bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential Formation in a Bounded Plasma System which is Terminated by an Electron Emitting Floating Collector Studied by a Particle‐in‐Cell Computer Simulation
Authors: Gyergyek T. , Kovačič J.
Published: March 2013

Potential formation in one‐dimensional bounded plasma system terminated by a floating, electron emitting collector is studied by particle‐in‐cell (PIC) computer simulation. Attention is focused to the case of rather strong space charge limited emission. Formation of a potential well (virtual cathode) in front of the collector is observed. As emission increases the floating potential of the electrode and the potential of the bottom of the potential well both increase. The floating potential increases faster than the virtual cathode potential and consequently the depth of the potential well in front of the collector increases also. As long as the emission is not to large (up to approximately 40 times the critical emission) the relation between the depth of the potential well and the normalized emission follows a simple logarithmic formula. For larger emissions the depth of the potential well is larger than predicted by the model. It seems that at very large emission the floating potential of the collector might even exceed the zero reference potential of the source electrode. Such phenomenon has been reported by [A. Marek et al. Contrib. Plasma Phys., 48, 491 (2008)], where it was observed that the floating potential of a strongly emissive probe exceeded the plasma potential determined from the knee of the current‐voltage characteristics when the same probe was used as a Langmuir probe. But before this actually happens the simulation breaks down. When positive ions start to be repelled by the positive collector back towards the source the system becomes unstable so that a steady state can not be reached and no results can be read from the output of the simulations. That electron emission may destabilize the sheath in front of it, was found also in Hall thrusters, see e.g. [Daren Yu et al. Phys. Plasmas, 15, 104501, 2008] and [F. Taccogna et al Appl. Phys. Lett., 94, 251502, 2009]. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Effect of Discharge Plasma Potential on Diffusion Plasma Parameters Controlled by a Mesh Grid in a Double Plasma Device
Authors: Mishra M. K. , Phukan A. , Chakraborty M.
Published: March 2013

The plasma region under investigation is separated from the discharge region by a mesh grid. Plasma potential and electron number densities and electron temperatures under bi‐Maxwellian approximation for electron distribution function of the multi‐dipole argon plasma are measured. The cold electrons in the diffusion region are produced by local ionization. The hot electrons are the ionizing electrons behaving as Maxwellian. The electron trapping process in the discharge region is produced by potential well due to positive plasma potential with respect to the anode and by a repulsive grid. The dependence of ratios of the density of the hot to the cold electrons NE (=Neh/Nec) and hot to cold electron temperature T(=Teh/Tec) in the diffusion region on the depth of the potential well has been investigated. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Generalized unmixing model for multispectral flow cytometry utilizing nonsquare compensation matrices
Authors: Novo David , Grégori Gérald , Rajwa Bartek
Published: March 2013

Multispectral and hyperspectral flow cytometry (FC) instruments allow measurement of fluorescence or Raman spectra from single cells in flow. As with conventional FC, spectral overlap results in the measured signal in any given detector being a mixture of signals from multiple labels present in the analyzed cells. In contrast to traditional polychromatic FC, these devices utilize a number of detectors (or channels in multispectral detector arrays) that is larger than the number of labels, and no particular detector is a priori dedicated to the measurement of any particular label. This data‐acquisition modality requires a rigorous study and understanding of signal formation as well as unmixing procedures that are employed to estimate labels abundance. The simplest extension of the traditional compensation procedure to multispectral data sets is equivalent to an ordinary least‐square (LS) solution for estimating abundance of labels in individual cells. This process is identical to the technique employed for unmixing spectral data in various imaging fields. The present study shows that multispectral FC data violate key assumptions of the LS process, and use of the LS method may lead to unmixing artifacts, such as population distortion (spreading) and the presence of negative values in biomarker abundances. Various alternative unmixing techniques were investigated, including relative‐error minimization and variance‐stabilization transformations. The most promising results were obtained by performing unmixing using Poisson regression with an identity‐link function within a generalized linear model framework. This formulation accounts for the presence of Poisson noise in the model of signal formation and subsequently leads to superior unmixing results, particularly for dim fluorescent populations. The proposed Poisson unmixing technique is demonstrated using simulated 8‐channel, 2‐fluorochrome data and real 32‐channel, 6‐fluorochrome data. The quality of unmixing is assessed by computing absolute and relative errors, as well as by calculating the symmetrized Kullback–Leibler divergence between known and approximated populations. These results are applicable to any flow‐based system with more detectors than labels where Poisson noise is the dominant contributor to the overall system noise and highlight the fact that explicit incorporation of appropriate noise models is the key to accurately estimating the true label abundance on the cells. © 2013 International Society for Advancement of Cytometry
Coping Successfully with Dyslexia: An Initial Study of an Inclusive School‐Based Resilience Programme
Authors: Firth Nola , Frydenberg Erica , Steeg Charlotte , Bond Lyndal
Published: March 2013

