape capacity in House Sparrows (Passer domesticus)
Authors: De Neve L. , Ibañez-Alamo J. D. , Soler M.
Published: October 2010

Sexual dimorphism and age-related differences are sources that contribute to morphologic and physiologic variation within animal populations. Measurement of animal performance may indicate whether this variation is functionally relevant. Our study aimed to experimentally test this statement in a captive population of House Sparrows ( Passer domesticus (L., 1758)) by examining age- and sex-related differences in escape response and its relationship to several morphological (tarsus, wing, tail lengths, and body mass) and physiological traits (cell-mediated immunity, natural antibodies, complement activity, hematocrit, and stress response). Escape response from a predator is considered a good variable to measure animal performance, because natural selection clearly favours individuals that avoid predators successfully. Our experimental design also aimed to standardize possible confounding factors affecting escape behaviour under natural conditions. We exposed sparrows to short episodes of high predation risk by simulating the attack of a predator and assumed that the capture order of individuals was related to their escape capacity. The optimal strategy was the immediate escape response for all individuals. We found that first-year males were the best escapers. In support of the hypothesis, juvenile males gathered a better optimum of several morphological and physiological characters that related to capture order.
GAUGE THEORY OF FADDEEV–SKYRME FUNCTIONALS
Authors: KOSHKIN SERGIY
Published: October 2010

We study geometric variational problems for a class of nonlinear σ-models in quantum field theory. Mathematically, one needs to minimize an energy functional on homotopy classes of maps from closed 3-manifolds into compact homogeneous spaces G/H. The minimizers are known as Hopfions and exhibit localized knot-like structure. Our main results include proving existence of Hopfions as finite energy Sobolev maps in each (generalized) homotopy class when the target space is a symmetric space. For more general spaces, we obtain a weaker result on existence of minimizers in each 2-homotopy class.

Our approach is based on representing maps into G/H by equivalence classes of flat connections. The equivalence is given by gauge symmetry on pullbacks of G → G/H bundles. We work out a gauge calculus for connections under this symmetry, and use it to eliminate non-compactness from the minimization problem by fixing the gauge.
OVERTAKING OPTIMAL HARVESTING OF AGE-STRUCTURED PREDATOR-PREY SYSTEMS
Authors: HE ZE-RONG , XU JIA-JIA
Published: October 2010

This article is concerned with an optimal harvesting problem over an infinite horizon for age-dependent predator-prey system and the analysis of long-term behaviors of the optimal-controlled system. Instead of usual concepts, overtaking (or catching-up) optimality is adopted. First-order necessary conditions for optimal controller are carefully derived by means of Dubovitskii–Milyutin functional analytical extremum theory, which differs from the Lagrangian multipliers and the variation of calculus. Another focus of the article is the investigation of turnpike properties of population densities. Our results demonstrate the convergence of the optimal trajectories to an equilibrium in the sense of integral average, weak and point-wise, respectively. This research extend the results for linear equations of single species to situations of interacting species, and provide a unified framework for the treatment of multi-dimensional problems.
STABILITY OF AN AGE-STRUCTURED SEIS EPIDEMIC MODEL WITH INFECTIVITY IN INCUBATIVE PERIOD
Authors: GUO SHU-MIN , LI XUE-ZHI , SONG XIN-YU
Published: October 2010

In this paper, an age-structured SEIS epidemic model with infectivity in incubative period is formulated and studied. The explicit expression of the basic reproduction number R0 is obtained. It is shown that the disease-free equilibrium is globally asymptotically stable if R0 < 1, at least one endemic equilibrium exists if R0 > 1. The stability conditions of endemic equilibrium are also given.
STABILITY AND BIFURCATION ANALYSIS OF A STAGE-STRUCTURED SIR MODEL WITH TIME DELAYS
Authors: JIANG ZHICHAO , HE CHUNJIANG , CHENG GUANGTAO
Published: October 2010

In this paper, we considered an SIR infectious disease model with two stages, immature and mature, with the time to maturity represented by a constant time delay. We obtain positivity and boundedness of solutions and analyze the equilibria and their stability properties.
Relationship between Dielectric Properties and Admittance Spectra of Oxide Ion Conductor Ce0.9Y0.1O2-δ
Authors: Yamamura Hiroshi , Satake Jun , Saito Miwa
Published: October 2010

The frequency dependences of the dielectric properties ε
r' and ε
r'' for 10 at. % Y-doped CeO2 (Ce0.9Y0.1O2-δ), which is a typical oxide-ion conductor, were investigated in a frequency range from 5 Hz to 13 MHz and in a temperature range from 673 to 1073 K in air. The complex dielectric constants were successfully analyzed, assuming both the polarizations of dopant-vacancy associates and charging or loss currents. The dielectric parameters estimated from the frequency dependences of dielectric constants were discussed in relation to admittance spectra, in addition to ac conductivity (σac) and dielectric loss tangent (tan
δ).
Nitrogen-Doping Effect on Ge2Sb2Te5 Chalcogenide Alloy Films during Annealing
Authors: Kim Ki-Hong , Park Ju-Cheol , Lee Jun-Ho , Chung Jae-Gwan , Heo Sung , Choi Sang-Jun
Published: October 2010

