bluuebunny/crossref_metadata_2025 huggingface dataset:
PRESSURE RATE DECONVOLUTION METHODS FOR WELL TEST ANALYSIS
Authors: ANDRECUT M.
Published: April 2009

The deconvolution method has received much attention recently, and is becoming one of the major tools for well test and production data analysis in oil and gas industry. Here, we present a new deconvolution approach, which we believe is relevant and can be an important addition to the existing efforts made in this field. We show that the solution of the deconvolution problem can be successfully represented as a linear combination of non-orthogonal exponential functions. Also, we present three deconvolution algorithms. The first two algorithms are based on regularization concepts borrowed from the well-known Tikhonov and Krylov methods, while the third algorithm is based on the stochastic Monte Carlo method.
EFFECT OF DEFECT LAYER THICKNESS ON SLOW LIGHT IN ONE-DIMENSIONAL PHOTONIC CRYSTALS
Authors: TIAN HUIPING , JI YUEFENG
Published: April 2009

Group velocity and dispersion property of slow light in one-dimensional photonic crystal with different defect layer thicknesses are studied. It is found that the increase of defect layer thickness will induce the decrease of group velocity, which is an advantage to the design of optical buffer. However, the dispersion slope is increased, inducing a limited factor to keep the shape of ultra-short pulses. Then the effect of slight violation of defect layer thicknesses, refractive index and incident angle on the slow light is studied. The result shows that these influences are smaller at the first gap which is useful for the practical uses.
SYNTHESIS OF ZnO NANOTUBE ARRAYS BY ANNEALING Zn NANOWIRE ARRAYS IN ANODIC ALUMINA MEMBRANE
Authors: LI GUAN-LAI , PENG XIAO-NIU , XIE MENG-YIN , YU LIAO , ZHOU LI
Published: April 2009

Uniform and aligned ZnO nanotube arrays have been synthesized by annealing Zn nanowire arrays in anodic aluminum oxide (AAO) membrane. In our method, Zn nanowire arrays were fabricated by electrochemical deposition technique based on ordered nanoporous AAO, and then a heat-treatment method was used to convert Zn nanowire arrays to ZnO nanotube arrays. The ZnO arrays were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and absorption spectra. The results show that the polycrystalline ZnO nanotubes have a diameter of about 45 nm. This method can also be used to fabricate other metal oxide nanotube arrays.
Synthesis and characterization of novel azo-embedded N-confused tetraphenylporphyrin
Authors: Toganoh Motoki , Hihara Takayoshi , Yonekura Kentaro , Ishikawa Yuichi , Furuta Hiroyuki
Published: April 2009

A unique class of azo porphyrin, 5,10,15,20-tetraphenyl-21-phenylazo-(2-aza-21-carbaporphyrin 1, in which an azophenyl group is embedded in N -confused porphyrin, was synthesized and characterized by 1 H NMR, 13 C NMR, UV-vis absorption, MS, and X-ray crystallographic analysis. Synthesis of 1 was achieved through a coupling reaction of 21-amino N -confused tetraphenylporphyrin with nitrosobenzene and subsequent deoxygenation of resulting azoxy derivative with a trioxo rhenium(VII) N -fused porphyrinato catalyst. The azo-conjugate molecule was exclusively obtained as a trans-isomer and no isomerization to the cis-isomer was observed under thermal or photoirradiation. The absorption spectrum of 1 shows a moderate red-shift due to the effective interaction between the porphyrinic π-system and the connecting azophenyl group. Upon protonation, this effect is essentially lost as a result of removing degeneracy of LUMO and LUMO+1.
Synthesis and characterization of periphery-functionalized porphyrazines containing mixed pyrrolyl and pyridylmethylamino groups
Authors: Goslinski Tomasz , Tykarska Ewa , Szczolko Wojciech , Osmalek Tomasz , Smigielska Aleksandra , Walorczyk Stanislaw , Zong Hong , Gdaniec Maria , Hoffman Brian M. , Mielcarek Jadwiga , Sobiak Stanislaw
Published: April 2009

The condensation reaction of 2-amino-3-[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile with a series of diketones led to novel dinitriles, of which 2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[methyl(3-pyridylmethylene)amino]-2(Z)-butene-1,4-dinitrile, the product of the Paal-Knorr reaction, was successfully utilized in the Linstead macrocyclization towards symmetrical and unsymmetrical porphyrazines. NMR and X-ray study revealed an almost perpendicular orientation of the pyrrolyl groups in relation to the porphyrazine platform. The newly synthesized macrocycles with different peripheral groups show interesting spectroscopic and electrochemical properties. Due to selective sensor/coordination properties they are expected to find applications as chemical sensors and electronic materials.
Design and synthesis of tetraazachlorins, tetraazabacteriochlorins and tetraazaisobacteriochlorins
Authors: Makarova Elena A. , Lukyanets Evgeny A.
Published: April 2009

