bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cellular Protein La Functions in Enhancement of Virus Release through Lipid Rafts Facilitated by Murine Leukemia Virus Glycosylated Gag
Authors: Nitta Takayuki , Tam Raymond , Kim Jung Woo , Fan Hung
Published: February 2011

Murine leukemia viruses (MuLVs) encode two forms of Gag polyprotein: the precursor for the viral core proteins (Pr65

gag

for Moloney MuLV [M-MuLV]) and a longer glycosylated form (glyco-gag, or gPr80

gag

). gPr80

gag

is translated from the same unspliced viral RNA as Pr65

gag

, from an upstream in-frame CUG initiation codon. As a result, gPr80

gag

contains 88 unique N-terminal amino acids that include a signal peptide that conducts gPr80

gag

into the rough endoplasmic reticulum, where it is glycosylated, exported to the cell surface, and cleaved into two proteins of 55 and 40 kDa. The amino-terminal 55-kDa protein remains cell associated with the 88 unique amino acids exposed to the cytosol. We previously showed that gPr80

gag

facilitates efficient M-MuLV release through lipid rafts. In this report, we found that the unique N-terminal domain of gPr80

gag

is sufficient to facilitate enhanced M-MuLV particle release from transfected 293T cells. A search for cellular proteins involved in gPr80

gag

function led to cellular La protein. Overexpression of mouse or human La enhanced M-MuLV particle release in the absence of glyco-gag, and the released virus had a reduced buoyant density characteristic of increased cholesterol content. Moreover, small interfering RNA (siRNA) knockdown of human La abolished glyco-gag enhancement of M-MuLV release. These results implicate La as a cellular protein involved in M-MuLV glyco-gag function. We also found that overexpression of mouse or human La could enhance HIV-1 release in the absence of gPr80

gag

. Therefore, M-MuLV and HIV-1 may share a pathway for release through lipid rafts involving La.

IMPORTANCE
Retroviruses cause diseases such as leukemia and AIDS. An important aspect of viral replication is how viruses are released from infected cells. We previously found that a unique protein encoded by murine leukemia viruses (MuLVs), glyco-gag (or gPr80

gag

), enhances efficient virus release through cholesterol-rich membrane subdomains called lipid rafts. In this study, we found that the N-terminal domain of gPr80

gag

is sufficient to enhance viral release. A search for cellular proteins that participate in gPr80

gag

function led to cellular La protein. Overexpression of La phenocopied glyco-gag in enhancing M-MuLV release, and knockdown of La abolished glyco-gag function. M-MuLV glyco-gag also enhanced release of HIV-1, as did overexpression La in the absence of glyco-gag. Thus, M-MuLV and HIV-1 may share a cellular pathway for release through lipid rafts involving La. These results may also be relevant for other viruses that are released through lipid rafts.
Ultrasound-guided injections of hyperosmolar dextrose for overuse patellar tendinopathy: a pilot study
Authors: Ryan Michael , Wong Anthony , Rabago David , Lee Kenneth , Taunton Jack
Published: February 2011

Purpose

To evaluate whether ultrasound-guided injection of hyperosmolar dextrose for treatment of patellar tendinopathy decreases pain scores and normalises the appearance of the patellar tendon on ultrasound.

Methods

Subjects were referred from primary care clinics and failed conservative treatment. Subjects received a diagnostic ultrasound examination, then ultrasound-guided injection of 25% dextrose with lidocaine into the area of tendinopathy until they were satisfied with treatment. The primary outcome measure was a three-part visual analogue scale (VAS; baseline and mean of 45 weeks after start of treatment) for pain at rest, activities of daily living (ADL) and during sport. Secondary outcomes included segmental ultrasound examinations assessing tendon hypoechogenicity (area and severity score), neovascularity (severity score) and the presence or absence of intratendinous tearing and calcification, irregularities of cortical bone and thickness.

Results

47 consecutive referrals were included. Subjects received a mean of four (±3) injection sessions. At mean 45 weeks post-enrollment, subjects reported a reduction in pain across the three VAS items (rest 38.4±25–18.7±18.4; ADL 51.1±22.9–25.8±20.1; sport 78.1±15.7–38.8±26.1; p<0.01). There was improvement in neovascularity following the dextrose injection. A significant correlation between hypoechogenicity severity scores and pain at follow-up is reported.

Conclusion

There was a reduction in pain and an improvement in ultrasound appearance following ultrasound-guided dextrose injections for refractory patellar tendinopathy. An improved hypoechoic appearance of the tendon was associated with decreased pain scores, suggesting that dextrose injections may modify patellar tendinopathy at the tissue level and that fibrillar changes may play a role in tendon nociception.
PERTURBATION OF NEAR THRESHOLD EIGENVALUES: CROSSOVER FROM EXPONENTIAL TO NON-EXPONENTIAL DECAY LAWS
Authors: DINU VICTOR , JENSEN ARNE , NENCIU GHEORGHE
Published: February 2011