The microstructural and electrical-property changes of undoped and 5.4% nitrogen-doped Ge2Sb2Te5 were investigated. The transition temperature of sheet resistance increased owing to nitrogen doping, which corresponded well with the observed phase-change states. The lattice parameters of the undoped and nitrogen-doped Ge2Sb2Te5 exhibited the same tendency of decrease with increasing annealing temperature. Considering the increase in the Ge2Sb2Te5 energy state owing to the presence of interstitial nitrogen, the increase in the crystallization temperature is contrary to the thermodynamic viewpoint. Nitrogen atoms and N2 gas can be located at the interstitial site without distorting the crystal structure.
Preparation of Composite Films of Conjugated Polymer and C60by Electrophoretic Deposition and Their Photovoltaic Effect
Authors: Tada Kazuya , Onoda Mitsuyoshi
Published: October 2010

Composite films of a polyfluorene derivative, poly[(9,9-dioctyl-2,7-divinylenefluorenylene)-alt-{2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylene}], and neat C60with various C60contents have been obtained by electrophoretic deposition from dilute suspensions. It has been observed that deposition from suspensions containing both components results in pinhole-free films that are applicable to photovoltaic devices, whereas inhomogeneous films are formed from the suspensions containing only one of the components. Much improvement in the power conversion efficiency was achieved in the photovoltaic devices using the polymer–C60composites compared with the devices with a pristine polymer film. The applicability of electrophoretic deposition to the fabrication of photovoltaic devices with polymer–C60composites has been successfully demonstrated, although the power conversion efficiency was only on the order of 10-3% at this stage.
Discrimination of Inflammable Liquids by Two-Dimensional Mapping of Complex Refractive Indices in the Terahertz Range
Authors: Yamaguchi Mariko , Ikeda Takeshi , Yamamoto Kohji , Matsushita Akira , Tatsuno Michiaki , Minami Yukio , Tani Masahiko , Hangyo Masanori
Published: October 2010

Terahertz time-domain spectroscopy has been applied to the discrimination of inflammable liquids. Indices of refraction and absorption coefficients of some inflammable liquids reflect those of their ingredients, such as alkanes and aromatic hydrocarbons. The inflammable liquids can be distinguished from each other by plotting their values on a two-dimensional map, in which two axes are the index of refraction and absorption coefficient at 30 cm-1. We also plotted the values of the inflammable liquids on a two-dimensional map, in which two axes are the amplitude transmittance and optical delay at the peak of the terahertz waveform. It demonstrates that the discrimination of inflammable liquids is possible without Fourier transformation of the terahertz waveform.
An Electrically Tunable Focusing Pico-Projector Adopting a Liquid Crystal Lens
Authors: Lin Hung-Chun , Lin Yi-Hsin
Published: October 2010

An electrically tunable pico-projector adopting a liquid crystal (LC) lens as an active optical element is demonstrated. The focal length of this pico-projector is electrically tunable from 350 to 14 cm and the tunable range is even wider than that of a manually focused pico-projector. The response times of turn-on and turn-off are approximately 313 and 880 ms, respectively. In addition, the location of the projection lens can affect the electrically tunable range of the system. A small shift of the projection lens results in the large tunable focusing range of the pico-projector and a tunable focusing range is determined by the LC lens. The optical analysis is also discussed. This concept can even be applied to design other electrically auto focusing pico-projectors based on other optical elements such as liquid lenses and spatial light modulators.
Multibit Polycristalline Silicon–Oxide–Silicon Nitride–Oxide–Silicon Memory Cells with High Density Designed Utilizing a Separated Control Gate
Authors: Kim Kyeong Rok , You Joo Hyung , Kwack Kae Dal , Kim Tae Whan
Published: October 2010

Unique multibit NAND polycrystalline silicon–oxide–silicon nitride–oxide–silicon (SONOS) memory cells utilizing a separated control gate (SCG) were designed to increase memory density. The proposed NAND SONOS memory device based on a SCG structure was operated as two bits, resulting in an increase in the storage density of the NVM devices in comparison with conventional single-bit memories. The electrical properties of the SONOS memory cells with a SCG were investigated to clarify the charging effects in the SONOS memory cells. When the program voltage was supplied to each gate of the NAND SONOS flash memory cells, the electrons were trapped in the nitride region of the oxide–nitride–oxide layer under the gate to supply the program voltage. The electrons were accumulated without affecting the other gate during the programming operation, indicating the absence of cross-talk between two trap charge regions. It is expected that the inference effect will be suppressed by the lower program voltage than the program voltage of the conventional NAND flash memory. The simulation results indicate that the proposed unique NAND SONOS memory cells with a SCG can be used to increase memory density.
Ion Desorption from Single-Walled Carbon Nanotubes Induced by Soft X-ray Illumination
Authors: Mera Yutaka , Fujiwara Takayuki , Ishizaki Kiichiro , Xiang Rong , Shiomi Junichiro , Maruyama Shigeo , Kakiuchi Takuhiro , Mase Kazuhiko , Maeda Koji
Published: October 2010

We have investigated ion desorption from single-walled carbon nanotubes (SWNTs) that is induced by soft X-ray illumination in the C 1s core-excitation energy range in order to have insight to the mechanism of defect formation caused by the similar excitation. The mass of desorbed ions was analyzed by a time-of-flight (TOF) spectrometer and the photon energy dependence of the ion yield or the desorption efficiency spectra were measured as a function of the monochromatic photon energy used for illumination. Experimental results exclude the simple detachment of carbon atoms constituting the nanotubes from the cause of the defect formation. Also the photo-induced etching of carbon atoms associated with C–H bond rupture is ruled out from the defect formation mechanism. Auger mechanisms to explain the photo-induced desorption are discussed.
Resin Elongation Phenomenon of Polystyrene Nanopillars in Nanoimprint Lithography
Authors: Kuwabara Kosuke , Miyauchi Akihiro , Sugimura Hiroyuki
Published: October 2010