Three approaches to the synthesis of reduced derivatives of tetraazaporphine such as tetraazachlorin, tetraazabacteriochlorin, and tetraazaisobacteriochlorin are reviewed. The first synthesis of alkyl-substituted tetraazachlorins was achieved by the catalytic hydrogenation of magnesium complexes of tetraazaporphines. Two other synthesis approaches for reduced tetraazaporphines based on the mixed condensation of the precursors with different hydrogenation levels and β–β addition reactions have been developed in the last decade. The use of tetramethylsuccinonitrile as the saturated component in the mixed condensation with derivatives of aromatic and heteroaromatic dicarboxylic acids enable the synthesis of oxidation-resistant benzo-; 1,2- and 2,3-naphtho-; pyrazino-; 2,3- and 3,4-pyridino-fused tetraazachlorins, tetraazabacteriochlorins, and tetraazaisobacteriochlorins. Fullerene conjugates of reduced tetraazaporphine derivatives were obtained using 1,2-dicyanofullerene as the source of the hydrogenated sites. Tetraazaporphine can act as dienophile in Diels-Alder reaction with dienes of the anthracene and cyclopentadiene series and also as dipolarophile in 1,3-dipolar cycloadditions with azomethine ylides and nitrones. In addition, the effect of the reduction of peripheral double bonds in tetraazaporphine macrocycle alone, and in combination with annelation of benzene or heterocyclic rings on the absorption spectra is discussed.
Synthesis of low-symmetry subphthalocyanines with diverse functionalization patterns
Authors: González-Rodríguez David , Claessens Christian G. , Torres Tomás
Published: April 2009

We report here on the synthesis, isolation and characterization of unsymmetrically substituted subphthalocyanines obtained from the mixed condensation of 4,5-substituted phthalonitriles and/or 4-substituted phthalonitriles in the presence of BCl 3. Compared to phthalocyanines, it is clear that the cone-shaped structure of subphthalocyanines facilitates the isolation of the different regioisomers formed by regular laboratory chromatographic techniques. However, we demonstrate that some factors, such as the solubility of the regioisomers formed or the intermolecular interactions between side chains, can sometimes impede their complete separation. We also show that the structural assignment of each regioisomeric compound can be performed by careful analysis of its 1 H NMR spectra and, in some cases, with the help of NOE NMR experiments and molecular modeling.
Synthesis and third-order nonlinear optical properties of novel ethynyl-linked heteropentamer composed of four porphyrins and one pyrene
Authors: Sheng Ning , Sun Jing , Bian Yongzhong , Jiang Jianzhuang , Xu Dong
Published: April 2009

Novel heteropentameric porphyrins-pyrene arrays, in which four meso-tetraphenyl porphyrins are linked to the center unit of pyrene by four acetylenyl bonds, were designed and synthesized. The newly synthesized heteropentameric compounds have been characterized by a wide range of spectroscopic methods. The third-order nonlinear optical (NLO) properties of both the metal-free and zinc compounds of the three-dimensional arrays were investigated by Z-scan experiments, showing enhanced NLO properties compared with that of the porphyrin and pyrene monomers.
Novel one-pot regioselective route towards heteroleptic lanthanide (phthalocyaninato)(porphyrinato) triple-decker complexes
Authors: Birin Kirill P. , Gorbunova Yulia G. , Yu. Tsivadze Aslan
Published: April 2009

A novel one-pot method for the regioselective preparation of early heteroleptic lanthanide (porphyrinato)(phthalocyaninato) complexes of double- and triple-decker structure [(Por) Ln ( Pc ) and (Por) Ln ( Pc ) Ln (Por), respectively] is developed. Sandwich-type complexes are synthesized for La, Ce and Pr following this procedure, with yields up to 30%. Tetrakis(15-crown-5)-phthalocyanine [(15C5)4 PcH 2] and tetrakis-meso-(4-methoxyphenyl)-porphyrin ( An 4 PH 2) are used as macrocyclic tetrapyrrolic ligands. The complexes are widely characterized with various physico-chemical methods (NMR and UV-vis spectroscopy, MALDI-TOF mass spectrometry). Quantum chemistry calculations for intermediates of the process are performed. The results of calculations explain the high regioselectivity of the triple-decker complex formation in the developed method.
Self-assembly of trinitrofluorenone derivatives with tetrasubstituted zinc phthalocyanines
Authors: Céspedes-Guirao Francisco J. , Martín-Gomis Luis , Fernández-Lázaro Fernando , Sastre-Santos Ángela
Published: April 2009

The synthesis and characterization of two novel tetrasubstituted zinc phthalocyanines bearing bulky alkylaryloxy substituents in the so-called peripheral (1) and non-peripheral (2) positions is reported. Due to the presence of these bulky substituents, the non-peripheral substituted ZnPc 2 can be isolated as a pure regioisomer just by column chromatography. This is the first case where an α,α,α,α-tetrasubstituted regioisomer is isolated by column chromatography. Moreover, we describe the supramolecular complexation of both Pcs with the new pyridine-substituted trinitrofluorenone derivative TNFPy (3), whose synthesis and characterization is also commented. 1 H NMR titration experiments show that the system 2/3 presents a binding constant 35 times higher than system 1/3, which suggests a better accessibility to the metallic center.
Deferring design pattern decisions and automating structural pattern changes using a design-pattern-based programming system
Authors: MacDonald Steve , Tan Kai , Schaeffer Jonathan , Szafron Duane
Published: April 2009

