bluuebunny/crossref_metadata_2025 huggingface dataset:
Urban Space and the Mediation of Political Action in Nepal: Local Television, Ritual Processions and Political Violence as Technologies of Enchantment
Authors: Wilmore Michael
Published: February 2009

This paper examines how political identities in the town of Tansen in the central western district of Palpa, Nepal, are mediated by contrasting forms of cultural and material practice: religious and secular processions and programs made by a local, cable‐television production organisation. These practices and their materiality are conceptualised as ‘technologies of enchantment’ (Gell 1992) through which political culture is made manifest in urban space. Paradigmatically ‘modern’ and ‘traditional’ technologies are juxtaposed in order to analyse the different ways that political action is embodied within the community. The loss of life in Tansen and the destruction of buildings associated with these practices in the course of the 10‐year Maoist insurgency provide a tragic confirmation of the conclusions reached in this paper.
Malignant Hyperthermia Associated with Ryanodine Receptor 1 (C7360G) Mutation in Quarter Horses
Authors: Aleman M. , Nieto J.E. , Magdesian K.G.
Published: February 2009

Background:Anesthetic‐induced malignant hyperthermia (MH) has been documented in Quarter Horses with a single point mutation in the ryanodine receptor 1 gene (RyR1) at nucleotide C7360G, generating a R2454G amino acid substitution. However, there have been no reports of nonanesthetic manifestations of MH in horses with the C7360G mutation.

Objective:To describe clinical manifestations of Quarter Horses with the C7360G mutation.

Animals:Eleven Quarter Horses with theRyR1C7360G mutation.

Methods:This prospective study included horses with suspected MH, undetermined etiology of sudden death, death within hours of onset of rhabdomyolysis, muscle rigidity, stiffness, intermittent sweating, and persistent increases in serum muscle enzyme activities. Whole blood in EDTA and skeletal muscle were processed for genetic and histochemical analysis. Medical records and pedigrees were collected when available.

Results:Both anesthetic‐ and non–anesthetic‐associated myopathic manifestations of MH occurred in halter Quarter Horses with mutation ofRyR1. The disease is inherited as an autosomal dominant trait. Clinical and laboratory abnormalities were similar in both forms. Rhabdomyolysis was a common finding in both groups of horses. Skeletal muscle histochemical findings were nonspecific and compatible with a noninflammatory myopathic process.

Conclusions and Clinical Importance:MH is a potentially fatal disease of Quarter Horses that could be triggered by halogenated anesthetics and other nonanesthetic factors that may include exercise, stress, breeding, illnesses, and concurrent myopathies.
Ammonia-free deposition of silicon nitride films using pulsed-plasma chemical vapor deposition under near atmospheric pressure
Authors: Matsumoto M. , Inayoshi Y. , Murashige S. , Suemitsu M. , Nakajima S. , Uehara T. , Toyoshima Y.
Published: February 2009

Ammonia-free deposition of silicon nitride (SiNX) films have been achieved on Si(100) substrate at low temperature (200°C) by using plasma enhanced chemical vapor deposition operated at near atmospheric pressure. A pulsed power supply enables a stable discharge of a SiH4–H2–N2 system at near atmospheric pressures without using any inert gases such as He. Characterization by x-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy indicates that the grown film is a SiNx film with its N∕Si ratio varying for 0.85–0.90, depending on the N2∕SiH4 flow ratio (1000–4000). Despite the use of N2 instead of NH3, a high rate growth (10–70nm∕min) is enabled, which would be beneficial in forming protection/passivation layers in solar cells. The breakdown field of 7.4MV∕cm seems also promising for its use as a gate insulator in amorphous-silicon-based thin film transistors (TFTs).
Gd silicate: A high-k dielectric compatible with high temperature annealing
Authors: Gottlob H. D. B. , Stefani A. , Schmidt M. , Lemme M. C. , Kurz H. , Mitrovic I. Z. , Werner M. , Davey W. M. , Hall S. , Chalker P. R. , Cherkaoui K. , Hurley P. K. , Piscator J. , Engström O. , Newcomb S. B.
Published: February 2009

The authors report on the investigation of amorphous Gd-based silicates as high-k dielectrics. Two different stacks of amorphous gadolinium oxide (Gd2O3) and silicon oxide (SiO2) on silicon substrates are compared after annealing at temperatures up to 1000°C. Subsequently formed metal oxide semiconductor capacitors show a significant reduction in the capacitance equivalent thicknesses after annealing. Transmission electron microscopy, medium energy ion scattering, and x-ray diffraction analysis reveal distinct structural changes such as consumption of the SiO2 layer and formation of amorphous Gd silicate. The controlled formation of Gd silicates in this work indicates a route toward high-k dielectrics compatible with conventional, gate first complementary metal-oxide semiconductor integration schemes.
Duplication of nanoimprint templates by a novel SU-8/SiO2/PMMA trilayer technique
Authors: Wan Jing , Shu Zhen , Deng Shao-Ren , Xie Shen-Qi , Lu Bing-Rui , Liu Ran , Chen Yifang , Qu Xin-Ping
Published: February 2009