We investigated the elongation of polystyrene nanopillars formed by thermal nanoimprint lithography. Silicone and perfluoropolyether were used as mold release agents to obtain molds with different adhesion forces against polystyrene to be imprinted. The adhesion force between the resin and release layers was evaluated as a force curve by atomic force microscope with a polystyrene colloid probe. Elongation depended on the aspect ratio of the corresponding microholes on the mold and the adhesion force against the release layer. The conditions under which the elongation occurred exhibited a clear threshold on the stress loaded on the foot area of the nanopillars.
Room-Temperature Epitaxial Growth of (Li,Ni)O Thin Film with Li Content up to 60 mol %
Authors: Shiraishi Naoki , Kato Yushi , Arai Hideki , Tsuchimine Nobuo , Kobayashi Susumu , Mitsuhashi Masahiko , Soga Masayasu , Kaneko Satoru , Yoshimoto Mamoru
Published: October 2010

NiO thin films containing up to 60 mol % Li were deposited on an ultra smooth sapphire (0001) substrate at room-temperature (RT) by the pulsed laser deposition (PLD) process. From in situ reflection high-energy electron diffraction (RHEED) and ex situ X-ray diffraction (XRD), it was found that the cubic NiO thin film containing 60 mol % Li, deposited at RT, could be epitaxially grown with (111) orientation; however the film became polycrystalline when deposited at 200 °C under the same atmosphere. These results indicate the possible exploration of novel growth of the oxide films using RT PLD process.
Sensitivity to stress-induced reproductive dysfunction is associated with a selective but not a generalized increase in activity of the adrenal axis
Authors: Herod S. M. , Dettmer A. M. , Novak M. A. , Meyer J. S. , Cameron J. L.
Published: October 2010

Stress-induced reproductive dysfunction is a relatively common cause of infertility in women. In response to everyday life stress, some individuals readily develop reproductive dysfunction (i.e., they are stress sensitive), whereas others are more stress resilient. Female cynomolgus monkeys, when exposed to mild combined psychosocial and metabolic stress (change in social environment + 20% reduced calorie diet), can be categorized as stress sensitive (SS; they rapidly become anovulatory in response to stress), medium stress resilient (MSR; they slowly become anovulatory in response to prolonged stress), or highly stress resilient (HSR; they maintain normal menstrual cycles in response to stress). In this study, we examined whether increased sensitivity to stress-induced reproductive dysfunction is associated with elevated adrenal axis activity by measuring 1) the diurnal release of ACTH and cortisol, 2) ACTH and cortisol in response to an acute psychological stress, 3) the percent suppression of cortisol in response to dexamethasone negative feedback, 4) the diurnal release of ACTH and cortisol following exposure to mild psychosocial and metabolic stress, 5) the concentration of cortisol in hair, and 6) adrenal weight. SS monkeys ( n = 5) did not differ from MSR ( n = 5) or HSR ( n = 7) monkeys in any measurement of baseline HPA axis activity or the integrated measurements of chronic HPA axis activity. However, MSR + SS monkeys ( n = 10) did secrete more cortisol than HSR monkeys during the daytime hours (1000–1800) following exposure to a novel social environment and reduced diet. We conclude that increased activity of the HPA axis is unlikely to be the primary mechanism causing increased sensitivity to stress-induced reproductive dysfunction.
Reducing selenoprotein P expression suppresses adipocyte differentiation as a result of increased preadipocyte inflammation
Authors: Zhang Yuanyuan , Chen Xiaoli
Published: October 2010

Oxidative stress and low-grade inflammation have been implicated in obesity and insulin resistance. As a selenium transporter, ubiquitously expressed selenoprotein P (SeP) is known to play a role in the regulation of antioxidant enzyme activity. However, SeP expression and regulation in adipose tissue in obesity and its role in inflammation and adipocyte biology remain unexplored. In this study, we examined Sepp1 gene expression and regulation in adipose tissue of obese rodents and characterized the role of Sepp1 in adipose inflammation and adipogenesis in 3T3-L1 adipocytes. We found that Sepp1 gene expression was significantly reduced in adipose tissue of ob/ob and high-fat diet-induced obese mice as well as in primary adipose cells isolated from Zucker obese rats. Rosiglitazone administration increased SeP protein expression in adipose tissue of obese mice. Treatment of either TNFα or H2O2significantly reduced Sepp1 gene expression in a time- and dose-dependent manner in 3T3-L1 adipocytes. Interestingly, Sepp1 gene silencing resulted in the reduction in glutathione peroxidase activity and the upregulation of inflammatory cytokines MCP-1 and IL-6 in preadipocytes, leading to the inhibition of adipogenesis and adipokine and lipogenic gene expression. Most strikingly, coculturing Sepp1 KD cells resulted in a marked inhibition of normal 3T3-L1 adipocyte differentiation. We conclude that SeP has an important role in adipocyte differentiation via modulating oxidative stress and inflammatory response.
Long-term treatment with atrial natriuretic peptide inhibits ATP production and insulin secretion in rat pancreatic islets
Authors: You Hui , Laychock Suzanne G.
Published: October 2010