For a two-channel model of the form [Formula: see text] appearing in the study of Feshbach resonances, we continue the rigorous study, begun in our paper (J. Math. Phys.50 (2009) 013516), of the decay laws for resonances produced by perturbation of unstable bound states close to a threshold. The operator H op is assumed to have the properties of a Schrödinger operator in odd dimensions, with a threshold at zero. We consider for ε small the survival probability |〈ψ0, e-itHεΨ0〉|2, where Ψ0 is the eigenfunction corresponding to E0 for ε = 0. For E0 in a small neighborhood of the origin independent of ε, the survival probability amplitude is expressed in terms of some special functions related to the error function, up to error terms vanishing as ε → 0. This allows for a detailed study of the crossover from exponential to non-exponential decay laws, and then to the bound state regime, as the position of the resonance is tuned across the threshold.
ASSET CORRELATIONS IN TURBULENT MARKETS AND THE IMPACT OF DIFFERENT REGIMES ON ASSET MANAGEMENT
Authors: BERNHART GERMAN , HÖCHT STEPHAN , NEUGEBAUER MICHAEL , NEUMANN MICHAEL , ZAGST RUDI
Published: February 2011

In this article, the dependence structure of the asset classes stocks, government bonds, and corporate bonds in different market environments and its implications on asset management are investigated for the US, European, and Asian market. Asset returns are modelled by a Markov-switching model which allows for two market regimes with completely different risk-return structures. Using major stock indices from all three regions, calm and turbulent market periods are identified for the time period between 1987 and 2009 and the correlation structures in the respective periods are compared. It turns out that the correlations between as well as within the asset classes under investigation are far from being stable and vary significantly between calm and turbulent market periods as well as in time. It also turns out that the US and European markets are much more integrated than the Asian and US/European ones. Moreover, the Asian market features more and longer turbulence phases. Finally, the impact of these findings is examined in a portfolio optimization context. To accomplish this, a case study using the mean-variance and the mean-conditional-value-at-risk framework as well as two levels of risk aversion is conducted. The results show that an explicit consideration of different market conditions in the modelling framework yields better portfolio performance as well as lower portfolio risk compared to standard approaches. These findings hold true for all investigated optimization frameworks and risk-aversion levels.
RISK MANAGEMENT UNDER A FACTOR STOCHASTIC VOLATILITY MODEL
Authors: ESCOBAR MARCOS , OLIVARES PABLO
Published: February 2011

In this paper, we study risk measures and portfolio problems based on a Stochastic Volatility Factor Model (SVFM). We analyze the sensitivity of Value at Risk (VaR) and Expected Shortfall (ES) to the changes in the parameters of the model. We compare the positions of a linear portfolio under assets following a SVFM, a Black–Scholes Model and a model with constant dependence structure. We consider an application to a portfolio of three selected Asian funds.
OPTION PRICING AND EXECUTIVE STOCK OPTION INCENTIVES: AN EMPIRICAL INVESTIGATION UNDER GENERAL ERROR DISTRIBUTION STOCHASTIC VOLATILITY MODEL
Authors: PAN MIN , TANG SHENGQIAO
Published: February 2011

This article investigates the valuation of executive stock options when the stock return volatility is governed by the general error distribution stochastic volatility model, involving both the features of the stock return volatility and the abnormal fluctuations of the stock price at the expiration date. We estimate the parameters in the general error distribution stochastic volatility model using the Markov Chain Monte Carlo method with Shanghai & Shenzhen 300 Index in China as a sample, and compare the executive stock option values calculated by Black-Scholes option pricing model and the option pricing model under general error distribution stochastic volatility model. The results show that the general error distribution stochastic volatility model has greater veracity in describing the volatility of stock market returns, and there is divergence between the two values estimated by Black-Scholes option pricing model and the option pricing model under general error distribution stochastic volatility model. The divergence varies with the discrepancy between the price of underlying stock at the granting date and the strike price of the option.
COULOMB'S LAW CORRECTIONS FROM A GAUGE-KINETIC MIXING
Authors: GAETE PATRICIO , SCHMIDT IVÁN
Published: February 2011

We study the connection or equivalence between two well-known extensions of the Standard Model, that is, for the coupling between the familiar massless electromagnetism U (1) QED and a hidden-sector U (1)h, and axionic electrodynamics. Our discussion is carried out using the gauge-invariant but path-dependent variables formalism, which is an alternative to the Wilson loop approach. When we compute in this way the static quantum potential for the coupling between the familiar massless electromagnetism U (1) QED and a hidden-sector U (1)h, the result of this calculation is a Yukawa correction to the usual static Coulomb potential. Previously,14, we have shown that axionic electrodynamics has a different structure which is reflected in a confining piece. Therefore, both extensions of the Standard Model are not equivalent. Interestingly, when the above calculation is done inside a superconducting box, the Coulombic piece disappears leading to a screening phase.
METASTABLE VACUA IN DEFORMED ${\mathcal N} = 2$ SUPERSYMMETRIC MODELS
Authors: HALYO EDI
Published: February 2011