In the design phase of software development, the designer must make many fundamental design decisions concerning the architecture of the system. Incorrect decisions are relatively easy and inexpensive to fix if caught during the design process, but the difficulty and cost rise significantly if problems are not found until after coding begins. Unfortunately, it is not always possible to find incorrect design decisions during the design phase. To reduce the cost of expensive corrections, it would be useful to have the ability to defer some design decisions as long as possible, even into the coding stage. Failing that, tool support for automating design changes would give more freedom to revisit and change these decisions when needed. This article shows how a design-pattern-based programming system based on
generative design patterns
can support the deferral of design decisions where possible, and automate changes where necessary. A generative design pattern is a parameterized pattern form that is capable of generating code for different versions of the underlying design pattern. We demonstrate these ideas in the context of a parallel application written with the CO
2
P
3
S pattern-based parallel programming system. We show that CO
2
P
3
S can defer the choice of execution architecture (shared-memory or distributed-memory), and can automate several changes to the application structure that would normally be daunting to tackle late in the development cycle. Although we have done this work with a pattern-based parallel programming system, it can be generalized to other domains.
Separation and information hiding
Authors: O'Hearn Peter W. , Yang Hongseok , Reynolds John C.
Published: April 2009

We investigate proof rules for information hiding, using the formalism of separation logic. In essence, we use the separating conjunction to partition the internal resources of a module from those accessed by the module's clients. The use of a logical connective gives rise to a form of dynamic partitioning, where we track the transfer of ownership of portions of heap storage between program components. It also enables us to enforce separation in the presence of mutable data structures with embedded addresses that may be aliased.
Expander flows, geometric embeddings and graph partitioning
Authors: Arora Sanjeev , Rao Satish , Vazirani Umesh
Published: April 2009

We give aO(√logn)-approximation algorithm for the sparsest cut, edge expansion, balanced separator, and graph conductance problems. This improves theO(logn)-approximation of Leighton and Rao (1988). We use a well-known semidefinite relaxation with triangle inequality constraints. Central to our analysis is a geometric theorem about projections of point sets inRd, whose proof makes essential use of a phenomenon called measure concentration.

We also describe an interesting and natural “approximate certificate” for a graph's expansion, which involves embedding ann-node expander in it with appropriate dilation and congestion. We call this an expander flow.
Polynomial flow-cut gaps and hardness of directed cut problems
Authors: Chuzhoy Julia , Khanna Sanjeev
Published: April 2009

We study the multicut and the sparsest cut problems in directed graphs. In the multicut problem, we are a given ann-vertex graphGalong withksource-sink pairs, and the goal is to find the minimum cardinality subset of edges whose removal separates all source-sink pairs. The sparsest cut problem has the same input, but the goal is to find a subset of edges to delete so as to minimize the ratio of the number of deleted edges to the number of source-sink pairs that are separated by this deletion. The natural linear programming relaxation for multicut corresponds, by LP-duality, to the well-studied maximum (fractional) multicommodity flow problem, while the standard LP-relaxation for sparsest cut corresponds to maximum concurrent flow. Therefore, the integrality gap of the linear programming relaxation for multicut/sparsest cut is also theflow-cut gap: the largest gap, achievable for any graph, between the maximum flow value and the minimum cost solution for the corresponding cut problem.

Our first result is that the flow-cut gap between maximum multicommodity flow and minimum multicut is Ω˜(n1/7) in directed graphs. We show a similar result for the gap between maximum concurrent flow and sparsest cut in directed graphs. These results improve upon a long-standing lower bound of Ω(logn) for both types of flow-cut gaps. We notice that these polynomially large flow-cut gaps are in a sharp contrast to the undirected setting where both these flow-cut gaps are known to be Θ(logn). Our second result is that both directed multicut and sparsest cut are hard to approximate to within a factor of 2Ω(log1-ϵn)for any constant ϵ > 0, unless NP ⊆ ZPP. This improves upon the recent Ω(logn/log logn)-hardness result for these problems. We also show that existence of PCP's for NP with perfect completeness, polynomially small soundness, and constant number of queries would imply a polynomial factor hardness of approximation for both these problems. All our results hold for directed acyclic graphs.
An
O
(
n
log
n
) algorithm for maximum
st
-flow in a directed planar graph
Authors: Borradaile Glencora , Klein Philip
Published: April 2009

We give the first correct
O
(
n
log
n
) algorithm for finding a maximum
st
-flow in a directed planar graph. After a preprocessing step that consists in finding single-source shortest-path distances in the dual, the algorithm consists of repeatedly saturating the leftmost residual
s
-to-
t
path.
Permuting streaming data using RAMs
Authors: Püschel Markus , Milder Peter A. , Hoe James C.
Published: April 2009

This article presents a method for constructing hardware structures that perform a fixed permutation on streaming data. The method applies to permutations that can be represented as linear mappings on the bit-level representation of the data locations. This subclass includes many important permutations such as stride permutations (corner turn, perfect shuffle, etc.), the bit reversal, the Hadamard reordering, and the Gray code reordering.

The datapath for performing the streaming permutation consists of several independent banks of memory and two interconnection networks. These structures are built for a given streaming width (i.e., number of inputs and outputs per cycle) and operate at full throughput for this streaming width.

We provide an algorithm that completely specifies the datapath and control logic given the desired permutation and streaming width. Further, we provide lower bounds on the achievable cost of a solution and show that for an important subclass of permutations our solution is optimal.