Atrial natriuretic peptide (ANP) levels correlate with hyperglycemia in diabetes mellitus, but ANP effects on pancreatic islet β-cell insulin secretion are controversial. ANP was investigated for short- and long-term effects on insulin secretion and mechanisms regulating secretion in isolated rat pancreatic islets. A 3-h incubation with ANP did not affect basal or glucose-stimulated islet insulin secretion. However, 7-day culture of islets with 5.5 mM glucose and ANP (1 nM - 1 μM) markedly inhibited subsequent glucose (11 mM)-stimulated insulin secretion; total islet insulin content was not affected. Following ANP removal for 24 h, the islet insulin-secretory response to glucose was restored. The insulin-secretory response to other insulin secretagogues, including α-ketoisocaproic acid, forskolin, potassium chloride, and ionomycin were also markedly inhibited by chronic exposure to ANP. However, the combination of potassium chloride and α-ketoisocaproic acid was sufficient to overcome the inhibitory effects of ANP on insulin secretion. The glucose-stimulated increases in islet ATP levels and the ATP/ADP ratio were completely inhibited in ANP 7-day-treated islets vs. control; removal of ANP for 24 h partially restored the glucose response. ANP did not affect islet glycolysis. ANP significantly increased levels of islet activated hormone-sensitive lipase and the expression of uncoupling protein-2 and peroxisome proliferator-activated receptor-δ and -α. Although islet ANP-binding natriuretic peptide receptor-A levels were reduced to 60% of control after 7-day culture with ANP, the ANP-stimulated cGMP levels remained similar to control islet levels. Thus, long-term exposure to ANP inhibits glucose-stimulated insulin secretion and ATP generation in isolated islets.
Hormonal regulation of energy-protein homeostasis in hemodialysis patients: an anorexigenic profile that may predispose to adverse cardiovascular outcomes
Authors: Suneja Manish , Murry Daryl J. , Stokes John B. , Lim Victoria S.
Published: October 2010

To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, α-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with energy homeostasis to adverse cardiovascular outcome in the HD patients.
Caveolin-1 is required for vascular endothelial insulin uptake
Authors: Wang Hong , Wang Aileen X. , Barrett Eugene J.
Published: October 2010

As insulin's movement from plasma to muscle interstitium is rate limiting for its metabolic action, defining the regulation of this movement is critical. Here, we address whether caveolin-1 is required for the first step of insulin's transendothelial transport, its uptake by vascular endothelial cells (ECs), and whether IL-6 and TNFα affect insulin uptake or caveolin-1 expression. Uptake of FITC-labeled insulin was measured using confocal microscopy in control bovine aortic ECs (bAECs), in bAECs in which caveolin-1 was either knocked down or overexpressed, in murine ECs from caveolin-1−/− mice and in bAECs exposed to inflammatory cytokines. Knockdown of caveolin-1 expression in bAECs using specific caveolin-1 siRNA reduced caveolin-1 mRNA and protein expression by ∼70%, and reduced FITC-insulin uptake by 67% ( P < 0.05 for each). Over-expression of caveolin-1 increased insulin uptake ( P < 0.05). Caveolin-1-null mouse aortic ECs did not take up insulin and re-expression of caveolin-1 by transfecting these cells with FLAG-tagged caveolin-1 DNA rescued FITC-insulin uptake. Knockdown of caveolin-1 significantly reduced both insulin receptor protein level and insulin-stimulated Akt1 phosphorylation. Knockdown of caveolin-1 also inhibited insulin-induced caveolin-1 and IGF-1 receptor translocation to the plasma membrane. Compared with controls, IL-6 or TNFα (20 ng/ml for 24 h) inhibited FITC-insulin uptake as well as the expression of caveolin-1 mRNA and protein ( P < 0.05 for each). IL-6 or TNFα also significantly reduced plasma membrane-associated caveolin-1. Thus, we conclude that insulin uptake by ECs requires expression of caveolin-1 supporting a role for caveolae mediating insulin uptake. Proinflammatory cytokines may inhibit insulin uptake, at least in part, by inhibiting caveolin-1 expression.
Causal relationships between heart period and systolic arterial pressure during graded head-up tilt
Authors: Porta Alberto , Catai Aparecida M. , Takahashi Anielle C. M. , Magagnin Valentina , Bassani Tito , Tobaldini Eleonora , van de Borne Philippe , Montano Nicola
Published: October 2010

In physiological conditions, heart period (HP) affects systolic arterial pressure (SAP) through diastolic runoff and Starling's law, but, the reverse relation also holds as a result of the continuous action of baroreflex control. The prevailing mechanism sets the dominant temporal direction in the HP-SAP interactions (i.e., causality). We exploited cross-conditional entropy to assess HP-SAP causality. A traditional approach based on phases was applied for comparison. The ability of the approach to detect the lack of causal link from SAP to HP was assessed on 8 short-term (STHT) and 11 long-term heart transplant (LTHT) recipients (i.e., less than and more than 2 yr after transplantation, respectively). In addition, spontaneous HP and SAP variabilities were extracted from 17 healthy humans (ages 21–36 yr, median age 29 yr; 9 females) at rest and during graded head-up tilt. The tilt table inclinations ranged from 15 to 75° and were changed in steps of 15°. All subjects underwent recordings at every step in random order. The approach detected the lack of causal relation from SAP to HP in STHT recipients and the gradual restoration of the causal link from SAP to HP with time after transplantation in the LTHT recipients. The head-up tilt protocol induced the progressive shift from the prevalent causal direction from HP to SAP to the reverse causality (i.e., from SAP to HP) with tilt table inclination in healthy subjects. Transformation of phases into time shifts and comparison with baroreflex latency supported this conclusion. The proposed approach is highly efficient because it does not require the knowledge of baroreflex latency. The dependence of causality on tilt table inclination suggests that “spontaneous” baroreflex sensitivity estimated using noncausal methods (e.g., spectral and cross-spectral approaches) is more reliable at the highest tilt table inclinations.
Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction
Authors: Kim Minjae , Park Sang Won , Kim Mihwa , D'Agati Vivette D. , Lee H. Thomas
Published: October 2010