In this work, a trilayer technique used in the nanoimprint lithography process to replicate the templates is developed. The SU8/SiO2/PMMA trilayer was used. The photosensitive epoxy (SU8 resist) which has a low glass transition temperature was used as the imprint layer. Polymethylmethacrylate (PMMA) was used as the transfer layer. A SiO2 layer is placed between the SU8 and PMMA to act as a protective layer due to its strong resistance to oxygen reactive ion etching. By optimizing imprint and etching processes, master templates with minimum feature size of 150 nm and period of 300 nm can be successfully duplicated.
Metal-oxide-semiconductor devices on p-type Ge with La2O3 and ZrO2/La2O3 as gate dielectric and the effect of postmetallization anneal
Authors: Galata S. F. , Mavrou G. , Tsipas P. , Sotiropoulos A. , Panayiotatos Y. , Dimoulas A.
Published: February 2009

In this work the authors investigate La2O3 and ZrO2/La2O3 high-k gate dielectrics on p-type Ge metal-insulator-semiconductor capacitors. La2O3 on Ge exhibits good electrical properties in terms of interface states density, but it may not be scalable yielding high equivalent oxide thickness (EOT) after annealing. By depositing a thin (2 nm) La2O3 passivating layer followed by a ZrO2 cap, a gate stack is obtained which is a very good insulator with improved EOT, retaining at the same time the good passivating properties of La2O3. This indicates that the ZrO2/La2O3 combination could be scalable gate stack to be considered as a candidate for Ge metal-oxide-semiconductor devices.
Complementary metal oxide semiconductor integration of epitaxial Gd2O3
Authors: Lemme M. C. , Gottlob H. D. B. , Echtermeyer T. J. , Schmidt M. , Kurz H. , Endres R. , Schwalke U. , Czernohorkky M. , Tetzlaff D. , Osten H. J.
Published: February 2009

In this paper, epitaxial gadolinium oxide (Gd2O3) is reviewed as a potential high-K gate dielectric, both “as deposited” by molecular beam epitaxy as well as after integration into complementary metal oxide semiconductor (CMOS) processes. The material shows promising intrinsic properties, meeting critical ITRS targets for leakage current densities even at subnanometer equivalent oxide thicknesses. These epitaxial oxides can be integrated into a CMOS platform by a “gentle” replacement gate process. While high temperature processing potentially degrades the material, a route toward thermally stable epitaxial Gd2O3 gate dielectrics is explored by carefully controlling the annealing conditions.
Five-element circuit model using linear-regression method to correct the admittance measurement of metal-oxide-semiconductor capacitor
Authors: Cheng Chao-Ching , Chien Chao-Hsin , Luo Guang-Li , Liu Jun-Cheng , Chen Yi-Cheng , Chang Yao-Feng , Wang Shin-Yuan , Kei Chi-Chung , Hsiao Chien-Nan , Chang Chun-Yen
Published: February 2009

The authors present a linear-regression method based on a five-element circuit model to correct measured capacitance-voltage and conductance-voltage curves. This model explains the effects of series resistance and parasitic capacitance/inductance on the frequency dispersion of measured capacitance and the magnification of measured conductance. These extracted parasitic components show significant dependencies on the geometry of capacitor structure, thereby causing different frequency-dependent capacitance characteristics in measurements.
Near field emission scanning electron microscopy
Authors: Kirk T. L. , Ramsperger U. , Pescia D.
Published: February 2009

The authors report on the development of a “near field emission scanning electron microscope.” In this instrument electrons are excited from the sample surface after undergoing interactions with a primary beam of electrons field emitted from a polycrystalline tungsten tip. The tip, with an emission radius of 2nm, is scanned at less than 80nm distance to the surface. Topographic images, determined from the intensity variations of secondary and backscattered electrons, yield a vertical resolution on an atomic scale and a lateral resolution of a couple nanometers. The topographic contrast of the extracted electrons and the field emission current are indistinguishable, in agreement with theoretical models of optimal spatial resolution.
Si
O
x
-planarized and transistor outlook-packaged oxide-confined vertical-cavity surface-emitting lasers with ring-shape geometry for high-speed (10Gb∕s) operation
Authors: Tsai Chia-Lung , Lin Jia-Qing , Lee Feng-Ming , Chou Yi-Lun , Wu Meng-Chyi
Published: February 2009

This study explores an alternative approach to fabricate the 850nm SiOx-planarized ring-shape vertical-cavity surface-emitting lasers (VCSELs) with stable lasing emission and high-speed operation. The fabricated ring-shape VCSELs have an inner oxide diameter of 9μm and an outer oxide diameter of 15μm. These devices show a threshold current of 3.65mA, a maximum light output power of 7.5mW at 25mA, and a differential resistance of 65Ω at room temperature. Furthermore, they exhibit a stable dual-mode behavior over the operation current of 25mA. Moreover, this TO-packaged 850nm VCSEL for small-signal analyses shows a maximum modulation frequency of about 8GHz, which is corresponding to a modulation-current efficiency factor of 2.47GHz∕mA1∕2. This VCSEL also shows a clear and symmetric eye-opening feature at 10.3Gbytes∕s and 18mA for back-to-back and 66m transmission tests. Based on these results, the excellent high-speed performance can be fulfilled by the SiOx-planarized and TO-packaged oxide-confined VCSELs with ring-shape geometry.
Band offsets and work function control in field effect transistors
Authors: Robertson John
Published: February 2009

The article summarizes the development of metal gate materials and the control of the effective work function on high dielectric constant (high K) oxides for use in advanced Si field effect transistors. The Schottky barrier heights of metals on HfO2 are calculated accurately for ideal interfaces of various stoichiometries and for interfaces with defects.
Relict Carbonate-Rich Sediments on Southwestern Grand Bank, Newfoundland
Authors: Müller Jens , Milliman John D.
Published: February 2009