We show that supersymmetric Abelian models that are obtained from deformations of those with [Formula: see text] supersymmetry also contain metastable vacua for a wide range of parameters. The deformations we consider are combinations of masses for charged and singlet fields, a singlet F-term and an anomalous D-term. We find that, in all cases, the nonsupersymmetric vacua are parametrically far from the supersymmetric ones and therefore metastable. Using retrofitting, we show that these metastable vacua may lead to semirealistic phenomenology.
GIANT MAGNETOIMPEDANCE BEHAVIOR IN MAGNETIC FIELD-DEPOSITED AMORPHOUS FeCuCrVSiB SINGLE AND MULTILAYERED FILMS
Authors: CHEN WEI-PING , XIAO SHU-QIN , FENG SHANG-SHEN , LIU YI-HUA
Published: February 2011

The magnetic and magnetoimpedance behavior of FeCuCrVSiB and ( F / SiO 2)3/ Ag /( SiO 2/ F )3( F = FeCuCrVSiB ) soft magnetic amorphous films deposited in a magnetic field have been investigated systematically. The samples were deposited by the RF sputtering with or without a static magnetic field of 900 Oe applied in the film plane. It is found that the magnetic field applied during the deposition process improves the soft magnetic properties of the sample significantly. The coercive force of the sample is about 0.8 Oe, which is much smaller than that deposited without a field. Moreover, remarkable GMI effects were obtained at relatively low frequencies, which contrasts with the samples deposited without field. In the magnetic field-deposited state, the maximum GMI ratios of 21.5% and 19.5% were achieved for the single-layer films in longitudinal and transverse fields at a frequency of 13 MHz, while for the multilayered films, the maximum values of longitudinal and transverse GMI ratios are 45% and 44% at a frequency of 6.81 MHz, respectively. These superior GMI behaviors of the as-deposited films are related to the magnetic field used in the preparation process and the inserted SiO 2 layers.
UNDERSTANDING FORCE CHAINS IN DENSE GRANULAR MATERIALS
Authors: SUN QICHENG , JIN FENG , LIU JIANGUO , ZHANG GUOHUA
Published: February 2011

When a load is applied to a dense granular material, the stress is largely transmitted by relatively rigid, heavily stressed chains of particles forming a sparse network of larger contact forces. Force chains act as the key determinant of mechanical properties such as stability, elasticity and flowability. To understand the structure and evolution of force chains, related physical processes and three corresponding characteristic time scales are analyzed in this study. We also propose three dimensionless numbers for the measurement of the relative importance of force chains. To solely study the effect of particle surface friction on force chains, uniaxial compression tests of 11,000 equal-sized particles in 2D were numerically simulated using the discrete element method. By proposing three conditions to define a force chain, the chain length distribution is found in the form of a power law. The exponent of 1.744 is independent of the surface friction. Although these results were obtained from partially crystallized jammed packings, they provide new insight into the physical processes and the structure of force chains, and thus will be helpful in the interpretation of force chains in other dense granular systems.
THERMOSTATISTIC PROPERTIES OF A RELATIVISTIC FERMI GAS
Authors: CAI SHUKUAN , SU GUOZHEN , CHEN JINCAN
Published: February 2011

Thermodynamic properties of a relativistic Fermi gas in any dimensional space are studied, in which the influence of particle–antiparticle pair production is taken into account. It is shown that relativistic effects cannot be ignored even at very low temperatures for the system with the Compton wavelength of a particle comparable with the average distance between particles. The pair production results in some novel characteristics, which include the asymptotic behavior of the chemical potential and the rapid increase in the heat capacity with temperature in the high temperature regions, etc.
RESONANT DRIFT OF SPIRAL WAVES INDUCED BY MECHANICAL DEFORMATION
Authors: CHEN JIANG-XING , XU JIANG-RONG , YING HE-PING
Published: February 2011

The drift of rigidly rotating spiral waves in an excitable medium induced by synchronous and asynchronous mechanical deformation is investigated numerically and analytically. The resonant drift of spiral waves induced by a mechanical deformation with ω = ω0 and ω = 3ω0 is observed. At ω = ω0, synchronous and greatest degree of asynchronous mechanical deformations are specially investigated. For the case ω = 3ω0, synchronous mechanism deformation locks the spiral while decreasing of degree of synchronization increases the drift velocity. We derive an approximate but explicit formula of the spiral drift velocity and direction which is consistent with the numerical results.
THE PHOTON ESCAPE PROBABILITY OF Na 330.3 nm RESONANCE LINE
Authors: HE JIAN , ZHANG QINGGUO , LIU GANG
Published: February 2011

In this paper, the photon escape probability of Na 330.3 nm resonance line is calculated, both for slab and cylindrical geometries. The dependence of the photon escape probability on the optical depth in the line center is considered. The oscillator strength, the number density of the absorbing atoms in the ground state, and the optical depth in the line center are discussed in this calculation. The changes of the photon escape probabilities with different concentrations are calculated. This calculation will provide a method to calculate the photon escape probability for different lines.
Atropisomerism and conformational aspects of meso-tetraarylporphyrins and related compounds
Authors: Tomé Augusto C. , Silva Artur M.S. , Alkorta Ibon , Elguero José
Published: February 2011