A dyslexia coping programme entitled Success and Dyslexia was implemented in two primary schools within a whole‐class coping programme and whole‐school dyslexia professional development context. One hundred and two year 6 students, 23 of whom had dyslexia, undertook surveys pretest, post‐test and at 1‐year follow‐up. Effectiveness of the coping programme and maintenance of effects for the students after transition to secondary school were investigated. Inclusion of contrast group data in the follow‐up year suggested significant positive changes at first and second follow‐ups in locus of control and nonproductive coping may also be associated with increase in age. Most trends were in the expected direction, especially for students with dyslexia. At follow‐up, students with dyslexia reported similar perceived control and adaptive coping to students without dyslexia rather than a decrease in these areas as is usually the case. A larger sample and an ongoing control group are needed to confirm these results. Copyright © 2013 John Wiley & Sons, Ltd.
Henry Reaction in Aqueous Media at Neutral pH
Authors: Bora Pranjal P. , Bez Ghanashyam
Published: March 2013

An efficient method for the synthesis of β‐nitro alcohols from nitro alkanes and aldehydes in aqueous phosphate buffer under neutral pH conditions at room temperature is reported. In the case of higher nitro alkanes, the reaction showed very good diastereoselectivity to give syn β‐nitro alcohols in preference to their anti products.
Potentiometric Quantification of the Benzoate Ion in Nonalcoholic Beverages Using a Solid Electrode Modified with a Polypyrrole‐Based Selective Membrane
Authors: Aguilar Lira G. Y. , Álvarez Romero G. A. , de J. Licona Sánchez T. , Páez Hernández M. E. , Galán Vidal C. A. , Romero Romo M. A.
Published: March 2013

This work presents the results obtained on the construction of a potentiometric ion‐selective electrode based on a polypyrrole (PPy) selective membrane to quantify the benzoate ion in nonalcoholic beverages. The electrode modification with benzoate (Benz−1) ion doped‐Ppy was carried out under an imposed potential, while the electrosynthesis optimization was undertaken using the modified Simplex method, such that the film’s sensitivity was maximized toward the benzoate ion. The maximum sensitivity recorded was −52.02±1.55 mV/decade [Benz−1] using a graphite powder‐araldite resin composite electrode. During the modified electrode’s characterization it was found out that the response and drift were relatively short, namely 2 min and 0.4 mV min−1 respectively, within the 7 to 9 pH range, exhibiting a detection limit of 7×10−4 mol L−1 and a quantification range of 3×10−3 at 10−1 mol L−1. Selectivity coefficients were evaluated with the Matched Potential Method obtaining in all cases values much less than 1. The benzoate concentration in commercially available juices and sweetened beverages was evaluated comparing the results obtained with the proposed ion‐selective electrode and those of HPLC, the usually accepted technique. A statistical analysis of the results led to the conclusion that there exists no meaningful difference between the results obtained with both techniques, which shows the usefulness of the ion‐selective electrode to proceed with the quantification in real samples.
Development and application of reduced‐order neural network model based on proper orthogonal decomposition for BOD5 monitoring in river systems: Uncertainty analysis
Authors: Noori Roohollah , Ashrafi Khosro , Karbassi Abdolreza , Ardestani Mojtaba , Mehrdadi Naser
Published: March 2013

Uncertainty of the reduced‐order neural network (RONN) models is one of the main challenges for developing a proper framework based on their results in water quality management. Hence, the main objective of the research is to determine and compare the uncertainty of both RONN and neural network (NN) models for online estimation of the 5‐day biochemical oxygen demand (BOD5). To achieve this goal, the Monte–Carlo method is used for determining uncertainty analysis of these models. Results indicated that bracketed predictions by 95% confidence bound in the testing steps for selected RONN and NN models are 90.5% and 71.4%, respectively. However, d‐factor of the selected RONN model is better than NN model. Furthermore, obtained results based on comparison between RONN and NN models for online estimation of BOD5 revealed that uncertainty of RONN models were less than NN model. Generally, results of the present research are another confirmation on the authors' previous study. © 2013 American Institute of Chemical Engineers Environ Prog, 32: 344‐349, 2013
Multichannel rivers: their definition and classification
Authors: Carling Paul , Jansen John , Meshkova Lyubov
Published: March 2013

The etymology and historic usage of such terms as ‘anabranch’, ‘anastamose’ and ‘braided’ within river science are reviewed. Despite several decades of modern research to define river channel typologies inclusive of single channels and multiple channel networks, typologies remain ill‐conditioned and consequently ill‐defined. Conventionally employed quantitative planform characteristics of river networks possibly cannot be used alone to define channel types, yet the planform remains a central part of all modern classification schemes, supplemented by sedimentological and other qualitative channel characteristics. Planform characteristics largely have been defined using non‐standardized metrics describing individual network components, such as link lengths, braiding intensity and bifurcation angles, which often fail to separate visually‐different networks of channels. We find that existing typologies remain pragmatically utilitarian rather than fundamentally physics‐based and too often fail to discriminate between two distinctive and important processes integral to new channel initiation and flow‐splitting: (i) in‐channel bar accretion, and (ii) channel avulsion and floodplain excision. It is suggested that, first, if channel planform is to remain central to river typologies, then more rigorous quantitative approaches to the analysis of extended integral channel networks at extended reach scales (rather than network components) are required to correctly determine whether ‘visually‐different’ channel patterns can be discriminated consistently; and, second, if such visually‐different styles do in fact differ in their governing processes of formation and maintenance. A significant question is why do so many seemingly equilibrium network geometries possess a large number of anabranches in excess of predictions from theoretical considerations? The key research frontier with respect to initiating and maintaining multichannel networks remains the understanding and discrimination of accretionary‐bar flow splitting versus avulsive processes. Existing and new knowledge on flow splitting processes needs to be better integrated into channel typologies. Copyright © 2013 John Wiley & Sons, Ltd.
Improvement of streams hydro‐geomorphological assessment using LiDAR DEMs
Authors: Biron Pascale M. , Choné Guénolé , Buffin‐Bélanger Thomas , Demers Sylvio , Olsen Taylor
Published: March 2013