Surface sediments on southwestern Grand Bank are composed mostly of sand, with local admixtures of mud and gravel. Most sediments are enriched with biogenic calcium carbonate, primarily barnacle valves with lesser amounts of mollusk, echinoid, and foraminifera fragments. In contrast to similar carbonate-rich sediments reported from other high-latitude areas, available data indicate that the barnacles were deposited in very shallow water during the last Würm regression. The other carbonate components, being fresher in appearance, may be younger in age.Apparently neither glaciers nor their melt waters extended far enough south on Grand Bank during the last Würm glaciation to dilute these carbonate-rich sediments with terrigenous debris. Similarly, the Holocene influx of fluvial terrigenous sediment appears to have been minor, because of both the lack of major river runoff and the active current regime in the area.
The Caraquet Dike: Its Tectonic Significance
Authors: Burke K. B. S. , Hamilton J. B. , Gupta V. K.
Published: February 2009

The Caraquet Dike has been mapped by ground magnetic traverses for a distance of 60 miles (97 km) between Caraquet and Wayerton, New Brunswick. A related lineament has also been recognized on aeromagnetic maps and confirmed at a few ground locations that would extend the dike and associated structural features for about another 250 miles (402 km) into the State of Maine. The age and trend of the dike support the idea that NW-SE tensile forces associated with the initial rifting of the Atlantic Ocean were operative in this nothern part of New Brunswick and Maine in late Triassic times. Post-intrusive offset faulting of the dike indicates changes in the initial stress system that could have been caused by variations in the rotational pole position during the subsequent opening of the Atlantic. Dike emplacement and faulting in former continental edges may therefore prove to be useful indicators of episodal changes in the development of ocean basins.
Alteration of Trace Lead Isotopic Ratios by Postore Metamorphic and Hydrothermal Activity
Authors: Cumming G. L. , Gudjurgis P. J.
Published: February 2009

Isotope analyses on leads in iron sulfides and trace galenas from two deposits (Big Ledge, British Columbia and Quemont Mine, Quebec) suggest that variations in the isotopic composition may be influenced by postmineralization alteration of ore. It is postulated that when the ore has been subject to regional metamorphism after emplacement, the metamorphism has homogenized the lead isotope ratios throughout the ore body as appears to have happened at Big Ledge, whereas, if postore activity is limited to minor hydrothermal alteration, as at Quemont, then the lead may be left with a wide range of isotopic composition.
Sedimentology, Mineral Facies, and Petrofabric of the Meaford–Dundas Formation (Upper Ordovician) in Southern Ontario
Authors: Czurda K. , Winder C. G. , Quigley R. M.
Published: February 2009

The Meaford–Dundas Formation in southern Ontario is a medium gray shale with good fissility and resistant interbeds of gray fossiliferous limestones and siltstones. The hard layers are up to 20 cm in thickness and comprise 10 to 20% of the formation. The shale layers vary in thickness from 50 cm to 2 m.The clay minerals are principally illite, iron-chlorite, and small amounts of vermiculite and mixed-layer types. The carbonate content seems constant across the area at about 4 to 5% of the formation, except for the southwestern area where the carbonate increases to 20 or 25%. This increase is chiefly in dolomite content, a feature which reflects such factors as original conditions of deposition and possibly diagenesis subsequent to burial. The quartz content in the shale beds, and especially in the hard interbeds, increases towards the north to an average of 35 to 40% compared with 10 to 15% in the south. Framboids (aggregates of pyrite grains in spheroidal clusters) are a striking feature of the shale beds of the Meaford–Dundas Formation in the Meaford area.Fabric studies by means of X-ray diffraction patterns and scanning electron photomicrographs reveal, in most cases, high parallelism of clay platelets in the bedding planes, resulting in the good fissility of the shale.The principal source rock areas are the Appalachian orogen in the east (Taconic Mountains), which probably supplied most of the clay minerals and some quartz, and the Canadian Shield in the north, which provided the basin of sedimentation in the south with heavy minerals and additional quartz.
Depositional Environments and Conodont-Based Correlation of the Long Point Formation (Middle Ordovician), Western Newfoundland
Authors: Fåhræus Lars E.
Published: February 2009

The depositional history of the neoautochthonous mid-Caradocian Long Point Formation, which overlies the lower clastic slices of the Humber Arm Klippe, is characterized by two major periods of sedimentation. Out of a total thickness of some 600 m, slightly less than 60 m make up a lower sequence of limestone, minor shales, and a basal sandstone unit, which appears to have been deposited in an environment (or series of environments) characterized by beachsands, mudflats, lagoons, (?) carbonate bank, and a fringing reef. The remainder of the Long Point deposits exhibit several criteria that are suggestive of the general environment of a prograding fluviomarine delta. It appears possible that uppermost Long Point strata are fluviatile in origin.In terms of graptolite and conodont zonations, the Long Point Formation belongs within the Diplograptus multidens and Amorphognathus tvaerensis Zones, respectively. The base of the Long Point Formation probably coincides with the base of the Climacograptus peltifer Zone of the British standard graptolite zonation and with that of the Prioniodus gerdae conodont subzone.
Studies of Glacial History in Arctic Canada. II. Interglacial Peat Deposits on Bathurst Island
Authors: Blake Jr. Weston
Published: February 2009