This review provides a comprehensive description of the atropisomerism of meso-di- and tetraarylporphyrins with substituents in ortho-positions of the aryl ring, as well as in corroles and in conveniently substituted phthalocyanines. Different methods of study were examined: X-ray crystallography, NMR spectroscopy (both static and dynamic aspects), classical kinetics, HPLC and theoretical calculations. Then the four atropisomers, the tautomerism of the inner protons, the 'picket fence' concept, conformationally restricted meso-tetraarylporphyrins and the influence of the metal on the conformation were discussed based on 250 references.
THE IMPACT OF TRADE POLICY REGIMES ON FIRMS' LEARNING FOR INNOVATION FROM SUPPLIERS
Authors: PEERALLY JAHAN ARA , CANTWELL JOHN
Published: February 2011

Using data on the textile-based Mauritius export processing zone (MEPZ) collected just prior to the demise of the preferential trade agreement (PTA) with Europe, we compare the acquisition and absorption of innovative technological capabilities (ITCs) of domestic firms and Asian-owned subsidiaries through domestic, Asian and European-based supplier linkages. Our results show that there are significant differences in learning for innovation from suppliers by MEPZ domestic firms and Asian-owned subsidiaries. The study firstly reveals that domestic supplier firms in a developing sub-Saharan African country like Mauritius can be an important source of ITCs to both domestic firms and foreign subsidiaries. Secondly, despite the presence of appropriate policies and institutions, Asian-owned subsidiaries did not fully harness learning opportunities and absorb acquired ITCs through supplier linkages in order to create new technology locally. We conjecture that their learning strategy was dictated by their foreseen exit from the MEPZ due to the anticipated end of the PTA. Thirdly, domestic firms exhibited a higher commitment to the acquisition and absorption of ITCs through supplier linkages and to the development of local ITCs. We infer that their learning strategy is a consequence of their need to continue to thrive and expand post-PTA.
SUPPLIER INVOLVEMENT IN INNOVATION PROCESSES: A TAXONOMY
Authors: AUNE TINA B. , GRESSETVOLD ESPEN
Published: February 2011

For many companies, suppliers play an important role in innovation processes. One key issue concerns the degree of cooperation, such as an arm's length approach versus the use of relationships. Another issue concerns the scope of company involvement on the supply side, such as involvement of one supplier versus involvement of a network of companies. This article presents a taxonomy of supplier involvement in innovation processes. The empirical data consists of a case study of Norske Skog Skogn, a paper mill that is part of the world's second largest producer of newsprint, and one of its suppliers, ABB, a global engineering company. The article directs attention towards a variety of approaches to organising supplier involvement in innovation processes. The taxonomy may be useful in initiatives to increase awareness of the organisation of innovation processes and improve innovation process performance.
MANAGING INTER-FIRM COLLABORATION IN THE FUZZY FRONT-END: STRUCTURE AS A TWO-EDGED SWORD
Authors: JÖRGENSEN JACOB HÖJ , BERGENHOLTZ CARSTEN , GODUSCHEIT RENÉ CHESTER , RASMUSSEN ERIK STAVNSAGER
Published: February 2011

Literature on innovation emphasises the potential for organisations to collaborate and network instead of carrying out innovation individually. Integrating suppliers, customers and other organisations into the innovation process is perceived as a key to success in innovation management (Chesbrough, 2003). Furthermore, the management of the initial phase of the innovation process has proven vital to the overall innovation success (Kim and Wilemon, 2002a,b). Although the merits of network-based innovations are widely acknowledged, the managerial challenges of the initial integration of external organisations in an innovation network are somewhat neglected in the literature. The aim of this paper is hence to address the challenges that an organisation faces when integrating a plurality of suppliers, customers and other organisations into the Fuzzy Front End of the innovation process.
NEW PRODUCT DEVELOPMENT (NPD) SERVICE SUPPLIERS IN OPEN INNOVATION PRACTICES: PROCESSES AND ORGANIZATION FOR KNOWLEDGE EXCHANGE AND INTEGRATION
Authors: COLOMBO GABRIELE , DELL'ERA CLAUDIO , FRATTINI FEDERICO
Published: February 2011

New Product Development (NPD) service providers have assumed a prominent role in enabling a more widespread use of Open Innovation strategies, thanks to their ability to acquire, recombine and sell specialized knowledge and technologies. This paper adopts the point of view of the NPD service provider to investigate the approaches it can employ in order to favor knowledge exchange with its clients, throughout the service delivery process. The research relies on a multiple case study, which focuses on three collaborative projects undertaken by a worldwide leading provider of NPD services with some of its most important clients. The analysis reveals some important findings. First, the NPD service provider uses standard approaches, both as regards process and organizational variables, to address two critical barriers toward a successful completion of the inter-organizational relationship: the tacit nature of the knowledge to be exchanged and the difficulties in predicting the content of collaboration activities. Second, in implementing these approaches, the NPD service provider takes into account the distinctive characteristics of each client and the peculiarities of the specific collaborative project. Besides providing several managerial insights that will be useful for managers working in NPD service providers, the paper contributes to the academic debate, e.g., investigating the importance of trust in successful inter-organizational knowledge exchange processes.
MULTIPLICITY RESULT FOR CRITICAL P–LAPLACIAN SYSTEMS WITH SINGULAR POTENTIAL
Authors: Ahammou Abdelaziz , Iskafi Khalid
Published: February 2011