Hydro‐geomorphological assessments are an essential component for riverine management plans. They usually require costly and time‐consuming field surveys to characterize the spatial variability of key variables such as flow depth, width, discharge, water surface slope, grain size and unit stream power throughout the river corridor. The objective of this research is to develop automated tools for hydro‐geomorphological assessments using high‐resolution LiDAR digital elevation models (DEMs). More specifically, this paper aims at developing geographic information system (GIS) tools to extract channel slope, width and discharge from 1 m‐resolution LiDAR DEMs to estimate the spatial distribution of unit stream power in two contrasted watersheds in Quebec: a small agricultural stream (Des Fèves River) and a large gravel‐bed river (Matane River). For slope, the centreline extracted from the raw LiDAR DEM was resampled at a coarser resolution using the minimum elevation value. The channel width extraction algorithm progressively increased the centerline from the raw DEM until thresholds of elevation differences and slopes were reached. Based on the comparison with over 4000 differential global positioning system (GPS) measurements of the water surface collected in a 50 km reach of the Matane River, the longitudinal profile and slope estimates extracted from the raw and resampled LiDAR DEMs were in very good agreement with the field measurements (correlation coefficients ranging from 0 · 83 to 0 · 87) and can thus be used to compute stream power. The extracted width also corresponded very well to the channel as seen from ortho‐photos, although the presence of bars in the Matane River increased the level of error in width estimates. The estimated maximum unit stream power spatial patterns corresponded well with field evidence of bank erosion, indicating that LiDAR DEMs can be used with confidence for initial hydro‐geomorphological assessments. Copyright © 2013 John Wiley & Sons, Ltd.
On capacity gain of antenna subset selection for multiple antenna multicasting
Authors: Park Seung Young
Published: March 2013

In this letter, we consider the transmit antenna subset selection scheme in multicast channels where the antenna subset is selected to maximise the minimum signal‐to‐noise power ratio among the associated users. Using an asymptotic analysis, the average capacity is derived for the large number of users asymptote under the assumption that the antennas are divided into non‐overlapping subsets, and each of them is independent, identical, spatially uncorrelated, and Rayleigh distributed. The numerical results demonstrate that the asymptotic average capacity is close to the exact capacity when signal‐to‐noise power ratio is not large or the number of users is large. Using this result, we compare the asymptotic average capacity of the selection scheme with that of the open‐loop multiple antenna multicasting scheme, in which only one antenna subset is employed, and its number of antennas is the same as that of the antenna subset of the selection scheme. Specifically, it is shown that the asymptotic capacity gain over the open‐loop scheme is significant when the number of antennas in each antenna subset is small. Copyright © 2013 John Wiley & Sons, Ltd.
Phytosociological behaviour and mineral allocation in Panicum turgidum Forssk. along the coast of the Arabian Gulf, Kuwait
Authors: El‐Sheikh Mohamed A. , Abbadi Ghanim A. , Alatar Abdulrahman A.
Published: March 2013

This study aims at analyzing the phytosociological behaviour, nutrient element allocation and soil‐plant relations of the Panicum turgidum, which inhabits the arid region of Failaka Island and Jal Az‐Zor along the coastal plain of Kuwait. The above and underground parts of P. turgidum, at 21 different sites distributed across two different localities, as well as surrounding soil, were analyzed. TWINSPAN, DCA and CCA multivariate techniques were applied to the plant species and soil data set, with all statistical calculations using SAS software. Multivariate analysis led to the identification of 4 vegetation groups associated with the distribution of P. turgidum. These groups were: Stipagrostis ciliata‐Cakile arabica, Plantago boissieri, Cyperus conglomeratus and Alhagi graecorum. The above and underground parts of P. turgidum in Failaka showed the presence of a wider range of mineral nutrients, whereas in Jal Az‐Zor there was a greater concentration of heavy metals in the analysed plant parts. These results suggested that Failaka, as an isolated island, exhibited better environmental conditions for the growth of P. turgidum with a more efficient uptake, use and recycling of minerals compared with the Jal Az‐Zor in which heavy metals tended to accumulate in the plants and soil (Br, Zn, Fe and Cu). (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
A high‐order scheme for the incompressible Navier–Stokes equations with open boundary condition
Authors: Sheng Z. , Thiriet M. , Hecht F.
Published: March 2013

We present a numerical scheme to solve the incompressible Navier–Stokes equations with open boundary condition. After replacing the incompressibility constraint by the pressure Poisson equation, the key is how to give an appropriate boundary condition for the pressure Poisson equation. We propose a new boundary condition for the pressure on the open boundary. Some numerical experiments are presented to verify the accuracy and stability of scheme. Copyright © 2013 John Wiley & Sons, Ltd.
Rank‐Based Robust Tests for Quantitative‐Trait Genetic Association Studies
Authors: Li Qizhai , Li Zhengbang , Zheng Gang , Gao Guimin , Yu Kai
Published: March 2013