We apply our algorithm to derive datapaths for several important permutations, including a detailed example that carefully illustrates each aspect of the design process. Lastly, we compare our permutation structures to those of Järvinen et al. [2004], which are specialized for stride permutations.
LTL with the freeze quantifier and register automata
Authors: Demri Stéphane , Lazić Ranko
Published: April 2009

A data word is a sequence of pairs of a letter from a finite alphabet and an element from an infinite set, where the latter can only be compared for equality. To reason about data words, linear temporal logic is extended by the freeze quantifier, which stores the element at the current word position into a register, for equality comparisons deeper in the formula. By translations from the logic to alternating automata with registers and then to faulty counter automata whose counters may erroneously increase at any time, and from faulty and error-free counter automata to the logic, we obtain a complete complexity table for logical fragments defined by varying the set of temporal operators and the number of registers. In particular, the logic with future-time operators and 1 register is decidable but not primitive recursive over finite data words. Adding past-time operators or 1 more register, or switching to infinite data words, causes undecidability.
Generalizing consistency and other constraint properties to quantified constraints
Authors: Bordeaux Lucas , Cadoli Marco , Mancini Toni
Published: April 2009

Quantified constraints and Quantified Boolean Formulae are typically much more difficult to reason with than classical constraints, because quantifier alternation makes the usual notion of
solution
inappropriate. As a consequence, basic properties of Constraint Satisfaction Problems (CSPs), such as consistency or substitutability, are not completely understood in the quantified case. These properties are important because they are the basis of most of the reasoning methods used to solve classical (existentially quantified) constraints, and it is desirable to benefit from similar reasoning methods in the resolution of quantified constraints.

In this article, we show that most of the properties that are used by solvers for CSP can be generalized to quantified CSP. This requires a rethinking of a number of basic concepts; in particular, we propose a notion of
outcome
that generalizes the classical notion of solution and on which all definitions are based. We propose a systematic study of the relations which hold between these properties, as well as complexity results regarding the decision of these properties. Finally, and since these problems are typically intractable, we generalize the approach used in CSP and propose weaker, easier to check notions based on
locality
, which allow to detect these properties incompletely but in polynomial time.
Analytic tableaux calculi for KLM logics of nonmonotonic reasoning
Authors: Giordano Laura , Gliozzi Valentina , Olivetti Nicola , Pozzato Gian Luca
Published: April 2009

We present tableau calculi for the logics of nonmonotonic reasoning defined by Kraus, Lehmann and Magidor (KLM). We give a tableau proof procedure for all KLM logics, namely preferential, loop-cumulative, cumulative, and rational logics. Our calculi are obtained by introducing suitable modalities to interpret conditional assertions. We provide a decision procedure for the logics considered and we study their complexity.
An algebra of quantum processes
Authors: Ying Mingsheng , Feng Yuan , Duan Runyao , Ji Zhengfeng
Published: April 2009

We introduce an algebra qCCS of pure quantum processes in which communications by moving quantum states physically are allowed and computations are modeled by super-operators, but no classical data is explicitly involved. An operational semantics of qCCS is presented in terms of (nonprobabilistic) labeled transition systems. Strong bisimulation between processes modeled in qCCS is defined, and its fundamental algebraic properties are established, including uniqueness of the solutions of recursive equations. To model sequential computation in qCCS, a reduction relation between processes is defined. By combining reduction relation and strong bisimulation we introduce the notion of strong reduction-bisimulation, which is a device for observing interaction of computation and communication in quantum systems. Finally, a notion of strong approximate bisimulation (equivalently, strong bisimulation distance) and its reduction counterpart are introduced. It is proved that both approximate bisimilarity and approximate reduction-bisimilarity are preserved by various constructors of quantum processes. This provides us with a formal tool for observing robustness of quantum processes against inaccuracy in the implementation of its elementary gates.
Tableau calculus for preference-based conditional logics
Authors: Giordano Laura , Gliozzi Valentina , Olivetti Nicola , Schwind Camilla
Published: April 2009

We present a tableau calculus for some fundamental systems of propositional conditional logics. We consider the conditional logics that can be characterized by
preferential
semantics (i.e., possible world structures equipped with a family of preference relations). For these logics, we provide a uniform completeness proof of the axiomatization with respect to the semantics, and a uniform labeled tableau procedure.
Differential recursion
Authors: Kawamura Akitoshi
Published: April 2009

We present a redevelopment of the theory of real-valued recursive functions that was introduced by C. Moore in 1996 by analogy with the standard formulation of the integer-valued recursive functions. While his work opened a new line of research on analog computation, the original paper contained some technical inaccuracies. We discuss possible attempts to remove the ambiguity in the behavior of the operators on partial functions, with a focus on his “primitive recursive” functions generated by the
differential recursion
operator that solves initial value problems. Under a reasonable reformulation, the functions in this class are shown to be analytic and computable in a strong sense in computable analysis. Despite this well-behavedness, the class turns out to be too big to have the originally purported relation to differentially algebraic functions, and hence to C. E. Shannon's model of analog computation.
A-twitter over Twitter
Authors: Zeichick Alan
Published: April 2009

Sometimes I feel like I'm the only person in the world who doesn't "get" Twitter. Paradoxically, many of my friends tell me they feel the same way.
Building (and navigating) the virtual museum
Authors: Treese Win
Published: April 2009

Give visitors an unforgettable immersive experience that reveals the detail lost in traditional physical media.
We the people and the right to broadband
Authors: Rowell Laurie
Published: April 2009

The push for universal broadband to rural America could be this century's stab at rural electrification and phone service.
Etopia
Authors: Bainbridge William Sims
Published: April 2009