Sixteen radiocarbon age determinations on peat deposits and buried organic layers at 10 localities within the Queen Elizabeth Islands have resulted in ages between >30 000 and >51 000 years. Similar results have been obtained from the southern Arctic islands, and as yet only one meaningful finite date in the 50 000 to 25 000 year-range has resulted from the dating of driftwood or in situ terrestrial organic materials in the entire archipelago.On Bathurst Island, where two dates of >50 000 years have been obtained, evidence from the assemblages of mosses, vascular plants, and insects in peat and organic layers indicates that climatic conditions were somewhat more favorable than at present when these deposits were forming. The available data are such that all deposits cannot necessarily be related to the same non-glacial interval, but the extensive deposits along the Stuart River are hereby assigned to the Stuart River Interglaciation.The lack of organic materials dating between 50 000 and 25 000 years in the Queen Elizabeth Islands may be because: (1) the area was ice-covered throughout Wisconsin time; (2) any mid-Wisconsin non-glacial interval was too short or had too severe a climate for deposits to accumulate; (3) organic deposits relating to this interval have been eroded; or (4) deposits of this age do exist but they have not been collected.
Paleomagnetic Study and Chemistry of Newer Dolerites from Singhbhum, Bihar, India
Authors: Verma R. K. , Prasad S. N.
Published: February 2009

Results of paleomagnetic studies on seventeen dikes sampled from the Newer Dolerites of Singhbhum, between latitude 22°0′N to 22°45′N and longitude 85°48′E to 86°25′E are reported. The dikes are of Precambrian age, probably older than 1000 my. Stable directions of magnetization were obtained for eleven sites by thermal demagnetization in a field free space in temperatures ranging from 250° to 400 °C. These studies showed that the dikes had been reheated by igneous activity of neighboring dikes of a younger age or by regional metamorphism of a younger period. Polished section studies carried out on these dikes showed that the magnetic mineral had been significantly altered as a result of these processes. Reliable virtual geomagnetic poles were obtained for ten different sites. These pole positions can be collected into three different groups which may represent three episodes of igneous activity of the Newer Dolerites. A very tentative polar wandering curve for the Precambrian in India is given.
The Stromatolite Archaeozoon acadiense from the Proterozoic Green Head Group of Saint John, New Brunswick
Authors: Hofmann H. J.
Published: February 2009

The columnar branching stromatolite Archaeozoon acadiense Matthew 1890 occurs in platy fault-slivers of a biohermal or biostromal limestone that accumulated on a shallow submerged platform, possibly during Neohelikian time. The columns show that the stromatolitic beds at Green Head face north, and can be used to provide a partial estimate of amount and type of local tectonic deformation. Archaeozoon Matthew has attributes similar to those for such Riphean groups as Tungussia, Baicalia and Jacutophyton, and it is likely that one or more of these are junior subjective synonyms of Archaeozoon, or represent at least morphologic variants.
Silurian Brachiopoda, Upper Allen Bay Formation, Griffiths Island, Arctic Archipelago, and Uppermost Whittaker Formation, Mackenzie Mountains, Northwest Territories
Authors: Lenz Alfred C.
Published: February 2009

A low diversity fauna of brachiopods is described from the top beds of the Whittaker Formation of the central Mackenzies, and the upper part of the Allen Bay Formation, Griffiths Island. The fauna of the two formations together total 10 species, although only two species are common to die two units. The faunas are dominated by the atrypid Spirigerina, and the rhynchonellids Ancillotoechia and Decorapitgnax. The faunas are correlated with the upper Wenlockian or lower Ludlovian, and are considered the equivalents of the shallow water Salopian or Sphaerirhynchia benthic communities.
Two pollen diagrams from Quaternary deposits in east-central Iowa, U.S.A.
Authors: Szabo John P.
Published: February 2009

Two pollen analyses from Quaternary deposits located outside both the Illinoian and Wisconsinan limits of glaciation in east-central Iowa, U.S.A., are similar to other analyses in the Midwest. One analysis from sediments between two pre-Illinoian tills is high in coniferous pollen. The analysis suggests a cool late interglacial or an interstadial climate. The other analysis is from Late Wisconsinan sediments synchronous with the last increment of loess deposition. The pollen diagram may be divided into three major zones: zone 1 may represent a boreal parkland, zone 2 contains the spruce maximum about 14 000 radiocarbon years before present, and zone 3 shows an increase in pine and oak pollen about 11 000 years ago.
Données nouvelles sur le protérozoïque inférieur du domaine nord-armoricain (France): age et signification
Authors: Auvray Bernard , Charlot René , Vidal Philippe
Published: February 2009

Orthogneisses from the Tregor area of the North Armorican Massif have been dated using the U/Pb method on zircons. Ages of between 1.8 and 2.0 Ga have been obtained, thus significantly extending the known size of the Lower Proterozoic basement in this area. It is argued that the presence of such a substantial area of basement is a further argument for an Upper Proterozoic (Brioverian) south-dipping subduction zone which was located to the north of the Armorican Massif. On the other hand, the similarities between the North Armorican block and the northern margin of the West African craton during the Proterozoic are emphasized.
TEMPORAL STABILITY OF A PARTICLE-LADEN BLASIUS BOUNDARY LAYER
Authors: XIE M. L. , LIN J. Z. , ZHOU H. C.
Published: February 2009