Acute kidney injury (AKI) frequently leads to systemic inflammation and extrarenal organ dysfunction. Volatile anesthetics are potent anti-inflammatory agents and protect against renal ischemia-reperfusion injury. Here, we sought to determine whether isoflurane, a commonly used volatile anesthetic, protects against AKI-induced liver and intestinal injury, the mechanisms involved in this protection, and whether this protection was independent of the degree of renal injury. Bilateral nephrectomy-induced AKI under pentobarbital sodium anesthesia led to severe hepatic and intestinal injury with periportal hepatocyte vacuolization, small intestinal necrosis, apoptosis, and proinflammatory mRNA upregulation. In contrast, isoflurane anesthesia reduced hepatic and intestinal injury after bilateral nephrectomy. Mechanistically, isoflurane anesthesia upregulated and induced small intestinal crypt sphingosine kinase-1 (SK1) as SK1 mRNA, protein, and enzyme activity increased with isoflurane treatment. Furthermore, isoflurane failed to protect mice treated with a selective SK inhibitor (SKI-II) or mice deficient in the SK1 enzyme against hepatic and intestinal dysfunction after bilateral nephrectomy, demonstrating the key role of SK1. Therefore, in addition to its potent anesthetic properties, isoflurane protects against AKI-induced liver and intestine injury via activation of small intestinal SK1 independently of the effects on the kidney. These findings may help to elucidate the cellular signaling pathways underlying volatile anesthetic-mediated hepatic and intestinal protection and result in novel clinical applications of volatile anesthetics to attenuate perioperative complications arising from AKI.
The role of microRNA in modulating myocardial ischemia-reperfusion injury
Authors: Ye Yumei , Perez-Polo Jose R. , Qian Jinqiao , Birnbaum Yochai
Published: October 2010

MicroRNAs (miRNAs) are small (∼22 nt) noncoding single-stranded RNA molecules that downregulate gene expression. Studies have shown that miRNAs control diverse aspects of heart disease, including hypertrophy, remodeling, heart failure, and arrhythmia. Recently, several studies have suggested that miRNAs contribute to ischemia-reperfusion injury by altering key signaling elements, thus making them potential therapeutic targets. By altering the expression of various key elements in cell survival and apoptosis [such as phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), Bcl-2, Mcl-1, heat shock protein (HSP)60, HSP70, HSP20, programmed cell death 4 (Pdcd4), LRRFIP1, Fas ligand (FasL), Sirt-1, etc.], miRNAs alter the response to ischemia-reperfusion injury. Studies using various in vivo, ex vivo, and in vitro models have suggested the possible involvement of miR-1, miR-21, miR-29, miR-92a, miR-133, miR-199a, and miR-320 in ischemia-reperfusion injury and/or remodeling after myocardial infarction. Thus miRNAs could be potential therapeutic targets for the treatment of heart disease. Inhibiting miRNAs by antisense strategies or pharmacological approaches is likely to emerge as an alternative and safe method for conferring short- and intermediate-term protection against ischemia-reperfusion injury.
Surface Lipids as Multifunctional Mediators of Skin Responses to Environmental Stimuli
Authors: De Luca Chiara , Valacchi Giuseppe
Published: October 2010

Skin surface lipid (SSL) film is a mixture of sebum and keratinocyte membrane lipids, protecting skin from environment. Its composition is unique for the high percentage of long chain fatty acids, and of the polyterpenoid squalene, absent in other human tissues, and in non-human Primates sebum. Here, the still incomplete body of information on SSL as mediators of external chemical, physical, and microbial signals and stressors is revised, focusing on the central event of the continuous oxidative modification induced by the metabolic activity of residential and pathological microbial flora, natural or iatrogenic UV irradiation, exposure to chemicals and cosmetics. Once alpha-tocopherol and ubiquinol-10 antioxidant defences of SSL are overcome, oxidation of squalene and cholesterol gives rise to reactive by-products penetrating deeper into skin layers, to mediate local defensive inflammatory, photo-protective, immune reactions or, at higher concentrations, inducing local but also systemic immune depression, ultimately implicating skin cancerogenesis. Qualitative modifications of SSL represent a pathogenetic sign of diagnostic value in dermatological disorders involving altered sebum production, like pytiriasis versicolor, acne, atopic or seborrheic dermatitis, as well as photo-aging. Achievements of nutriceutical interventions aimed at restoring normal SSL composition and homeostasis are discussed, as feasible therapeutic goals and major means of photo-protection.
Identification of Susceptibility Loci in a Mouse Model of KRASG12D-Driven Pancreatic Cancer
Authors: Jorgenson Tonia C. , Williams Bret R. , Wendland Allyson , Bilger Andrea , Sandgren Eric P. , Drinkwater Norman R.
Published: October 2010