The larger the number of participants in broadband-enabled society, the more likely traditional mass culture will fragment into smaller subcultures online.
AmazonViz
Authors: Sawant Amit Prakash , Healey Christopher G. , Chen Dongfeng , Chirkova Rada
Published: April 2009

This article describes a technique to visualize query results, representing purchase orders placed on Amazon.com, along a traditional 2-D scatter plot and a space-filling spiral. We integrate 3-D objects that vary their spatial placement, color, and texture properties into a visualization algorithm. This algorithm represents important aspects of a purchase order based on experimental results from human vision, computer graphics, and psychology. The resulting visual abstractions are used by viewers to rapidly and effectively explore and analyze the underlying purchase orders data.
A tale of human-competitiveness in bioinformatics
Authors: Bacardit Jaume , Stout Michael , Krasnogor Natalio
Published: April 2009

A key open problem, which has defied scientists for decades is the problem of predicting the 3D structure of proteins (Protein Structure Prediction - PSP) based on its primary sequence: the amino acids that compose a protein chain. Full atomistic molecular dynamics simulations are, for all intents and purposes, impractical as current empirical models may require massive computational resources. One of the possible ways of alleviating this cost and making the problem easier is to simplify the protein representation based on which the native 3D state is searched for. We have proposed a protocol based on evolutionary algorithms to perform this simplification of the protein representation. Our protocol does not use any domain knowledge. Instead it uses a well known information theory metric, Mutual Information, to generate a reduced representation that is able to maintain the crucial information needed for PSP. The evaluation process of our method has shown that it generates alphabets that have competent performance against the original, non-simplified, representation. Moreover, these reduced alphabets obtain better-than-human performance when compared to some classic reduced alphabets.
Is this the future of academic publishing?
Authors: Langdon William B.
Published: April 2009

The Field Guide to Genetic Programming [1] has now been freely available as a PDF to down load for three months. According to figures provided by the publisher, lulu.com, during the first three months it was down loaded 11533 times. If the current trend (see Figure 1) continues, the total for the first year would be in the region of 27000 down loads.
Androgen sensitivity of prostate epithelium is enhanced by postnatal androgen receptor inactivation
Authors: Simanainen Ulla , McNamara Keely , Gao Yan Ru , Handelsman David J.
Published: April 2009

Postnatal inactivation of epithelial androgen receptor (AR) in prostate epithelial AR knockout (PEARKO) mice results in hindered differentiation but enhanced proliferation of epithelial cells. As this resembles the precancerous proliferative atrophy of human prostates with undifferentiated but intensively replicating epithelial cells, we utilized the PEARKO mice to characterize the epithelial response to castration-induced involution with a focus on identifying the potential role of stromal AR and responsiveness of the androgen-deprived epithelia to the aromatizable androgen testosterone (T) or its nonaromatizable metabolite dihydrotestosterone (DHT). PEARKO and littermate control mice were orchidectomized at 8 wk of age and treated 2 wk later with subdermal implantation of 1-cm Silastic tubing filled with T or DHT for a week. Following castration, the prostatic involution and epithelial apoptosis did not significantly differ between control (intact AR) and PEARKO (only stromal AR) males, demonstrating that prostate epithelial involution following castration is mediated primarily via stromal AR-dependent apoptotic signals. Androgen replacement (T/DHT) for 7 days induced significant growth and epithelial proliferation in all prostate lobes in both control and PEARKO, but full regrowth was observed only in controls treated with T. In PEARKO, prostate androgen (T and DHT) treatment induced significant epithelial cell “shedding” into the lumen, with T treatment resulting in acinar disorganization, cyst formation, and aberrant epithelial structures, described as a “gland within a gland.” These data suggest that epithelial AR inactivation during postnatal prostate development sensitizes prostate epithelial cells to paracrine signaling mediated by stromal AR activity leading to indirectly androgen-induced epithelial hyperproliferation and formation of epithelial hyperplastic cysts by aromatizable androgens.
Participation of ERα and ERβ in glucose homeostasis in skeletal muscle and white adipose tissue
Authors: Barros Rodrigo P. A. , Gabbi Chiara , Morani Andrea , Warner Margaret , Gustafsson Jan-Åke
Published: April 2009

Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER)β agonists. In the present study, to investigate the relative contributions of ERα and ERβ in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER−/− mice. ERβ−/− mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ERα−/− mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ERα−/− mice, Tam increased GLUT4 and improved insulin sensitivity. i.e., it behaved as an ERβ antagonist in SM but had no effect on WAT. In ERβ−/− mice, Tam did not affect GLUT4 in SM but acted as an ERα antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ERα and ERβ, ERβ-mediated repression of GLUT4 predominates in SM but ERα-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ERα predominates in WAT and ERβ in SM.
Effects of growth differentiation factor 9 on cell cycle regulators and ERK42/44 in human granulosa cell proliferation
Authors: Huang Qing , Cheung Anthony P. , Zhang Yu , Huang He-Feng , Auersperg Nelly , Leung Peter C. K.
Published: April 2009