The temporal instability of incompressible particle-laden Blasius boundary layer is investigated numerically using perturbation method and finite difference. The stability characteristics are calculated for varying Stokes' numbers and particle concentrations. The results, some of which agree with the calculations of earlier authors, show that the addition of fine particles tends to destabilize the flow while addition of the coarse particles has a stabilizing action. There is critical value for the effect of Stokes' number, and the value is about 1. The stabilizing effect of particles depends monotonously on the particle concentration, the critical Reynolds' number is directly proportional to the concentration in the range of stabilizing area, and vice versa for small Stokes' number. The most damped mode occurs when Stokes' number is of order 10 for different particle concentrations. The difference of perturbation velocity between the particle-laden flow and the clean gas flow is insignificant for fine particles, while the difference for coarse particles is obvious. For fine particles laden flow, the viscosity is reduced relatively because of the addition of particles, and the critical Reynolds' number is smaller than that of clean gas. For coarse particles, the interaction between particles and clean gas is remarkable because of the difference of perturbation velocity, and then the viscous dissipation tends to stabilize the flow.
ELECTRON THERMODYNAMICS OF NANOFILM-STRUCTURES
Authors: MARKOSKI B. S. , ŠETRAJČIĆ J. P. , DŽAMBAS Lj. , Lj. MIRJANIĆ D. , VUČENOVIĆ S. M.
Published: February 2009

Recent research of physical properties of materials have shown that low-dimensional systems have more emphasized characteristics than bulk ones, due to quantum size effects. Superconductive films with higher critical parameters than the bulk ones are especially interesting. The basic characteristic of dispersion law of electrons in superconductive films is the presence of energy gaps. The gap size depends strongly on film thickness. Thermodynamic behavior of this system is strongly influenced by gap presence. Electron contribution in specific heat and entropy of superconductive thin film were analyzed on the basis of electron dispersion law in long-wave approximation, as well as their behavior in low temperature (T<TC). It has been shown that both of them linearly depend on temperature, similarly as in bulk structures, but with different slope coefficient (film heat capacity is lower and entropy is higher than in the bulk at the same temperature). Due to poor heat (as well as electric) conducting properties, films are better superconductors (which is experimentally proved). Films are also less ordered systems and closer to the equilibrium state. The explanation of high temperature superconductivity can be found by studying spatially-bounded systems.
HYPERGEOMETRIC FUNCTION REPRESENTATION OF RELATIVISTIC TRANSITION MATRIX ELEMENTS FOR HYDROGENIC ATOMS
Authors: SOLDATOV A. V. , SEKE J. , ADAM G. , POLAK M.
Published: February 2009

By using the plane-wave expansion for the electromagnetic-field vector potential, relativistic bound–bound, bound–unbound and unbound–unbound transition matrix elements for hydrogenic atoms are expressed universally in terms of hypergeometric functions. By applying the obtained formulas, these transition matrix elements can be evaluated analytically and numerically with arbitrarily high precision. The newfound representation for the matrix elements is very convenient for direct numerical evaluation of the Lamb shift because of its universality, conciseness and reliance on functions already built in the standard computational packages. All of this is highly favorable for programming of computationally efficient algorithms.
LOCALIZED SURFACE PLASMON OF THIN GOLD FILM WITH PERIODIC ARRAYS OF NANOHOLES
Authors: ZHANG ZONG-SUO , SU XIONG-RUI , LI JIAN-BO , HAO ZHONG-HUA , ZHOU LI
Published: February 2009

The localized surface plasmon (LSP) resonances properties of periodic arrays of nanoholes in thin gold films are investigated by using the method of discrete dipole approximation (DDA). The surface plasmon polaritons (SPPs) play important roles in amplification or suppression of the LSP resonances in the film. The LSP-SPP coupling is affirmed based on the extinction spectra calculated by the DDA. The intensity of the LSP resonances can be controlled through changing the edge-to-edge separation distances between nanoholes, the number and the diameter of the nanoholes. The calculations also indicate that the LSP resonance peak decreases with increasing the thickness of the gold film.
A TRANSFORMATION-BASED APPROACH TO APPLICATION MODEL DEVELOPMENT: CLASS DIAGRAM GENERATION
Authors: NACO AJAREE , WUWONGSE VILAS , ANUTARIYA CHUTIPORN
Published: February 2009

Application software development is normally the process of developing slightly different application models of the same application domain for different companies. Each application model corresponds to general features of the application domain and additionally involves supplementary requirements of a particular company. An application model for each individual company is always redesigned even though the general features can be reused. This leads to the need for new approaches to the development of a generic application model that can be reused with respect to a company's requirements. This paper presents a new development approach, namely Transformation-based Model Generation (TMG), which enhances the productivity of application development. It focuses on the reuse of a generic application model to automatically generate specific application models that satisfy different requirements of the same problem domain. The concepts of model representation and model generation are taken from Model Driven Architecture (MDA). XML Declarative Description (XDD) is the underlying theory for implementing the TMG. The knowledge for generating specific application models is domain-independent, hence it can be applied to various problem domains.
Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity
Authors: Liang Huiyun , Balas Bogdan , Tantiwong Puntip , Dube John , Goodpaster Bret H. , O'Doherty Robert M. , DeFronzo Ralph A. , Richardson Arlan , Musi Nicolas , Ward Walter F.
Published: February 2009