The aim of this paper is to prove the existence of multiple positive solutions to the following critical p–Laplacian system with singular potential [Formula: see text] where Ω is a starshaped bounded domain of ℝNwith respect to the origin, p* and q* denote the critical Sobolev exponents and the parameters λ, α, β and γ satisfy some mild conditions. Our system corresponds to a perturbed critical problem which has no positive solutions (λ = 0). We show that the form of the associated energy functional has a local property and satisfies the requirements of the Mountain–Pass geometry; then the Ekeland variational principle and the concept of Palais–Smale sequences will be useful.
RIGHT GORENSTEIN GLOBAL DIMENSION OF AN (ALMOST) EXCELLENT EXTENSION
Authors: Mahdou Najib , Tamekkante Mohammed
Published: February 2011

In this paper, we study the right Gorenstein global dimension and the r.IFD(–) of an (almost) excellent extension of ring.
A NONLINEAR BACKWARD PARABOLIC PROBLEM: REGULARIZATION BY QUASI-REVERSIBILITY AND ERROR ESTIMATES
Authors: Tuan Nguyen Huy , Quan Pham Hoang , Trong Dang Duc , Nhat Nguyen Do Minh
Published: February 2011

In this paper, we consider an inverse time problem for a nonlinear parabolic equation in the form ut + Au(t) = f(t, u(t)), u(T) = φ, where A is a positive self-adjoint unbounded operator and f is a Lipschitz function. As known, it is ill-posed. Using a quasi-reversibility method, we shall construct regularization solutions depended on a small parameter ϵ. We show that the regularized problem is well-posed and that their solution uϵ(t) converges on [0, T] to the exact solution u(t). This paper extends the work by Dinh Nho Hao et al. [8] to nonlinear ill-posed problems. Some numerical tests illustrate that the proposed method is feasible and effective.
Global deficits in development, function, and gene expression in the endocrine pancreas in a deletion mouse model of Prader-Willi syndrome
Authors: Stefan Mihaela , Simmons Rebecca A. , Bertera Suzanne , Trucco Massimo , Esni Farzad , Drain Peter , Nicholls Robert D.
Published: February 2011

Prader-Willi syndrome (PWS) is a multisystem disorder caused by genetic loss of function of a cluster of imprinted, paternally expressed genes. Neonatal failure to thrive in PWS is followed by childhood-onset hyperphagia and obesity among other endocrine and behavioral abnormalities. PWS is typically assumed to be caused by an unknown hypothalamic-pituitary dysfunction, but the underlying pathogenesis remains unknown. A transgenic deletion mouse model (TgPWS) has severe failure to thrive, with very low levels of plasma insulin and glucagon in fetal and neonatal life prior to and following onset of progressive hypoglycemia. In this study, we tested the hypothesis that primary deficits in pancreatic islet development or function may play a fundamental role in the TgPWS neonatal phenotype. Major pancreatic islet hormones (insulin, glucagon) were decreased in TgPWS mice, consistent with plasma levels. Immunohistochemical analysis of the pancreas demonstrated disrupted morphology of TgPWS islets, with reduced α- and β-cell mass arising from an increase in apoptosis. Furthermore, in vivo and in vitro studies show that the rate of insulin secretion is significantly impaired in TgPWS β-cells. In TgPWS pancreas, mRNA levels for genes encoding all pancreatic hormones, other secretory factors, and the ISL1 transcription factor are upregulated by either a compensatory response to plasma hormone deficiencies or a primary effect of a deleted gene. Our findings identify a cluster of imprinted genes required for the development, survival, coordinate regulation of genes encoding hormones, and secretory function of pancreatic endocrine cells, which may underlie the neonatal phenotype of the TgPWS mouse model.
Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge
Authors: Borges Beatriz C. , Rorato Rodrigo , Avraham Yosefa , da Silva Lilian E. C. M. , Castro Margaret , Vorobiav Lia , Berry Elliot , Antunes-Rodrigues Jose , Elias Lucila L. K.
Published: February 2011

Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMP-activated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p-STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance.
Characterization of glucose-insulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus
Authors: Green Alice S. , Macko Antoni R. , Rozance Paul J. , Yates Dustin T. , Chen Xiaochuan , Hay William W. , Limesand Sean W.
Published: February 2011