GDF-9 stimulates granulosa cell proliferation and plays important roles during folliclogenesis. However, its molecular mechanisms are still far from clear, particularly its roles in human granulosa cells around the periovulatory stage. Therefore, we investigated the effects of GDF-9 on cell cycle distribution, regulatory molecules, and signaling pathways involved in human luteinized granulosa (hLG) cells in vitro. Primary cultures of hLG cells obtained from women undergoing IVF and treated with and without recombinant GDF-9 were evaluated with and without a specific inhibitor to activin receptor-like kinase 5 (ALK5; SB-431542), ERK42/44 (PD-098059), or Smad3 (SIS3). Cell proliferation, cell cycle distribution, mRNA expression, and protein expression of relevant cell cycle molecules were determined by [3H]thymidine incorporation, flow cytometry, quantitative PCR, and immunoblotting, respectively. GDF-9 stimulated [3H]thymidine incorporation, enhanced cell transition from G0/G1to S and G2/M phases (whereas both SB-431542 and PD-098059 attenuated these changes), increased mRNA and protein expression of cyclin D1and E, and decreased those of the cyclin-dependent kinase (CDK) inhibitors p15INK4Band p16INK4A. GDF-9 also activated Rb protein (a critical G1to S-phase regulator), ERK42/44, and Smad3. PD-098059 blocked Rb protein phorsphorylation and the increase in cyclin D1and E but not the decrease in p15INK4Band p16INK4Ainduced by GDF-9. In contrast, SIS3 reversed the decrease in p15INK4Band p16INK4Abut not the increase in cyclin D1and E induced by GDF-9. GDF-9 stimulates hLG cell proliferation by stimulating cyclin D1and E and suppressing p15INK4Band p16INK4Avia both Smad-dependent and Smad-independent pathways.
Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation
Authors: Hoy Andrew J. , Brandon Amanda E. , Turner Nigel , Watt Matthew J. , Bruce Clinton R. , Cooney Gregory J. , Kraegen Edward W.
Published: April 2009

Type 2 diabetes is characterized by hyperlipidemia, hyperinsulinemia, and insulin resistance. The aim of this study was to investigate whether acute hyperlipidemia-induced insulin resistance in the presence of hyperinsulinemia was due to defective insulin signaling. Hyperinsulinemia (∼300 mU/l) with hyperlipidemia or glycerol (control) was produced in cannulated male Wistar rats for 0.5, 1 h, 3 h, or 5 h. The glucose infusion rate required to maintain euglycemia was significantly reduced by 3 h with lipid infusion and was further reduced after 5 h of infusion, with no difference in plasma insulin levels, indicating development of insulin resistance. Consistent with this finding, in vivo skeletal muscle glucose uptake (31%, P < 0.05) and glycogen synthesis rate (38%, P < 0.02) were significantly reduced after 5 h compared with 3 h of lipid infusion. Despite the development of insulin resistance, there was no difference in the phosphorylation state of multiple insulin-signaling intermediates or muscle diacylglyceride and ceramide content over the same time course. However, there was an increase in cumulative exposure to long-chain acyl-CoA (70%) with lipid infusion. Interestingly, although muscle pyruvate dehydrogenase kinase 4 protein content was decreased in hyperinsulinemic glycerol-infused rats, this decrease was blunted in muscle from hyperinsulinemic lipid-infused rats. Decreased pyruvate dehydrogenase complex activity was also observed in lipid- and insulin-infused animals (43%). Overall, these results suggest that acute reductions in muscle glucose metabolism in rats with hyperlipidemia and hyperinsulinemia are more likely a result of substrate competition than a significant early defect in insulin action or signaling.
Rimonabant prevents additional accumulation of visceral and subcutaneous fat during high-fat feeding in dogs
Authors: Richey Joyce M. , Woolcott Orison O. , Stefanovski Darko , Harrison L. Nicole , Zheng Dan , Lottati Maya , Hsu Isabel R. , Kim Stella P. , Kabir Morvarid , Catalano Karyn J. , Chiu Jenny D. , Ionut Viorica , Kolka Cathryn , Mooradian Vahe , Bergman Richard N.
Published: April 2009

We investigated whether rimonabant, a type 1 cannabinoid receptor antagonist, reduces visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in dogs maintained on a hypercaloric high-fat diet (HHFD). To determine whether energy expenditure contributed to body weight changes, we also calculated resting metabolic rate. Twenty male dogs received either rimonabant (1.25 mg·kg−1·day−1, orally; n = 11) or placebo ( n = 9) for 16 wk, concomitant with a HHFD. VAT, SAT, and nonfat tissue were measured by magnetic resonance imaging. Resting metabolic rate was assessed by indirect calorimetry. By week 16 of treatment, rimonabant dogs lost 2.5% of their body weight ( P = 0.029), whereas in placebo dogs body weight increased by 6.2% ( P < 0.001). Rimonabant reduced food intake ( P = 0.027), concomitant with a reduction of SAT by 19.5% ( P < 0.001). In contrast with the VAT increase with placebo ( P < 0.01), VAT did not change with rimonabant. Nonfat tissue remained unchanged in both groups. Body weight loss was not associated with either resting metabolic rate ( r2 = 0.24; P = 0.154) or food intake ( r2 = 0.24; P = 0.166). In conclusion, rimonabant reduced body weight together with a reduction in abdominal fat, mainly because of SAT loss. Body weight changes were not associated with either resting metabolic rate or food intake. The findings provide evidence of a peripheral effect of rimonabant to reduce adiposity and body weight, possibly through a direct effect on adipose tissue.
Functional Role of GABAergic and Glycinergic Inhibition in the Intermediate Nucleus of the Lateral Lemniscus of the Big Brown Bat
Authors: Kutscher Andrew , Covey Ellen
Published: April 2009