Type 2 diabetes is characterized by fasting hyperglycemia, secondary to hepatic insulin resistance and increased glucose production. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcriptional coactivator that is thought to control adaptive responses to physiological stimuli. In liver, PGC-1α expression is induced by fasting, and this effect promotes gluconeogenesis. To examine whether PGC-1α is involved in the pathogenesis of hepatic insulin resistance, we generated transgenic (TG) mice with whole body overexpression of human PGC-1α and evaluated glucose homeostasis with a euglycemic-hyperinsulinemic clamp. PGC-1α was moderately (∼2-fold) overexpressed in liver, skeletal muscle, brain, and heart of TG mice. In liver, PGC-1α overexpression resulted in increased expression of hepatocyte nuclear factor-4α and the gluconeogenic enzymes phospho enolpyruvate carboxykinase and glucose-6-phosphatase. PGC-1α overexpression caused hepatic insulin resistance, manifested by higher glucose production and diminished insulin suppression of gluconeogenesis. Paradoxically, PGC-1α overexpression improved muscle insulin sensitivity, as evidenced by elevated insulin-stimulated Akt phosphorylation and peripheral glucose disposal. Content of myoglobin and troponin I slow protein was increased in muscle of TG mice, indicating fiber-type switching. PGC-1α overexpression also led to lower reactive oxygen species production by mitochondria and reduced IKK/IκB signaling in muscle. Feeding a high-fat diet to TG mice eliminated the increased muscle insulin sensitivity. The dichotomous effect of PGC-1α overexpression in liver and muscle suggests that PGC-1α is a fuel gauge that couples energy demands (muscle) with the corresponding fuel supply (liver). Thus, under conditions of physiological stress (i.e., prolonged fast and exercise training), increased hepatic glucose production may help sustain glucose utilization in peripheral tissues.
Berberine suppresses proinflammatory responses through AMPK activation in macrophages
Authors: Jeong Hyun Woo , Hsu Kuan Chi , Lee Joo-Won , Ham Mira , Huh Jin Young , Shin Hyun Jung , Kim Woo Sik , Kim Jae Bum
Published: February 2009

Berberine (BBR) has been shown to improve several metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, by stimulating AMP-activated protein kinase (AMPK). However, the effects of BBR on proinflammatory responses in macrophages are poorly understood. Here we show that BBR represses proinflammatory responses through AMPK activation in macrophages. In adipose tissue of obese db/db mice, BBR treatment significantly downregulated the expression of proinflammatory genes such as TNF-α, IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Consistently, BBR inhibited LPS-induced expression of proinflammatory genes including IL-1β, IL-6, iNOS, MCP-1, COX-2, and matrix metalloprotease-9 in peritoneal macrophages and RAW 264.7 cells. Upon various proinflammatory signals including LPS, free fatty acids, and hydrogen peroxide, BBR suppressed the phosphorylation of MAPKs, such as p38, ERK, and JNK, and the level of reactive oxygen species in macrophages. Moreover, these inhibitory effects of BBR on proinflammatory responses were abolished by AMPK inhibition via either compound C, an AMPK inhibitor, or dominant-negative AMPK, implying that BBR would downregulate proinflammatory responses in macrophages via AMPK stimulation.
Tumor and Vascular Targeting of a Novel Oncolytic Measles Virus Retargeted against the Urokinase Receptor
Authors: Jing Yuqi , Tong Caili , Zhang Jin , Nakamura Takafumi , Iankov Ianko , Russell Stephen J. , Merchan Jaime R.
Published: February 2009

Oncolytic measles virus (MV) induces cell fusion and cytotoxicity in a CD46-dependent manner. Development of fully retargeted oncolytic MVs would improve tumor selectivity. The urokinase-type plasminogen activator receptor (uPAR) is a tumor and stromal target overexpressed in multiple malignancies. MV-H glycoproteins fully retargeted to either human or murine uPAR were engineered and their fusogenic activity was determined. Recombinant human (MV-h-uPA) and murine (MV-m-uPA) uPAR–retargeted MVs expressing enhanced green fluorescent protein (eGFP) were rescued and characterized. Viral expression of chimeric MV-H was shown by reverse transcription-PCR and Western blot. In vitro viral replication was comparable to MV-GFP control. The receptor and species specificity of MV-uPAs was shown in human and murine cells with different levels of uPAR expression. Removal of the NH2-terminal fragment ligand from MV-uPA by factor X(a) treatment ablated the MV-uPA functional activity. Cytotoxicity was shown in uPAR-expressing human and murine cells. MV-h-uPA efficiently infected human endothelial cells and capillary tubes in vitro. I.v. administration of MV-h-uPA delayed tumor growth and prolonged survival in the MDA-MB-231 breast cancer xenograft model. Viral tumor targeting was confirmed by immunohistochemistry. MV-m-uPA transduced murine mammary tumors (4T1) in vivo after intratumor administration. MV-m-uPA targeted murine tumor vasculature after systemic administration, as shown by dual (CD31 and MV-N) staining of tumor capillaries in the MDA-MB-231 model. In conclusion, MV-uPA is a novel oncolytic MV associated with potent and specific antitumor effects and tumor vascular targeting. This is the first retargeted oncolytic MV able to replicate in murine cells and target tumor vasculature in a uPAR-dependent manner. [Cancer Res 2009;69(4):1459–68]
RECK Negatively Regulates Matrix Metalloproteinase-9 Transcription
Authors: Takagi Satoshi , Simizu Siro , Osada Hiroyuki
Published: February 2009