Genetic background affects susceptibility to pancreatic ductal adenocarcinoma in the Ela-KRASG12D mouse model. In this model, KRAS oncogene expression is driven by an elastase promoter in acinar cells of the pancreas on an FVB/NTac (FVB) background [FVB-Tg(Ela-KRASG12D)] with the transgene carried on the Y chromosome. Through linkage analysis of crosses between the C57BL/6J (B6), BALB/cJ (BALB), and DBA/2J (D2) inbred strains of mice and resistant FVB-Tg(Ela-KRASG12D), we have identified six susceptibility loci that affect mean preinvasive lesion multiplicity. Markers on chromosome 2 segregated with high tumor multiplicity in all three strains; these loci were designated Prsq1-3 (pancreatic ras susceptibility quantitative trait loci 1-3; combined F2 and N2 LODW, 6.0, 4.1, and 2.7, respectively). Susceptibility loci on chromosome 4, designated Prsq4 and Prsq5, were identified in crosses between FVB transgenic mice and B6 or BALB mice (combined F2 and N2 LODW, 3.6 and 2.9, respectively). A marker on chromosome 12 segregated with tumor multiplicity in a BALB × FVB-Tg(Ela-KRASG12D) cross and was designated Prsq6 (LODW, ∼2.5). B6-Chr YFVB-Tg(Ela-KRASG12D) and BALB-Chr YFVB-Tg(Ela-KRASG12D) consomics, which carry the KRAS transgene on the FVB Y chromosome on an otherwise inbred B6 or BALB background, developed ∼4-fold (B6) and ∼10-fold (BALB) more lesions than FVB-Tg(Ela-KRASG12D) mice. By 12 months of age, 10% of BALB-Chr YFVB-Tg(Ela-KRASG12D) mice developed invasive carcinomas. Our findings provide evidence that regions of chromosomes 2, 4, and 12 influence the development and progression of pancreatic neoplasms initiated by an oncogenic allele of KRAS in mice. Cancer Res; 70(21); 8398–406. ©2010 AACR.
Loss of PTEN Expression by Blocking Nuclear Translocation of EGR1 in Gefitinib-Resistant Lung Cancer Cells Harboring Epidermal Growth Factor Receptor–Activating Mutations
Authors: Yamamoto Chizuko , Basaki Yuji , Kawahara Akihiko , Nakashima Kazutaka , Kage Masayoshi , Izumi Hiroto , Kohno Kimitoshi , Uramoto Hidetaka , Yasumoto Kosei , Kuwano Michihiko , Ono Mayumi
Published: October 2010

Gefitinib (Iressa) and erlotinib (Tarceva), which target the epidermal growth factor receptor (EGFR), are approved for treatment of patients with advanced non–small cell lung cancer (NSCLC). Patients whose tumors harbor mutations in the EGFR gene, including delE746-A750 in exon 19 and L858R in exon 21, may benefit in particular from gefitinib treatment. However, acquired resistance to gefitinib has been a serious clinical problem, and further optimization is needed for application of EGFR-targeted drugs in lung cancer patients. In this study, we established gefitinib-resistant NSCLC cells from PC-9 cell line, which harbors the delE746-A750 mutation, by exposing the cell line to gefitinib for over 7 months. Gefitinib-resistant PC-9/GEFs cell lines showed a marked downregulation of PTEN expression and increased Akt phosphorylation. In revertant, gefitinib-sensitive clones (PC-9/Rev) derived from PC-9/GEF1-1 and PC-9/GEF2-1, PTEN expression, as well as sensitivity to gefitinib and erlotinib, was restored. Knockdown of PTEN expression using small interfering RNA specific for PTEN in PC-9 cells resulted in drug resistance to gefitinib and erlotinib. Nuclear translocation of the EGR1 transcription factor, which regulates PTEN expression, was shown to be suppressed in resistant clones and restored in their revertant clones. Reduced PTEN expression was also seen in tumor samples from a patient with gefitinib-refractory NSCLC. This study thus strongly suggests that loss of PTEN expression contributes to gefitinib and erlotinib resistance in NSCLC. Our findings reinforce the therapeutic importance of PTEN expression in the treatment of NSCLC with EGFR-targeted drugs. Cancer Res; 70(21); 8715–25. ©2010 AACR.
RAP80 Acts Independently of BRCA1 in Repair of Topoisomerase II Poison-Induced DNA Damage
Authors: Iijima Junko , Zeng Zhihong , Takeda Shunichi , Taniguchi Yoshihito
Published: October 2010

The tumor suppressor BRCA1 functions in DNA homologous recombination, and mutations in BRCA1 increase the risk of breast and ovarian cancers. RAP80 is a component of BRCA1-containing complexes that is required for recruitment of BRCA1 to sites of DNA damage. To evaluate the role of RAP80 in DNA damage repair, we genetically disrupted both RAP80 alleles in the recombinogenic avian DT40 cell line. The resulting RAP80−/− cells were proficient at homologous recombination and nonhomologous end-joining (NHEJ), but were specifically sensitized to the topoisomerase II inhibitor etoposide. Notably, doubly mutant RAP80−/−BRCA1−/− cells were more sensitive to etoposide than were BRCA1−/− cells, revealing that RAP80 performs a BRCA1-independent repair function. Moreover, jointly impairing the function of CtIP, a distinct BRCA1 effector protein, rendered RAP80−/− cells more sensitive to etoposide compared with singly mutant cells, again illustrating a BRCA1-independent role of RAP80. Based on our findings, we propose that RAP80 exerts a specific function in repair of the topoisomerase-cleavage complex, such as the removal of covalently bound polypeptides from double-strand break ends independently of BRCA1. Cancer Res; 70(21); 8467–74. ©2010 AACR.
Gprc5a Deletion Enhances the Transformed Phenotype in Normal and Malignant Lung Epithelial Cells by Eliciting Persistent Stat3 Signaling Induced by Autocrine Leukemia Inhibitory Factor
Authors: Chen Yulong , Deng Jiong , Fujimoto Junya , Kadara Humam , Men Taoyan , Lotan Dafna , Lotan Reuben
Published: October 2010