GSIS is often measured in the sheep fetus by a square-wave hyperglycemic clamp, but maximal β-cell responsiveness and effects of fetal number and sex difference have not been fully evaluated. We determined the dose-response curve for GSIS in fetal sheep (0.9 of gestation) by increasing plasma glucose from euglycemia in a stepwise fashion. The glucose-insulin response was best fit by curvilinear third-order polynomial equations for singletons ( y = 0.018 x3 − 0.26 x2 + 1.2 x − 0.64) and twins ( y = −0.012 x3 + 0.043 x2 + 0.40 x − 0.16). In singles, maximal insulin secretion was achieved at 3.4 ± 0.2 mmol/l glucose but began to plateau after 2.4 ± 0.2 mmol/l glucose (90% of maximum), whereas the maximum for twins was reached at 4.8 ± 0.4 mmol/l glucose. In twin ( n = 18) and singleton ( n = 49) fetuses, GSIS was determined with a square-wave hyperglycemic clamp >2.4 mmol/l glucose. Twins had a lower basal glucose concentration, and plasma insulin concentrations were 59 ( P < 0.01) and 43% ( P < 0.05) lower in twins than singletons during the euglycemic and hyperglycemic periods, respectively. The basal glucose/insulin ratio was approximately doubled in twins vs. singles ( P < 0.001), indicating greater insulin sensitivity. In a separate cohort of fetuses, twins ( n = 8) had lower body weight ( P < 0.05) and β-cell mass ( P < 0.01) than singleton fetuses ( n = 7) as a result of smaller pancreata ( P < 0.01) and a positive correlation ( P < 0.05) between insulin immunopositive area and fetal weight ( P < 0.05). No effects of sex difference on GSIS or β-cell mass were observed. These findings indicate that insulin secretion is less responsive to physiological glucose concentrations in twins, due in part to less β-cell mass.
Regulation of HIF-1α activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia
Authors: He Qing , Gao Zhanguo , Yin Jun , Zhang Jin , Yun Zhong , Ye Jianping
Published: February 2011

The transcription factor HIF-1α activity is increased in adipose tissue to contribute to chronic inflammation in obesity. However, its upstream and downstream events remain to be characterized in adipose tissue in obesity. We addressed this issue by investigating adipocyte HIF-1α activity in response to obesity-associated factors, such as adipogenesis, insulin, and hypoxia. In adipose tissue, both HIF-1α mRNA and protein were increased by obesity. The underlying mechanism was investigated in 3T3-L1 adipocytes. HIF-1α mRNA and protein were augmented by adipocyte differentiation. In differentiated adipocytes, insulin further enhanced HIF-1α in both levels. Hypoxia enhanced only HIF-1α protein, not mRNA. PI3K and mTOR activities are required for the HIF-1α expression. Function of HIF-1α protein was investigated in the regulation of VEGF gene transcription. ChIP assay shows that HIF-1α binds to the proximal hypoxia response element in the VEGF gene promoter, and its function is inhibited by a corepressor composed of HDAC3 and SMRT. These observations suggest that of the three obesity-associated factors, all of them are able to augment HIF-1α protein levels, but only two (adipogenesis and insulin) are able to enhance HIF-1α mRNA activity. Adipose tissue HIF-1α activity is influenced by multiple signals, including adipogenesis, insulin, and hypoxia in obesity. The transcriptional activity of HIF-1α is inhibited by HDAC3-SMRT corepressor in the VEGF gene promoter.
Radiative Mixed Convection over an Isothermal Cone Embedded in a Porous Medium with Variable Permeability
Authors: El-Amin M. F. , Ebrahiem N. A. , Salama Amgad , Sun Shuyu
Published: February 2011

The interaction of mixed convection with thermal radiation of an optical dense viscous fluid adjacent to an isothermal cone imbedded in a porous medium with Rosseland diffusion approximation incorporating the variation of permeability and thermal conductivity is numerically investigated. The transformed conservation laws are solved numerically for the case of variable surface temperature conditions. Numerical results are given for the dimensionless temperature profiles and the local Nusselt number for various values of the mixed convection parameter χ, the cone angle parameter m, the radiation‐conduction parameter Rd, and the surface temperature parameter H.
Expansion of CD16-Negative Natural Killer Cells in the Peripheral Blood of Patients with Metastatic Melanoma
Authors: Holtan Shernan G. , Creedon Douglas J. , Thompson Michael A. , Nevala Wendy K. , Markovic Svetomir N.
Published: February 2011

Altered natural killer (NK) cell function is a component of the global immune dysregulation that occurs in advanced malignancies. Another condition associated with altered NK homeostasis is normal pregnancy, where robust infiltration with CD16− CD9+ NK cells can be identified in decidual tissues, along with a concomitant expansion of CD16− NK cells in the maternal peripheral blood. In metastatic melanoma, we identified a similar expansion of peripheral blood CD16− NK cells (median 7.4% in 41 patients with melanoma compared with 3.0% in 29 controls,P<.001). A subset of NK cells in melanoma patients also expresses CD9, which is characteristically expressed only on NK cells within the female reproductive tract. Expansion of CD16− NK cells was associated with elevated plasma transforming growth factor-beta (TGF-βlevels (median 20 ng/ml, Spearman'sρ=0.81,P=.015)). These findings suggest the possibility of exploring anti-TGF-βtherapy to restore NK function in melanoma.
Medical Treatment for Burn Patients with Eating Disorders: A Case Report
Authors: Akimoto Minekatsu , Takeda Akira , Nagashima Kazutaka , Uehara Rie , Nemoto Mitsuru , Uchinuma Eiju
Published: February 2011