Standard linear regression is commonly used for genetic association studies of quantitative traits. This approach may not be appropriate if the trait, on its original or transformed scales, does not follow a normal distribution. A rank‐based nonparametric approach that does not rely on any distributional assumptions can be an attractive alternative. Although several nonparametric tests exist in the literature, their performance in the genetic association setting is not well studied. We evaluate various nonparametric tests for the analysis of quantitative traits and propose a new class of nonparametric tests that have robust performance for traits with various distributions and under different genetic models. We demonstrate the advantage of our proposed methods through simulation study and real data applications.
Survival in dementia and predictors of mortality: a review
Authors: Todd Stephen , Barr Stephen , Roberts Mark , Passmore A Peter
Published: March 2013

Objective

Dementia is an important cause of mortality and, with the ageing population and increasing prevalence of dementia, reliable data on prognosis and survival will be of interest to patients and caregivers as well as providers and commissioners of health and social care. A review of the literature was undertaken to determine the rates of survival in dementia and Alzheimer's disease (AD) and to identify factors that are or are not predictive of mortality in dementia and AD.

Methods

Relevant articles on mortality in dementia were identified following a search of several electronic databases from 1990 to September 2012. Inclusion criteria were reports on prospective community or clinic based cohorts published in English since 1990, to reflect more recent recognition of possible predictors.

Results

Median survival time from age of onset of dementia ranges from 3.3 to 11.7 years, with most studies in the 7 to 10‐year period. Median survival time from age of disease diagnosis ranges from 3.2 to 6.6 years for dementia or AD cohorts as a whole. Age was consistently reported as a predictor of mortality, with male gender a less consistent predictor. Increased disease severity and functional impairment were often associated with mortality.

Conclusions

Substantial heterogeneity in the design of included studies limits the ability to prognosticate for individual patients. However, it is clear that dementia and AD are associated with significant mortality. Reasons for the increased mortality are not established. Copyright © 2013 John Wiley & Sons, Ltd.
Radiation of inertial kinetic energy as near‐inertial waves forced by tropical Pacific Easterly waves
Authors: Soares S. M. , Richards K. J.
Published: March 2013

Easterly waves (EW) are low level tropical atmospheric disturbances able to resonantly force strong mixed layer inertial currents. Using data from two Tropical Atmosphere Ocean/Eastern Pacific Investigation of Climate Processes (TAO/EPIC) buoys located along 95°W and a multiparameterization one‐dimensional turbulence model, we examine how the EW‐forced surface inertial kinetic energy (IKE) loss is partitioned between turbulent dissipation and near‐inertial wave (NIW) radiation. Several EW‐forcing events are individually simulated with a version of the General Ocean Turbulence Model modified to include a linear damping coefficient to account for the NIW radiation energy sink. The kinetic energy budget of these simulations shows that NIW radiation accounted for typically 50–60% of the IKE loss and in some cases up to 80%. These empirically derived estimates of the contribution of the radiated NIWs to the loss of wind‐induced surface IKE are substantially higher than recently published numerical estimates. Furthermore, the results indicate that the vertical NIW energy flux increases linearly with the wind input of IKE, an easily obtained quantity. The NIW vertical energy flux estimated for a single near‐resonant event is comparable to extreme north Pacific wintertime‐averaged fluxes, indicating the existence of important episodic sources of near‐inertial energy available for mixing within and below the thermocline in the tropical region.
The Degree of Liver Injury Determines the Role of P21 in Liver Regeneration And Hepatocarcinogenesis in Mice
Authors: Buitrago-Molina Laura Elisa , Marhenke Silke , Longerich Thomas , Sharma Amar Deep , Boukouris Aristeidis E. , Geffers Robert , Guigas Bruno , Manns Michael P. , Vogel Arndt
Published: March 2013

Hepatocellular carcinoma (HCC) frequently arises in the context of chronic injury that promotes DNA damage and chromosomal aberrations. The cyclin-dependent kinase inhibitor p21 is an important transcriptional target of several tumor suppressors, which promotes cell cycle arrest in response to many stimuli. The aim of this study was to further delineate the role of p21 in the liver during moderate and severe injury and to specify its role in the initiation and progression of HCC. Deletion of p21 led to continuous hepatocyte proliferation in mice with severe injury allowing animal survival but also facilitated rapid tumor development, suggesting that control of compensatory proliferation by high levels of p21 is critical to the prevention of tumor development. Unexpectedly, however, liver regeneration and hepatocarcinogenesis was impaired in p21-deficient mice with moderate injury. Mechanistically, loss of p21 was compensated by activation of Sestrin2, which impaired mitogenic mammalian target of rapamycin (mTOR) signaling and activated cytoprotective Nrf2 signaling. Conclusion: The degree of liver injury and the strength of p21 activation determine its effects on liver regeneration and tumor development in the liver. Moreover, our data uncover a molecular link in the complex mTOR, Nrf2, and p53/p21-signaling network through activation of Sestrin2, which regulates hepatocyte proliferation and tumor development in mice with liver injury. (Hepatology 2013;53:1143–1152)
Sirtuin-6–Dependent Genetic And Epigenetic Alterations Are Associated With Poor Clinical Outcome in Hepatocellular Carcinoma Patients
Authors: Marquardt Jens U. , Fischer Kerstin , Baus Katharina , Kashyap Anubha , Ma Shengyun , Krupp Markus , Linke Matthias , Teufel Andreas , Zechner Ulrich , Strand Dennis , Thorgeirsson Snorri S. , Galle Peter R. , Strand Susanne
Published: March 2013

Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD+–dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. The role of SIRT6 in development and progression of hepatocellular carcinoma is currently unknown. We first investigated SIRT6 expression in 153 primary human liver cancers and in normal and cirrhotic livers using microarray analysis. SIRT6 was significantly down-regulated in both cirrhotic livers and cancer. A Sirt6 knockout (KO) gene expression signature was generated from primary hepatoctyes isolated from 3-week-old Sirt6-deficient animals. Sirt6-deficient hepatocytes showed up-regulation of established hepatocellular carcinoma (HCC) biomarkers alpha-fetoprotein (Afp), insulin-like growth factor 2 (Igf2), H19, and glypican-3. Furthermore, decreased SIRT6 expression was observed in hepatoma cell lines that are known to be apoptosis-insensitive. Re-expression of SIRT6 in HepG2 cells increased apoptosis sensitivity to CD95-stimulation or chemotherapy treatment. Loss of Sirt6 was characterized by oncogenic changes, such as global hypomethylation, as well as metabolic changes, such as hypoglycemia and increased fat deposition. The hepatocyte-specific Sirt6-KO signature had a prognostic impact and was enriched in patients with poorly differentiated tumors with high AFP levels as well as recurrent disease. Finally, we demonstrated that the Sirt6-KO signature possessed a predictive value for tumors other than HCC (e.g., breast and lung cancer). Conclusion: Loss of SIRT6 induces epigenetic changes that may be relevant to chronic liver disease and HCC development. Down-regulation of SIRT6 and genes dysregulated by loss of SIRT6 possess oncogenic effects in hepatocarcinogenesis. Our data demonstrate that deficiency in one epigenetic regulator predisposes a tumorigenic phenotype that ultimately has relevance for outcome of HCC and other cancer patients. (Hepatology 2013;53:1054–1064)
From groundwater abstraction to vegetative response in fen ecosystems
Authors: Johansen Ole Munch , Jensen Jacob Birk , Pedersen Morten Lauge
Published: March 2013

Hydrological effects of groundwater abstraction near a Danish river valley have been assessed by integrated hydrological modelling. The study site contains groundwater‐dependent terrestrial ecosystems in terms of fen and spring habitats that are highly dependent on regional and local scale hydrology. Fens are rare and threatened worldwide due to pressures from agriculture, to lack of appropriate management and to altered catchment hydrology. A solid foundation for hydrological modelling was established based on intensive monitoring at the site, combined with full‐scale pumping tests in the area. A regional groundwater model was used to describe the dynamics in groundwater recharge and the large‐scale discharge to streams. A local grid refinement approach was then applied in a detailed assessment of damage in order to balance the computational effort and the need for a high spatial resolution. A considerable flow reduction in the natural spring was monitored during a full‐scale pumping test while no significant effects on the water table in the fen habitats were observed. A modelled abstraction scenario predicted a lowering of 2–3 cm in the centre of the main fen area during summer periods. The predicted change in water table conditions in the fen habitat is compared to the variability found in 35 Danish fens, and the ecological response is discussed based on statistical water‐level vegetation relations. The results provide a rare quantitative foundation for decision making in relation to management of groundwater‐dependent terrestrial ecosystems. Copyright © 2013 John Wiley & Sons, Ltd.
Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells
Authors: Honegger Anja , Leitz Jenny , Bulkescher Julia , Hoppe‐Seyler Karin , Hoppe‐Seyler Felix
Published: March 2013

The human papillomavirus (HPV) E6/E7 oncogenes play a crucial role in the HPV‐induced carcinogenesis. In this study, the authors investigated whether silencing of endogenous HPV E6/E7 expression may influence the contents or amounts of extracellular microvesicles (eMVs) released from HPV‐positive cancer cells. It was found that eMVs secreted from HeLa cells are enriched for Survivin protein. RNA interference studies revealed that maintenance of both intracellular and microvesicular Survivin amounts was strongly dependent on continuous E6/E7 expression. This indicates that intracellular HPV activities are translated into visible alterations of protein contents in eMVs. Besides Survivin, eMVs from HeLa cells contain additional members of the inhibitor of apoptosis protein (IAP) family (XIAP, c‐IAP1 and Livin). In contrast, no evidence for the presence of the HPV E6 and E7 oncoproteins in eMVs was obtained. Moreover, it was found that silencing of HPV E6/E7 expression led to a significant increase of exosomes—representing eMVs of endocytic origin—released from HeLa cells. This effect was associated with the reinduction of p53, stimulation of the p53 target genes TSAP6 and CHMP4C that can enhance exosome production and induction of senescence. Taken together, these results show that silencing of HPV E6/E7 oncogene expression profoundly affects both the composition and amounts of eMVs secreted by HPV‐positive cancer cells. This indicates that HPVs can induce molecular signatures in eMVs that may affect intercellular communication and could be explored for diagnostic purposes.
Effect of various forms of postmenopausal hormone therapy on the risk of ovarian cancer—A population‐based case control study from Finland
Authors: Koskela‐Niska Virpi , Pukkala Eero , Lyytinen Heli , Ylikorkala Olavi , Dyba Tadeusz
Published: March 2013