Signal transducers and activators of transcription 3 (Stat3) is activated by cytokines and growth factors in lung cancers and regulates expression of genes implicated in cell growth, survival, and transformation. Previously, we found that mice with a deletion of the G protein–coupled receptor, family C, group 5, member a (Gprc5a) gene develop lung tumors, indicating that Gprc5a is a tumor suppressor. Herein, we show that epithelial cells from Gprc5a knockout mouse lung (Gprc5a−/− cells) survive better in vitro in medium deprived of exogenous growth factors and form more colonies in semisolid medium than their counterparts from wild-type mice (Gprc5a+/+ cells). Stat3 tyrosine 705 phosphorylation and expression of several Stat3-regulated antiapoptotic genes were higher in Gprc5a−/− than in Gprc5a+/+ cells. Both cell types secreted leukemia inhibitory factor (Lif); however, whereas Stat3 activation was persistent in Gprc5a−/− cells, it was transient in Gprc5a+/+ cells. Lung adenocarcinoma cells isolated from Gprc5a−/− mice also exhibited autocrine Lif-mediated Stat3 activation. The level of Socs3, the endogenous Stat3 inhibitory protein, was higher in Gprc5a+/+ than in Gprc5a−/− cells, and expression of the tumor suppressor stabilized Socs3. Inhibition of Stat3 signaling in Gprc5a−/− normal and cancer cells by the Janus-activated kinase 2 inhibitor AG490 or by a dominant negative Stat3(Y705F) increased starvation-induced apoptosis and inhibited colony formation. These results show that persistent Stat3 activation is important for the survival and transformation of Gprc5a−/− lung cells and suggest that the tumor suppressive effects of Gprc5a are mediated, at least in part, by inhibition of Stat3 signaling through Socs3 stabilization. Cancer Res; 70(21); 8917–26. ©2010 AACR.
Synthetic Lethality Screens Reveal RPS6 and MST1R as Modifiers of Insulin-like Growth Factor-1 Receptor Inhibitor Activity in Childhood Sarcomas
Authors: Potratz Jenny C. , Saunders Darren N. , Wai Daniel H. , Ng Tony L. , McKinney Steven E. , Carboni Joan M. , Gottardis Marco M. , Triche Timothy J. , Jürgens Heribert , Pollak Michael N. , Aparicio Samuel A. , Sorensen Poul H.B.
Published: October 2010

The insulin-like growth factor-1 receptor (IGF1R) is emerging as a promising therapeutic target in human cancers. In the high-risk childhood sarcomas Ewing family tumor and rhabdomyosarcoma, IGF1R-blocking antibodies show impressive antitumor activity in some but not all patients, and acquired resistance is observed. Because tumor IGF1R mutations are not described, the basis of IGF1R inhibitor resistance remains unknown. We hypothesized that compensatory signaling cascades bypassing targeted IGF1R inhibition might be involved. To test this systematically, we performed small interfering RNA (siRNA) screens in sarcoma cell lines to identify IGF1R pathway components or related protein tyrosine kinase (PTK) networks that modulate the antitumor efficacy of the BMS-536924 IGF1R kinase inhibitor. This strategy revealed (a) that sarcoma cells are exquisitely sensitive to loss of distal rather than proximal IGF1R signaling components, such as ribosomal protein S6 (RPS6); (b) that BMS-536924 fails to block RPS6 activation in resistant sarcoma cell lines; and (c) that siRNA knockdown of the macrophage-stimulating 1 receptor tyrosine kinase (MST1R; also known as RON) restores BMS-536924 efficacy, even in highly drug-resistant cell lines. We confirmed MST1R expression across a broad panel of childhood sarcomas, and found that loss of MST1R by RNA interference blocks downstream RPS6 activation when combined with BMS-536924 in vitro. These findings underscore the importance of fully understanding PTK networks for successful clinical implementation of kinase inhibitor strategies. Cancer Res; 70(21); 8770–81. ©2010 AACR.
FTY720 (Fingolimod) Sensitizes Prostate Cancer Cells to Radiotherapy by Inhibition of Sphingosine Kinase-1
Authors: Pchejetski Dmitri , Bohler Torsten , Brizuela Leyre , Sauer Lysann , Doumerc Nicolas , Golzio Muriel , Salunkhe Vishal , Teissié Justin , Malavaud Bernard , Waxman Jonathan , Cuvillier Olivier
Published: October 2010