There have been many cases of burn patients who also suffer from psychiatric problems, including eating disorders. We present a case of a 38-year-old female with an eating disorder and depression who became light-headed and fell, spilling boiling water from a kettle on herself at home sustaining partial thickness and full thickness burns over 5% of her total body surface area: left buttock and right thigh and calf. Eating disorders (in the present case, anorexia nervosa) cause emaciation and malnutrition, and consent for hospitalization from the patient and/or family is often difficult. During the medical treatment of burns for these patients, consideration not only of physical symptoms caused by malnutrition but also the psychiatric issues is required. Therefore, multifaceted and complex care must be given to burn patients with eating disorders.
Microwave Attenuation and Prediction of Rain Outage for Wireless Networks in Pakistan's Tropical Region
Authors: Siddique Uzma , Ahmad Laeeq , Raja Gulistan
Published: February 2011

The microwave attenuation due to rainfall in tropical regions has not been very widely studied yet. In Pakistan's tropical environment, line-of-sight microwave communication links were set up and have been operated for several years to study the microwave attenuation characteristics due to tropical rainfall. In this paper the experimental results are presented, including the cumulative distributions of microwave attenuation and the relationship between specific attenuation and rainfall rate. In addition, a rain outage prediction model is proposed which not only predicts microwave radio link performance but will also be useful in calculating the link degradations due to interference issues. The main focus of this research work has been done keeping in mind the wireless networks of Pakistan. The results show that the rainfall rate, the microwave propagation characteristics, and outage predictions in Pakistan differ from the International Radio Consultative Committee predictions and ITU recommendation P530.7/8, respectively.
The Traditional Herbal Medicine, Dangkwisoo‐San, Prevents Cerebral Ischemic Injury through Nitric Oxide‐Dependent Mechanisms
Authors: Kim Ji Hyun , Park Sun Haeng , Kim Young Whan , Ha Jung Min , Bae Sun Sik , Lee Guem San , Cho Su In , Choi Byung Tae , Shin Hwa Kyoung
Published: February 2011

Dangkwisoo‐San (DS) is an herbal extract that is widely used in traditional Korean medicine to treat traumatic ecchymosis and pain by promoting blood circulation and relieving blood stasis. However, the effect of DS in cerebrovascular disease has not been examined experimentally. The protective effects of DS on focal ischemic brain were investigated in a mouse model. DS stimulated nitric oxide (NO) production in human brain microvascular endothelial cells (HBMECs). DS (10–300 μg/mL) produced a concentration‐dependent relaxation in mouse aorta, which was significantly attenuated by the nitric oxide synthase (NOS) inhibitor L‐NAME, suggesting that DS causes vasodilation via a NO‐dependent mechanism. DS increased resting cerebral blood flow (CBF), although it caused mild hypotension. To investigate the effect of DS on the acute cerebral injury, C57/BL6J mice received 90 min of middle cerebral artery occlusion followed by 22.5 h of reperfusion. DS administered 3 days before arterial occlusion significantly reduced cerebral infarct size by 53.7% compared with vehicle treatment. However, DS did not reduce brain infarction in mice treated with the relatively specific endothelial NOS (eNOS) inhibitor, N5‐(1‐iminoethyl)‐L‐ornithine, suggesting that the neuroprotective effect of DS is primarily endothelium‐dependent. This correlated with increased phosphorylation of eNOS in the brains of DS‐treated mice. DS acutely improves CBF in eNOS‐dependent vasodilation and reduces infarct size in focal cerebral ischemia. These data provide causal evidence that DS is cerebroprotective via the eNOS‐dependent production of NO, which ameliorates blood circulation.
Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer
Authors: Avilla Elvira , Guarino Valentina , Visciano Carla , Liotti Federica , Svelto Maria , Krishnamoorthy GnanaPrakasam , Franco Renato , Melillo Rosa Marina
Published: February 2011

Thyroid cancer is the most common endocrine cancer, but its key oncogenic drivers remain undefined. In this study we identified the TYRO3 and AXL receptor tyrosine kinases as transcriptional targets of the chemokine CXCL12/SDF-1 in CXCR4-expressing thyroid cancer cells. Both receptors were constitutively expressed in thyroid cancer cell lines but not normal thyroid cells. AXL displayed high levels of tyrosine phosphorylation in most cancer cell lines due to constitutive expression of its ligand GAS6. In human thyroid carcinoma specimens, but not in normal thyroid tissues, AXL and GAS6 were often coexpressed. In cell lines expressing both receptors and ligand, blocking each receptor or ligand dramatically affected cell viability and decreased resistance to apoptotic stimuli. Stimulation of GAS6-negative cancer cells with GAS6 increased their proliferation and survival. Similarly, siRNA-mediated silencing of AXL inhibited cancer cell viability, invasiveness, and growth of tumor xenografts in nude mice. Our findings suggest that a TYRO3/AXL-GAS6 autocrine circuit sustains the malignant features of thyroid cancer cells and that targeting the circuit could offer a novel therapeutic approach in this cancer. Cancer Res; 71(5); 1792–804. ©2011 AACR.
Gap Junction–Mediated Import of MicroRNA from Bone Marrow Stromal Cells Can Elicit Cell Cycle Quiescence in Breast Cancer Cells
Authors: Lim Philip K. , Bliss Sarah A. , Patel Shyam A. , Taborga Marcelo , Dave Meneka A. , Gregory Larissa A. , Greco Steven J. , Bryan Margarette , Patel Prem S. , Rameshwar Pranela
Published: February 2011