Postmenopausal hormone therapy (HT) associates with an increased risk of ovarian cancer, but its' influence on tumor histology is not as well known. Therefore, we evaluated the effect of various types of HT on the risk of epithelial ovarian cancer by histological subtype. All Finnish women diagnosed with ovarian cancer (n = 3,958) aged over 50 during 1995–2007 were identified from the Finnish Cancer Registry. For each case, three controls, matched for age and place of residence, were recruited from the Finnish National Population Register, which also provided data on parity and ages at deliveries. After exclusion of controls with oophorectomy, 11,325 controls remained. The prescription register provided HT use from age 50. Odds ratios (OR) for different HTs were estimated by conditional logistic regression: adjusted for parity, ages at deliveries and hysterectomy. Estradiol‐only therapy use for 5 years or more associated with an increased risk (OR 1.45; 95% confidence interval 1.20–1.75) of a serous subtype, but with a decreased risk of mucinous subtype (0.35; 0.19–0.67). Use of sequential estradiol‐progestin therapy (EPT) for 5 years or more associated with an increase in overall ovarian cancer risk (1.35; 1.20–1.63) and with an increase in the endometrioid subtype (1.88; 1.24–2.86) particularly. Continuous EPT, estradiol + levonorgestrel‐releasing intrauterine system or tibolone had no effect on overall ovarian cancer risk. In conclusion, only sequential EPT use for 5 years or more associates with an increased risk of overall ovarian cancer. Furthermore, HT regimens differ significantly in their association with various histological types of ovarian cancer.
Vemurafenib reverses immunosuppression by myeloid derived suppressor cells
Authors: Schilling Bastian , Sucker Antje , Griewank Klaus , Zhao Fang , Weide Benjamin , Görgens André , Giebel Bernd , Schadendorf Dirk , Paschen Annette
Published: March 2013

Myeloid derived suppressor cells (MDSCs) suppress innate and adaptive immunity, thereby limiting anti‐tumor immune responses in cancer patients. In patients with advanced melanoma, the phenotype and function of MDSCs remains controversial. In our study, we further explored two distinct subpopulations of MDSCs and investigated the impact of Vemurafenib on these cells. Flow cytometry analysis revealed that in comparison to healthy donors and patients with localized disease, PBMCs from patients with metastatic melanoma showed an increased frequency of CD14+HLA‐DR−/low monocytic MDSCs (moMDSCs) and of a previously unrecognized population of CD14−CD66b+Arginase1+ granulocytic MDSCs (grMDSCs). In vitro, both populations suppressed autologous T‐cell proliferation, which was tested in CFSE‐based proliferation assays. Vemurafenib treatment of melanoma patients reduced the frequency of both moMDSCs and grMDSCs. According to our in vivo finding, conditioned medium (CM) from Vemurafenib treated melanoma cells was less active in inducing moMDSCs in vitro than CM from untreated melanoma cells. In conclusion, patients with advanced melanoma show increased levels of moMDSCs, and of a population of CD14−CD66b+Arginase1+ grMDSCs. Both MDSCs are distinct populations capable of suppressing autologous T‐cell responses independently of each other. In vitro as well as in vivo, Vemurafenib inhibits the generation of human moMDSCs. Thus, Vemurafenib decreases immunosuppression in patients with advanced melanoma, indicating its potential as part of future immunotherapies.
Ligand‐independent activation of MET through IGF‐1/IGF‐1R signaling
Authors: Varkaris Andreas , Gaur Sanchaika , Parikh Nila U. , Song Jian H. , Dayyani Farshid , Jin Jung‐Kang , Logothetis Christopher J. , Gallick Gary E.
Published: March 2013

The receptor tyrosine kinase, MET, has been implicated in tumorigenesis and metastasis of many solid tumors, by multiple mechanisms, including cross talk with epidermal growth factor receptor. In this study, we examined the role of insulin‐like growth factor receptor‐1 (IGF‐1R) signaling in MET activation, focusing on prostate cancer cells. Stimulation of the prostate cancer cell line PC3 with IGF‐1 induces a delayed phosphorylation of MET at multiple sites (indicative of full activation), reaching a maximum 18 hr after IGF‐1 addition. MET activation does not require the sole MET ligand hepatocyte growth factor (HGF), but does require transcription to occur. Furthermore, direct injection of IGF‐1 is sufficient to induce MET activation in vivo, in a PC3 xenograft model. Pharmacologic or genetic inhibition of the tyrosine kinase, Src, abolishes MET phosphorylation, and expression of activated Src is sufficient to induce Met phosphorylation in the absence of IGF‐1 stimulation. Activated MET is essential for IGF‐1‐mediated increased migration of PC3 cells, demonstrating an important biologic effect of IGF‐1‐mediated MET activation. Finally, we demonstrate that IGF‐1‐induced delayed MET activation occurs in multiple cell lines which express both the receptors, suggesting that IGF‐1R‐mediated MET activation may contribute to tumorigenic properties of multiple cancer types when both growth factor receptors are expressed. The results further suggest that MET may be activated by multiple receptor tyrosine kinase receptors, and dual targeting of these receptors may be important therapeutically.
miRNA expression profiling of inflammatory breast cancer identifies a 5‐miRNA signature predictive of breast tumor aggressiveness
Authors: Lerebours Florence , Cizeron‐Clairac Geraldine , Susini Aurelie , Vacher Sophie , Mouret‐Fourme Emmanuelle , Belichard Catherine , Brain Etienne , Alberini Jean‐Louis , Spyratos Frédérique , Lidereau Rosette , Bieche Ivan
Published: March 2013