The intermediate nucleus of the lateral lemniscus (INLL) is a major input to the inferior colliculus (IC), the auditory midbrain center where multiple pathways converge to create neurons selective for specific temporal features of sound. However, little is known about how INLL processes auditory information or how it contributes to integrative processes at the IC. INLL receives excitatory projections from the cochlear nucleus and inhibitory projections from the medial nucleus of the trapezoid body (MNTB), so it must perform some form of integration. To address the question of what role inhibitory synaptic inputs play in the INLL of the big brown bat ( Eptesicus fuscus), we recorded sound-evoked responses of single neurons and iontophoretically applied bicuculline to block GABAA receptors or strychnine to block glycine receptors. Neither bicuculline nor strychnine had a consistent effect on response latency or frequency response areas. Bicuculline increased spike counts and response durations in most units, suggesting that GABAergic input suppressed the late part of the response and provided some gain control. Strychnine reduced the responses of some units with sustained discharge patterns to one or a few spikes at stimulus onset, but increased others. INLL is the only part of the auditory system where reduced responsiveness has been seen in vivo while blocking glycine. However, in vitro studies in the MNTB suggest that glycine can be facilitatory, possibly through presynaptic action. These results show that GABA consistently reduces spike counts and response durations, whereas glycine is suppressive in some INLL neurons but facilitatory in others.
Dynamics of Smooth Pursuit Maintenance
Authors: Tavassoli Abtine , Ringach Dario L.
Published: April 2009

Smooth pursuit eye movements allow the approximate stabilization of a moving visual target on the retina. To study the dynamics of smooth pursuit, we measured eye velocity during the visual tracking of a Gabor target moving at a constant velocity plus a noisy perturbation term. The optimal linear filter linking fluctuations in target velocity to evoked fluctuations in eye velocity was computed. These filters predicted eye velocity to novel stimuli in the 0- to 15-Hz band with good accuracy, showing that pursuit maintenance is approximately linear under these conditions. The shape of the filters were indicative of fast dynamics, with pure delays of merely ∼67 ms, times-to-peak of ∼115 ms, and effective integration times of ∼45 ms. The gain of the system, reflected in the amplitude of the filters, was inversely proportional to the size of the velocity fluctuations and independent of the target mean speed. A modest slow-down of the dynamics was observed as the contrast of the target decreased. Finally, the temporal filters recovered during fixation and pursuit were similar in shape, supporting the notion that they might share a common underlying circuitry. These findings show that the visual tracking of moving objects by the human eye includes a reflexive-like pathway with high contrast sensitivity and fast dynamics.
Microarray gene expression profiles of fasting induced changes in liver and adipose tissues of pigs expressing the melanocortin-4 receptor D298N variant
Authors: Lkhagvadorj Sender , Qu Long , Cai Weiguo , Couture Oliver P. , Barb C. Richard , Hausman Gary J. , Nettleton Dan , Anderson Lloyd L. , Dekkers Jack C. M. , Tuggle Christopher K.
Published: April 2009

Transcriptional profiling coupled with blood metabolite analyses were used to identify porcine genes and pathways that respond to a fasting treatment or to a D298N missense mutation in the melanocortin-4 receptor (MC4R) gene. Gilts (12 homozygous for D298 and 12 homozygous for N298) were either fed ad libitum or fasted for 3 days. Fasting decreased body weight, backfat, and serum urea concentration and increased serum nonesterified fatty acid. In response to fasting, 7,029 genes in fat and 1,831 genes in liver were differentially expressed (DE). MC4R genotype did not significantly affect gene expression, body weight, backfat depth, or any measured serum metabolite concentration. Pathway analyses of fasting-induced DE genes indicated that lipid and steroid synthesis was downregulated in both liver and fat. Fasting increased expression of genes involved in glucose sparing pathways, such as oxidation of amino acids and fatty acids in liver, and in extracellular matrix pathways, such as cell adhesion and adherens junction in fat. Additionally, we identified DE transcription factors (TF) that regulate many DE genes. This confirms the involvement of TF, such as PPARG, SREBF1, and CEBPA, which are known to regulate the fasting response, and implicates additional TF, such as ESR1. Interestingly, ESR1 controls several fasting induced genes in fat that are involved in cell matrix morphogenesis. Our findings indicate a transcriptional response to fasting in two key metabolic tissues of pigs, which was corroborated by changes in blood metabolites, and the involvement of novel putative transcriptional regulators in the immediate adaptive response to fasting.
Adiponectin-Activated AMPK Stimulates Dephosphorylation of AKT through Protein Phosphatase 2A Activation
Authors: Kim Kun-yong , Baek Ahmi , Hwang Ji-Eun , Choi Yeon A. , Jeong Joon , Lee Myeong-Sok , Cho Dea Ho , Lim Jong-Seok , Kim Keun Il , Yang Young
Published: April 2009