Radiotherapy is widely used as a radical treatment for prostate cancer, but curative treatments are elusive for poorly differentiated tumors where survival is just 15% at 15 years. Dose escalation improves local response rates but is limited by tolerance in normal tissues. A sphingosine analogue, FTY720 (fingolimod), a drug currently in phase III studies for treatment of multiple sclerosis, has been found to be a potent apoptosis inducer in prostate cancer cells. Using in vitro and in vivo approaches, we analyzed the impact of FTY720 on sphingolipid metabolism in hormone-refractory metastatic prostate cancer cells and evaluated its potential as a radiosensitizer on cell lines and prostate tumor xenografts. In prostate cancer cell lines, FTY720 acted as a sphingosine kinase 1 (SphK1) inhibitor that induced prostate cancer cell apoptosis in a manner independent of sphingosine-1-phosphate receptors. In contrast, γ irradiation did not affect SphK1 activity in prostate cancer cells yet synergized with FTY720 to inhibit SphK1. In mice bearing orthotopic or s.c. prostate cancer tumors, we show that FTY720 dramatically increased radiotherapeutic sensitivity, reducing tumor growth and metastasis without toxic side effects. Our findings suggest that low, well-tolerated doses of FTY720 could offer significant improvement to the clinical treatment of prostate cancer. Cancer Res; 70(21); 8651–61. ©2010 AACR.
E-Cadherin and Transglutaminase-1 Epithelial Barrier Restoration Precedes Type IV Collagen Basement Membrane Reconstruction following Vocal Fold Mucosal Injury
Authors: Ling Changying , Raasch Jennifer L. , Welham Nathan V.
Published: October 2010

The vocal fold epithelium is critical to upper airway immunologic defense and water/ion transport; therefore, any form of physical trauma or insult increases the vulnerability of this structure to functional impairment and pathogen invasion/infection. In this study, we examined the reestablishment of epithelial and basement membrane barrier structures in a well-established rat model of vocal fold mucosal injury. We observed active cell recruitment culminating in peak hyperplasia at 3 days postinjury, the establishment of robust E-cadherin+ and transglutaminase-1+ biochemical barrier signals along the epithelial surface by 3 days postinjury, and the persistent absence of a type IV collagen+ basement membrane at 7 days postinjury. The distinct spatial and temporal immunoactivity of these molecules is consistent with a programmed repair process driving the restoration of vocal fold mucosal integrity and permeability. These data may inform future efforts to optimize functional mucosal recovery postinjury and avoid undesirable events such as barrier compromise or epithelial metaplasia.
Oral Appliance Therapy versus Nasal Continuous Positive Airway Pressure in Obstructive Sleep Apnea: A Randomized, Placebo-Controlled Trial
Authors: Aarab Ghizlane , Lobbezoo Frank , Hamburger Hans L. , Naeije Machiel
Published: October 2010

Background: Previous randomized controlled trials have addressed the efficacy of mandibular advancement devices (MADs) in the treatment of obstructive sleep apnea (OSA). Their common control condition, nasal continuous positive airway pressure (nCPAP), was frequently found to be superior to MAD therapy. However, in most of these studies, only nCPAP was titrated objectively but not MAD. To enable an unbiased comparison between both treatment modalities, the MAD should be titrated objectively as well. Objective: The aim of the present study was to compare the treatment effects of a titrated MAD with those of nCPAP and an intra-oral placebo device. Methods: Sixty-four mild/moderate patients with obstructive sleep apnea (OSA; 52.0 ± 9.6 years) were randomly assigned to three parallel groups: MAD, nCPAP and placebo device. From all patients, two polysomnographic recordings were obtained at the hospital: one before treatment and one after approximately 6 months of treatment. Results: The change in the apnea-hypopnea index (ΔAHI) between baseline and therapy evaluation differed significantly between the three therapy groups (ANCOVA; p = 0.000). No differences in the ΔAHI were found between the MAD and nCPAP therapy (p = 0.092), whereas the changes in AHI in these groups were significantly larger than those in the placebo group (p = 0.000 and 0.002, respectively). Conclusion: There is no clinically relevant difference between MAD and nCPAP in the treatment of mild/moderate OSA when both treatment modalities are titrated objectively.
Bone Marrow-Derived Endothelial Progenitor Cells: A Promising Therapeutic Alternative for Corneal Endothelial Dysfunction
Authors: Shao Chunyi , Fu Yao , Lu Wenjuan , Fan Xianqun
Published: October 2010

Background: The global shortage of donor corneas has motivated the development of bioengineered corneas. Although corneal endothelium has been reconstituted using corneal endothelial cells (CEC) and precursor cells with various carrier materials, all of the current options require corneal tissue and are also limited by the scarcity of donor corneas. Here, we explored the feasibility of inducing bone marrow-derived endothelial progenitor cells (BEPC) to differentiate into CEC for the repair of corneal endothelial defects. Materials and Methods: BEPC were isolated from human fetal bone marrow, and identified using several antigen markers. BEPC were cocultured with CEC for 10 days in a transwell system with conditioned medium from CEC, and cell transdifferentiation was then examined. With a porcine corneal acellular matrix (PCACM) as the carrier, the induced BEPC were transplanted onto a cat’s cornea from which Descemet’s membrane and the endothelium had been stripped. Results: The induced BEPC resembled CEC in polygonal shape, expressing aquaporin-1, tightly opposed cell junctions, and neurone-specific enolase. Twenty-eight days after surgery, the transparency gradually returned to the corneas transplanted with the induced BEPC on PCACM. Conclusions: Human fetal BEPC transdifferentiate into corneal endothelial-like cells in vitro. Features of the induced BEPC indicated that they may be useful for the repair of corneal endothelial dysfunction.