IBC (inflammatory breast cancer) is a rare but very aggressive form of breast cancer with a particular phenotype. The molecular mechanisms responsible for IBC remain largely unknown. In particular, genetic and epigenetic alterations specific to IBC remain to be identified. MicroRNAs, a class of small noncoding RNAs able to regulate gene expression, are deregulated in breast cancer and may therefore serve as tools for diagnosis and prediction. This study was designed to determine miRNA expression profiling (microRNAome) in IBC. Quantitative RT‐PCR was used to determine expression levels of 804 miRNAs in a screening series of 12 IBC compared to 31 non‐stage‐matched non‐IBC and 8 normal breast samples. The differentially expressed miRNAs were then validated in a series of 65 IBC and 95 non‐IBC. From a set of 18 miRNAs of interest selected from the screening series, 13 were differentially expressed with statistical significance in the validation series of IBC compared to non‐IBC. Among these, a 5‐miRNA signature comprising miR‐421, miR‐486, miR‐503, miR‐720 and miR‐1303 was shown to be predictive for IBC phenotype with an overall accuracy of 89%. Moreover, multivariate analysis showed that this signature was an independent predictor of poor Metastasis‐Free Survival in non‐IBC patients.
Plasma 25‐hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: A nested case–control study
Authors: Kühn Tilman , Kaaks Rudolf , Becker Susen , Eomois Piia‐Piret , Clavel‐Chapelon Françoise , Kvaskoff Marina , Dossus Laure , Tjønneland Anne , Olsen Anja , Overvad Kim , Chang‐Claude Jenny , Lukanova Annekatrin , Buijsse Brian , Boeing Heiner , Trichopoulou Antonia , Lagiou Pagona , Bamia Christina , Masala Giovanna , Krogh Vittorio , Sacerdote Carlotta , Tumino Rosario , Mattiello Amalia , Buckland Genevieve , Sánchez María‐José , Menéndez Virginia , Chirlaque María‐Dolores , Barricarte Aurelio , Bueno‐de‐Mesquita H. Bas , van Duijnhoven Fränzel J.B. , van Gils Carla H. , Bakker Marije F. , Weiderpass Elisabete , Skeie Guri , Brustad Magritt , Andersson Anne , Sund Malin , Wareham Nick , Khaw Kay Tee , Travis Ruth C. , Schmidt Julie A. , Rinaldi Sabina , Romieu Isabelle , Gallo Valentina , Murphy Neil , Riboli Elio , Linseisen Jakob
Published: March 2013

Experimental evidence suggests that vitamin D might play a role in the development of breast cancer. Although the results of case–control studies indicate that circulating 25‐hydroxyvitamin D [25(OH)D] is inversely associated with the risk of breast cancer, the results of prospective studies are inconsistent. A case–control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) was carried out comprising 1,391 incident breast cancer cases and 1,391 controls. Multivariable conditional logistic regression models did not reveal a significant overall association between season‐standardized 25(OH)D levels and the risk of breast cancer (ORQ4–Q1 [95% CI]: 1.07 [0.85–1.36], ptrend = 0.67). Moreover, 25(OH)D levels were not related to the risks of estrogen receptor positive tumors (ORQ4–Q1 [95% CI]: 0.97 [0.67–1.38], ptrend = 0.90) and estrogen receptor negative tumors (ORQ4–Q1 [95% CI]: 0.97 [0.66–1.42], ptrend = 0.98). In hormone replacement therapy (HRT) users, 25(OH)D was significantly inversely associated with incident breast cancer (ORlog2 [95% CI]: 0.62 [0.42–0.90], p = 0.01), whereas no significant association was found in HRT nonusers (ORlog2 [95% CI]: 1.14 [0.80–1.62], p = 0.48). Further, a nonsignificant inverse association was found in women with body mass indices (BMI) < 25 kg/m2 (ORlog2 [95% CI]: 0.83 [0.67–1.03], p = 0.09), as opposed to a borderline significant positive association in women with BMI ≥ 25 kg/m2 (ORlog2 [95% CI]: 1.30 [1.0–1.69], p = 0.05). Overall, prediagnostic levels of circulating 25(OH)D were not related to the risk of breast cancer in the EPIC study. This result is in line with findings in the majority of prospective studies and does not support a role of vitamin D in the development of breast cancer.
Order of HPV/Chlamydia infections and cervical high‐grade precancer risk: A case‐cohort study
Authors: Luostarinen Tapio , Namujju Proscovia B. , Merikukka Marko , Dillner Joakim , Hakulinen Timo , Koskela Pentti , Paavonen Jorma , Surcel Heljä‐Marja , Lehtinen Matti
Published: March 2013