Bone marrow (BM) metastasis of breast cancer (BC) can recur even decades after initial diagnosis and treatment, implying the long-term survival of disseminated cancer cells in a dormant state. Here we investigated the role of microRNAs (miRNA) transmitted from BM stroma to BC cells via gap junctions and exosomes in tumor cell quiescence. MDA-MB-231 and T47D BC cells arrest in G0 phase of the cell cycle when cocultured with BM stroma. Analyses of miRNA expression profiles identified numerous miRNAs implicated in cell proliferation including miR-127, -197, -222, and -223 targeting CXCL12. Subsequently, we showed that these CXCL12-specific miRNAs are transported from BM stroma to BC cells via gap junctions, leading to reduced CXCL12 levels and decreased proliferation. Stroma-derived exosomes containing miRNAs also contributed to BC cell quiescence, although to a lesser degree than miRNAs transmitted via gap junctions. This study shows that the transfer of miRNAs from BM stroma to BC cells might play a role in the dormancy of BM metastases. Cancer Res; 71(5); 1550–60. ©2011 AACR.
Systematic Analysis of MicroRNAs Targeting the Androgen Receptor in Prostate Cancer Cells
Authors: Östling Päivi , Leivonen Suvi-Katri , Aakula Anna , Kohonen Pekka , Mäkelä Rami , Hagman Zandra , Edsjö Anders , Kangaspeska Sara , Edgren Henrik , Nicorici Daniel , Bjartell Anders , Ceder Yvonne , Perälä Merja , Kallioniemi Olli
Published: February 2011

Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3′UTR of AR (and other genes) is much longer than currently used in miRNA target prediction programs. Our own analyses predicted that most of the miRNA regulation of AR would target an extended 6 kb 3′UTR. 3′UTR-binding assays validated 13 miRNAs that are able to regulate this long AR 3′UTR (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371–3p, miR-421, miR-449a, miR-449b, miR-634, miR-654–5p, and miR-9). Fifteen AR downregulating miRNAs decreased androgen-induced proliferation of prostate cancer cells. In particular, analysis of clinical prostate cancers confirmed a negative correlation of miR-34a and miR-34c expression with AR levels. Our findings establish that miRNAs interacting with the long 3′UTR of the AR gene are important regulators of AR protein levels, with implications for developing new therapeutic strategies to inhibit AR function and androgen-dependent cell growth. Cancer Res; 71(5); 1956–67. ©2011 AACR.
Integrative Genomics Identifies Molecular Alterations that Challenge the Linear Model of Melanoma Progression
Authors: Rose Amy E. , Poliseno Laura , Wang Jinhua , Clark Michael , Pearlman Alexander , Wang Guimin , Vega y Saenz de Miera Eleazar C. , Medicherla Ratna , Christos Paul J. , Shapiro Richard , Pavlick Anna , Darvishian Farbod , Zavadil Jiri , Polsky David , Hernando Eva , Ostrer Harry , Osman Iman
Published: February 2011

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathologic, and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (6.0; Affymetrix) with gene expression array (U133A 2.0; Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N = 114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P < 0.05; Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted in reduced cell growth. The differential expression of another metabolic-related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level by using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM. Cancer Res; 71(7); 2561–71. ©2011 AACR.
TLR3 as a Biomarker for the Therapeutic Efficacy of Double-stranded RNA in Breast Cancer
Authors: Salaun Bruno , Zitvogel Laurence , Asselin-Paturel Carine , Morel Yannis , Chemin Karine , Dubois Clarisse , Massacrier Catherine , Conforti Rosa , Chenard Marie Pierre , Sabourin Jean-Christophe , Goubar Aicha , Lebecque Serge , Pierres Michel , Rimoldi Donata , Romero Pedro , Andre Fabrice
Published: February 2011

The discovery of a targeted therapeutic compound along with its companion predictive biomarker is a major goal of clinical development for a personalized anticancer therapy to date. Here we present evidence of the predictive value of TLR3 expression by tumor cells for the efficacy of Poly (A:U) dsRNA in 194 breast cancer patients enrolled in a randomized clinical trial. Adjuvant treatment with double-stranded RNA (dsRNA) was associated with a significant decrease in the risk of metastatic relapse in TLR3 positive but not in TLR3-negative breast cancers. Moreover, we show the functional relevance of TLR3 expression by human tumor cells for the antitumor effects mediated by dsRNA in several preclinical mouse models carried out in immunocompromised animals. These 2 independent lines of evidence relied upon the generation of a novel tool, an anti-TLR3 antibody (40F9.6) validated for routine detection of TLR3 expression on paraffin-embedded tissues. Altogether, these data suggest that dsRNA mediates its therapeutic effect through TLR3 expressed on tumor cells, and could therefore represent an effective targeted treatment in patients with TLR3-positive cancers. Cancer Res; 71(5); 1607–14. ©2011 AACR.