RECK, a glycosylphosphatidylinositol-anchored glycoprotein, inhibits the enzymatic activities of some matrix metalloproteinases (MMP), thereby suppressing tumor cell metastasis; however, the detailed mechanism is still obscure. In this study, we compared the gene expression profiles between mock- and RECK-transfected HT1080 cells and showed that RECK decreases MMP-9 mRNA levels but not other MMP mRNA levels. Moreover, treatment with RECK-specific siRNA increased MMP-9 mRNA in RECK-expressing cells. The promoter assay showed that MMP-9 promoter activity was suppressed by RECK and that RECK-mediated suppression of MMP-9 promoter activity requires 12-O-tetradecanoylphorbol-13-acetate–responsive element (TRE) and κB sites. Moreover, the binding ability of Fra-1 and c-Jun to TRE within the MMP-9 promoter region was suppressed by RECK. Thus, these results show that RECK is a negative regulator of MMP-9 transcription. [Cancer Res 2009;69(4):1502–8]
Host-Derived Angiopoietin-2 Affects Early Stages of Tumor Development and Vessel Maturation but Is Dispensable for Later Stages of Tumor Growth
Authors: Nasarre Patrick , Thomas Markus , Kruse Karoline , Helfrich Iris , Wolter Vivien , Deppermann Carleen , Schadendorf Dirk , Thurston Gavin , Fiedler Ulrike , Augustin Hellmut G.
Published: February 2009

The angiopoietin/Tie2 system has been identified as the second vascular-specific receptor tyrosine kinase system controlling vessel assembly, maturation, and quiescence. Angiopoietin-2 (Ang-2) is prominently up-regulated in the host-derived vasculature of most tumors, making it an attractive candidate for antiangiogenic intervention. Yet, the net outcome of Ang-2 functions on tumor angiogenesis is believed to be contextual depending on the local cytokine milieu. Correspondingly, Ang-2 manipulatory therapies have been shown to exert protumorigenic as well as antitumorigenic effects. To clarify the role of Ang-2 for angiogenesis and tumor growth in a definite genetic experimental setting, the present study was aimed at comparatively studying the growth of different tumors in wild-type and Ang-2–deficient mice. Lewis lung carcinomas, MT-ret melanomas, and B16F10 melanomas all grew slower in Ang-2–deficient mice. Yet, tumor growth in wild-type and Ang-2–deficient mice dissociated during early stages of tumor development, whereas tumor growth rates during later stages of primary tumor progression were similar. Analysis of the intratumoral vascular architecture revealed no major differences in microvessel density and perfusion characteristics. However, diameters of intratumoral microvessels were smaller in tumors grown in Ang-2–deficient mice, and the vasculature had an altered pattern of pericyte recruitment and maturation. Ang-2–deficient tumor vessels had higher pericyte coverage indices. Recruited pericytes were desmin and NG2 positive and predominately α-smooth muscle actin negative, indicative of a more mature pericyte phenotype. Collectively, the experiments define the role of Ang-2 during tumor angiogenesis and establish a better rationale for combination therapies involving Ang-2 manipulatory therapies. [Cancer Res 2009;69(4):1324–33]
Specific Cross-talk between Epidermal Growth Factor Receptor and Integrin αvβ5 Promotes Carcinoma Cell Invasion and Metastasis
Authors: Ricono Jill M. , Huang Miller , Barnes Leo A. , Lau Steven K. , Weis Sara M. , Schlaepfer David D. , Hanks Steven K. , Cheresh David A.
Published: February 2009

Tyrosine kinase receptors and integrins play essential roles in tumor cell invasion and metastasis. Previously, we showed that epidermal growth factor (EGF) stimulation of pancreatic carcinoma cells led to invasion and metastasis that was blocked by antagonists of integrin αvβ5. Here, we show that EGF stimulates metastasis of carcinoma cells via a Src-dependent phosphorylation of p130 CAS leading to activation of Rap1, a small GTPase involved in integrin activation. Specifically, EGF receptor (EGFR)–induced Src activity leads to phosphorylation of a region within the CAS substrate domain, which is essential for Rap1 and αvβ5 activation. This pathway induces αvβ5-mediated invasion and metastasis in vivo yet does not influence primary tumor growth or activation of other integrins on these cells. These findings show cross-talk between a tyrosine kinase receptor and an integrin involved in carcinoma cell invasion and metastasis and may explain in part how inhibitors of EGFR affect malignant disease. [Cancer Res 2009;69(4):1383–91]
Depletion of Cytosolic Phospholipase A2 in Bone Marrow–Derived Macrophages Protects against Lung Cancer Progression and Metastasis
Authors: Weiser-Evans Mary C.M. , Wang Xue-Qing , Amin Jay , Van Putten Vicki , Choudhary Rashmi , Winn Robert A. , Scheinman Robert , Simpson Peter , Geraci Mark W. , Nemenoff Raphael A.
Published: February 2009