Interactions of carcinogenic human papillomaviruses (most notably HPV types 16/18/31/33/45), and HPV6 or Chlamydia trachomatis are not well understood. We have used seroconversions to study effects the order of these infections has on the risk of high‐grade cervical precancer. In a cohort of 94,349 Finnish women with paired sera from consecutive pregnancies within an average of 2.4 years, 490 were diagnosed with cervical CIN3/AIS. Serum antibodies to HPV6/16/18/31/33/45 and C. trachomatis were measured in paired sera of the cases and a subcohort of 2,796 women with a minimum of two pregnancies. HPV16‐adjusted rate ratios (RR) and confidence intervals were estimated by stratified Cox model. Compared to dual seropositivity already at the first serum sampling, RRs related to HPV6 seropositivity before and after HPV31 seroconversion were 0.4 (95% CI 0.0, 4.4) and 10 (95% CI 1.8, 57). Furthermore, RR related to seroconversions of both HPV18/45 and C.trachomatis between the consecutive pregnancies was 28 (95% CI 4.3, 190). Virtually concomitant HPV18/45 and C.trachomatis infections are associated with very high CIN3 risk.
A SYSTEM DYNAMICS APPROACH TO MODEL REHABILITATION OF IRRIGATION NETWORKS CASE STUDY: QAZVIN IRRIGATION NETWORK, IRAN
Authors: Vaez Tehrani Mahsa , Monem Mohammad Javad , Bagheri Ali
Published: March 2013

Assessment of irrigation networks shows that their utility is less than what is expected because of poor performance. Poor performance of irrigation networks is partly due to their aged condition, which requires rehabilitation. Rehabilitation of irrigation systems is commonly practised on a basis lacking integration; thus they have not led to considerable improvement. Integration requires a systemic approach and system dynamics methodology provides a practical tool to implement integration in a complex system such as an irrigation system. Using system dynamics modelling, the paper intends to evaluate several rehabilitation policies in the Qazvin Irrigation Network, in mid‐northern Iran, and then the effects of policies on performance elements (efficiency) will be investigated.

The main elements that affect network utility are considered to be efficiency, adequacy, equity, flexibility and stability in water delivery. Three policies for network rehabilitation are considered to be: fixing the crop area, decreasing drawdown of groundwater, and increasing investment in renovation projects. The results show that all of these three policies improve system utility; however, the ‘fixing the crop area' policy showed a better improvement. Copyright © 2013 John Wiley & Sons, Ltd.
TESTS OF EQUAL FORECAST ACCURACY FOR OVERLAPPING MODELS
Authors: Clark Todd E. , Mccracken Michael W.
Published: March 2013

This paper examines the asymptotic and finite‐sample properties of tests of equal forecast accuracy when the models being compared are overlapping in the sense of Vuong (Econometrica 1989; 57: 307–333). Two models are overlapping when the true model contains just a subset of variables common to the larger sets of variables included in the competing forecasting models. We consider an out‐of‐sample version of the two‐step testing procedure recommended by Vuong but also show that an exact one‐step procedure is sometimes applicable. When the models are overlapping, we provide a simple‐to‐use fixed‐regressor wild bootstrap that can be used to conduct valid inference. Monte Carlo simulations generally support the theoretical results: the two‐step procedure is conservative, while the one‐step procedure can be accurately sized when appropriate. We conclude with an empirical application comparing the predictive content of credit spreads to growth in real stock prices for forecasting US real gross domestic product growth. Copyright © 2013 John Wiley & Sons, Ltd.
Targeted disruption of leucine-rich repeat kinase 1 but not leucine-rich repeat kinase 2 in mice causes severe osteopetrosis
Authors: Xing Weirong , Liu Jeff , Cheng Shaohong , Vogel Peter , Mohan Subburaman , Brommage Robert
Published: March 2013

To assess the roles of Lrrk1 and Lrrk2, we examined skeletal phenotypes in Lrrk1 and Lrrk2 knockout (KO) mice. Lrrk1 KO mice exhibit severe osteopetrosis caused by dysfunction of multinucleated osteoclasts, reduced bone resorption in endocortical and trabecular regions, and increased bone mineralization. Lrrk1 KO mice have lifelong accumulation of bone and respond normally to the anabolic actions of teriparatide treatment, but are resistant to ovariectomy-induced bone boss. Precursors derived from Lrrk1 KO mice differentiate into multinucleated cells in response to macrophage colony-stimulating factor (M-CSF)/receptor activator of NF-κB ligand (RANKL) treatment, but these cells fail to form peripheral sealing zones and ruffled borders, and fail to resorb bone. The phosphorylation of cellular Rous sarcoma oncogene (c-Src) at Tyr-527 is significantly elevated whereas at Tyr-416 is decreased in Lrrk1-deficient osteoclasts. The defective osteoclast function is partially rescued by overexpression of the constitutively active form of Y527F c-Src. Immunoprecipitation assays in osteoclasts detected a physical interaction of Lrrk1 with C-terminal Src kinase (Csk). Lrrk2 KO mice do not show obvious bone phenotypes. Precursors derived from Lrrk2 KO mice differentiate into functional multinucleated osteoclasts. Our finding of osteopetrosis in Lrrk1 KO mice provides convincing evidence that Lrrk1 plays a critical role in negative regulation of bone mass in part through modulating the c-Src signaling pathway in mice.