Low serum levels of adiponectin are a high risk factor for various types of cancer. Although adiponectin inhibits proliferation and metastasis of breast cancer cells, the underlying molecular mechanisms remain obscure. In this study, we show that adiponectin-activated AMPK reduces the invasiveness of MDA-MB-231 cells by stimulating dephosphorylation of AKT by increasing protein phosphatase 2A (PP2A) activity. Among the various regulatory B56 subunits, B56γ was directly phosphorylated by AMPK at Ser298 and Ser336, leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr307. We also show that both the blood levels of adiponectin and the tissue levels of PP2A activity were decreased in breast cancer patients and that the direct administration of adiponectin into tumor tissues stimulates PP2A activity. Taken together, these findings show that adiponectin, derived from adipocytes, negatively regulates the invasiveness of breast cancer cells by activating the tumor suppressor PP2A. [Cancer Res 2009;69(9):4018–26]
p53-Altered FBXW7 Expression Determines Poor Prognosis in Gastric Cancer Cases
Authors: Yokobori Takehiko , Mimori Koshi , Iwatsuki Masaaki , Ishii Hideshi , Onoyama Ichiro , Fukagawa Takeo , Kuwano Hiroyuki , Nakayama Keiichi I. , Mori Masaki
Published: April 2009

A molecular target associated with the progression of gastric cancer has not yet been uncovered. FBXW7 is a tumor suppressor gene transcriptionally controlled by p53 that plays a role in the regulation of cell cycle exit and reentry via c-Myc degradation. Few studies have addressed the clinical significance of FBXW7 expression in gastric cancer. Therefore, we examined FBXW7 mRNA expression to determine its clinicopathologic significance in 100 cases of gastric cancer. Low expression levels of FBXW7 in primary gastric cancer contributed to malignant potential, such as lymph node metastasis (P = 0.0012), tumor size (P = 0.0003), and poor prognosis (P = 0.018). In comparison with 52 cases of gastric cancer without the p53 mutation, 29 cases with the mutation exhibited lower expression levels of FBXW7 (P = 0.0034), revealing a significant relationship between p53 mutation and FBXW7 expression. Furthermore, we found that gastric cancer patients who had low FBXW7 expression levels and p53 mutation had a distinctively poor prognosis in comparison with other subgroups (P = 0.0033). In conclusion, we showed a role for p53 in the transcriptional regulation of FBXW7 expression in clinical gastric cancer cases and showed that disruption of both p53 and FBXW7 contributes to poor prognosis. [Cancer Res 2009;69(9):3788–94]
A Double Hit to Kill Tumor and Endothelial Cells by TRAIL and Antiangiogenic 3TSR
Authors: Ren Bin , Song Keli , Parangi Sareh , Jin Taiguang , Ye Min , Humphreys Robin , Duquette Mark , Zhang Xuefeng , Benhaga Nordine , Lawler Jack , Khosravi-Far Roya
Published: April 2009

As tumor development relies on a coordination of angiogenesis and tumor growth, an efficient antitumor strategy should target both the tumor and its associated vessels. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner. Additionally, thrombospondin-1, a naturally occurring inhibitor of angiogenesis, and a recombinant protein containing functional domains of thrombospondin-1, 3TSR, have been shown to be necessary and sufficient to inhibit tumor angiogenesis. Here, we show that a combination of a TRAIL receptor 2 agonist antibody, Lexatumumab, and 3TSR results in a significantly enhanced and durable tumor inhibition. We further observed that 3TSR induces apoptosis in primary endothelial cells by up-regulating the expression of TRAIL receptors 1 and 2 in a CD36 and Jun NH2-terminal kinase-dependent manner leading to the activation of both intrinsic and extrinsic apoptotic machineries. The modulation of these pathways is critical for 3TSR-induced apoptosis as disrupting either via specific inhibitors reduced apoptosis. Moreover, 3TSR attenuates the Akt survival pathway. These studies indicate that 3TSR plays a critical role in regulating the proapoptotic signaling pathways that control growth and death in endothelial cells and that a combination of TRAIL and 3TSR acts as a double hit against tumor and tumor-associated vessels. [Cancer Res 2009;69(9):3856–65]
Sorafenib Induces Apoptosis Specifically in Cells Expressing BCR/ABL by Inhibiting Its Kinase Activity to Activate the Intrinsic Mitochondrial Pathway
Authors: Kurosu Tetsuya , Ohki Manabu , Wu Nan , Kagechika Hiroyuki , Miura Osamu
Published: April 2009

Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myelogenous leukemia and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia, relapse with emerging imatinib resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we show that the multikinase inhibitor sorafenib inhibits proliferation and induces apoptosis at much lower concentrations in Ton.B210 cells when driven by inducibly expressed BCR/ABL than when driven by interleukin-3. The increased sensitivity to sorafenib was also observed in cells inducibly expressing BCR/ABL with the imatinib-resistant E255K or T315I mutation. Sorafenib-induced apoptosis in these cells and Ph+ leukemic cells was synergistically enhanced by rottlerin, bortezomib, or ABT-737 and inhibited by the pan-caspase inhibitor BOC-d-fmk or the overexpression of Bcl-XL. It was further revealed that sorafenib activates Bax and caspase-3 and reduces mitochondrial membrane potential specifically in BCR/ABL–driven cells. Sorafenib also inhibited BCR/ABL–induced tyrosine phosphorylation of its cellular substrates and its autophosphorylation in Ton.B210. It was finally shown that sorafenib inhibits the kinase activity of BCR/ABL as well as its E255K and T315I mutants in in vitro kinase assays. These results indicate that sorafenib induces apoptosis of BCR/ABL–expressing cells, at least partly, by inhibiting BCR/ABL to activate the mitochondria-mediated apoptotic pathway. Thus, sorafenib may provide an effective therapeutic measure to treat Ph+ leukemias, particularly those expressing the T315I mutant, which is totally resistant to imatinib and the second generation BCR/ABL inhibitors. [Cancer Res 2009;69(9):3927–36]