Cancer progression and metastasis involves interactions between tumor cells and the tumor microenvironment (TME). We reported that mice deficient for cytosolic phospholipase A2 (cPLA2-KO) are protected against the development of lung tumors. The goal of this study was to examine the role of cPLA2 in the TME. Mouse lung cancer cells (CMT167 and Lewis lung carcinoma cells) injected directly into lungs of syngeneic mice formed a primary tumor, and then metastasized to other lobes of the lung and to the mediastinal lymph nodes. Identical cells injected into cPLA2-KO mice showed a dramatic decrease in the numbers of secondary metastatic tumors. This was associated with decreased macrophage staining surrounding the tumor. Wild-type mice transplanted with cPLA2-KO bone marrow had a marked survival advantage after inoculation with tumor cells compared with mice receiving wild-type (WT) bone marrow. In vitro, coculturing CMT167 cells with bone marrow–derived macrophages from WT mice increased production of interleukin 6 (IL-6) by cancer cells. This increase was blocked in cocultures using cPLA2-KO macrophages. Correspondingly, IL-6 staining was decreased in tumors grown in cPLA2-KO mice. These data suggest that stromal cPLA2 plays a critical role in tumor progression by altering tumor-macrophage interactions and cytokine production. [Cancer Res 2009;69(5):1733–8]
Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion
Authors: Wrage Michaela , Ruosaari Salla , Eijk Paul P. , Kaifi Jussuf T. , Hollmén Jaakko , Yekebas Emre F. , Izbicki Jakob R. , Brakenhoff Ruud H. , Streichert Thomas , Riethdorf Sabine , Glatzel Markus , Ylstra Bauke , Pantel Klaus , Wikman Harriet
Published: February 2009

Purpose: Bone marrow is a common homing organ for early disseminated tumor cells (DTC) and their presence can predict the subsequent occurrence of overt metastasis and survival in lung cancer. It is still unclear whether the shedding of DTC from the primary tumor is a random process or a selective release driven by a specific genomic pattern.

Experimental Design: DTCs were identified in bone marrow from lung cancer patients by an immunocytochemical cytokeratin assay. Genomic aberrations and expression profiles of the respective primary tumors were assessed by microarrays and fluorescence in situ hybridization analyses. The most significant results were validated on an independent set of primary lung tumors and brain metastases.

Results: Combination of DNA copy number profiles (array comparative genomic hybridization) with gene expression profiles identified five chromosomal regions differentiating bone marrow-negative from bone marrow-positive patients (4q12-q32, 10p12-p11, 10q21-q22, 17q21, and 20q11-q13). Copy number changes of 4q12-q32 were the most prominent finding, containing the highest number of differentially expressed genes irrespective of chromosomal size (P = 0.018). Fluorescence in situ hybridization analyses on further primary lung tumor samples confirmed the association between loss of 4q and bone marrow-positive status. In bone marrow-positive patients, 4q was frequently lost (37% versus 7%), whereas gains could be commonly found among bone marrow-negative patients (7% versus 17%). The same loss was also found to be common in brain metastases from both small and non-small cell lung cancer patients (39%).

Conclusions: Thus, our data indicate, for the first time, that early hematogenous dissemination of tumor cells might be driven by a specific pattern of genomic changes.
Targeting Akt3 Signaling in Malignant Melanoma Using Isoselenocyanates
Authors: Sharma Arati , Sharma Arun K. , Madhunapantula SubbaRao V. , Desai Dhimant , Huh Sung Jin , Mosca Paul , Amin Shantu , Robertson Gavin P.
Published: February 2009

Purpose: Melanoma is the most invasive and deadly form of skin cancer. Few agents are available for treating advanced disease to enable long-term patient survival, which is driving the search for new compounds inhibiting deregulated pathways causing melanoma. Akt3 is an important target in melanomas because its activity is increased in ∼70% of tumors, decreasing apoptosis in order to promote tumorigenesis.

Experimental Design: Because naturally occurring products can be effective anticancer agents, a library was screened to identify Akt3 pathway inhibitors. Isothiocyanates were identified as candidates, but low potency requiring high concentrations for therapeutic efficacy made them unsuitable. Therefore, more potent analogs called isoselenocyanates were created using the isothiocyanate backbone but increasing the alkyl chain length and replacing sulfur with selenium. Efficacy was measured on cultured cells and tumors by quantifying proliferation, apoptosis, toxicity, and Akt3 pathway inhibition.

Results: Isoselenocyanates significantly decreased Akt3 signaling in cultured melanoma cells and tumors. Compounds having 4 to 6 carbon alkyl side chains with selenium substituted for sulfur, called ISC-4 and ISC-6, respectively, decreased tumor development by ∼60% compared with the corresponding isothiocyanates, which had no effect. No changes in animal body weight or in blood parameters indicative of liver-, kidney-, or cardiac-related toxicity were observed with isoselenocyanates. Mechanistically, isoselenocyanates ISC-4 and ISC-6 decreased melanoma tumorigenesis by causing an ∼3-fold increase in apoptosis.

Conclusions: Synthetic isoselenocyanates are therapeutically effective for inhibiting melanoma tumor development by targeting Akt3 signaling to increase apoptosis in melanoma cells with negligible associated systemic toxicity.
A Systems Perspective of Ras Signaling in Cancer
Authors: Stites Edward C. , Ravichandran Kodi S.
Published: February 2009

The development of cancer reflects the complex interactions and properties of many proteins functioning as part of large biochemical networks within the cancer cell. Although traditional experimental models have provided us with wonderful insights on the behavior of individual proteins within a cancer cell, they have been deficient in simultaneously keeping track of many proteins and their interactions in large networks. Computational models have emerged as a powerful tool for investigating biochemical networks due to their ability to meaningfully assimilate numerous network properties. Using the well-studied Ras oncogene as an example, we discuss the use of models to investigate pathologic Ras signaling and describe how these models could play a role in the development of new cancer drugs and the design of individualized treatment regimens.