bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytochrome P450 3A activities and their modulation by α-naphthoflavone in vitro are dictated by the efficiencies of model experimental systems
Authors: Bořek-Dohalská Lucie , Stiborová Marie
Published: February 2010

The knowledge on efficiencies of differentin vitrosystems containing cytochromes P450 (CYP) of a 3A subfamily is crucial to screen potential substrates of these CYPs. We evaluated and compared efficiencies of severalin vitroCYP3A enzymatic systems to oxidize the model substrates, α-NF and testosterone, under the standardized experimental conditions. Five CYP3A systems were tested: (i) human hepatic microsomes rich in CYP3A4, (ii) hepatic microsomes of rabbits treated with a CYP3A6 inducer, rifampicine, (iii) microsomes of Baculovirus transfected insect cells containing recombinant human CYP3A4 and NADPH:CYP reductase with or without cytochrome b5(SupersomesTM), (iv) membranes isolated fromEscherichia coli, containing recombinant human CYP3A4, NADPH:CYP reductase and cytochrome b5, and (v) human CYP3A4 or rabbit CYP3A6 reconstituted with NADPH:CYP reductase with or without cytochrome b5in liposomes. All systems oxidize testosterone to its 6β-hydroxylated metabolite and α-NF to trans-7,8-dihydrodiol and 5,6-epoxide. The most efficient systems oxidizing both compounds were CYP3A4-SupersomesTMcontaining cytochrome b5, followed by human hepatic microsomes. This finding suggests these systems to be suitable for general evaluating a variety of compounds as potential substrates of CYP3A4. The lowest efficiencies to oxidize α-NF and testosterone were found for CYP3A4 expressed in membranes ofE. coli, and for reconstituted CYP3A4 or CYP3A6. Utilizing the tested enzymatic systems, we also explain here the discrepancies, which showed previously the controversial effects of α-NF on CYP3A-mediated reactions. We demonstrate that inhibition or stimulation of the CYP3A-mediated testosterone hydroxylation by α-NF is dictated by efficiencies of individual enzymatic systems to oxidize the CYP3A substrates.
CAUSAL PROPAGATION FOR ELKO FIELDS
Authors: FABBRI LUCA
Published: February 2010

We shall consider the general problem of causal propagation for spinor fields, focus attention in particular on the case constituted by ELKO fields and will show that the problem of causal propagation for ELKO fields is always solvable.
EXTENDED FEYNMAN FORMULA FOR THE HARMONIC OSCILLATOR BY THE DISCRETE TIME METHOD
Authors: FUNAHASHI KUNIO
Published: February 2010

We revisit the extended Feynman formula for the harmonic oscillator beyond and at caustics. The extension has been made by some authors, however, it is not obtained by the discrete formulation of path integral, which we consider the most reliable regularization of it. We derive the result by, especially at caustics, more rigorous method than previous.
ON THE MONOTONICITY OF ENTROPY FOR MULTILAYER CELLULAR NEURAL NETWORKS
Authors: BAN JUNG-CHAO , CHANG CHIH-HUNG
Published: February 2010

This work investigates the monotonicity of topological entropy for one-dimensional multilayer cellular neural networks. The interacting radius and number of layers are treated as parameters. Fix either one of them; the set of topological entropies grows as a strictly nested sequence with respect to one another. Apart from the comparison of the set of topological entropies, maximal and minimal templates are indicators of a dynamical system. Our results demonstrate that maximal and minimal templates of larger interacting radius (respectively number of layers) dominate those of smaller one. To be precise, the strict monotonicity of topological entropy is demonstrated through the comparison of the maximal and minimal templates as the parameters are varied.
SIMPLIFIED TREATMENT OF TEMPLATES BOUNDED BY A GENUS-1 TORUS
Authors: MARTÍN J. C. , USED J.
Published: February 2010

We present a simplified treatment of templates used to summarize the topological properties of chaotic attractors bounded by a genus-1 torus. The reduction is based on determinism and flow continuity, which impose tight relations between torsions of each branch, rotations between pairs of branches and the order in which they join at the branch line. This way, the number of integer parameters necessary to characterize a template can be reduced. Apart from the purely theoretical interest, the new treatment simplifies the procedure for template determination starting from a time series, with a consequential save in computation time.
LIMIT CYCLES FOR SOME ABEL EQUATIONS HAVING COEFFICIENTS WITHOUT FIXED SIGNS
Authors: BRAVO J. L. , FERNÁNDEZ M. , GASULL A.
Published: February 2010

We prove that some 2π-periodic generalized Abel equations of the form x′ = A(t)xn+ B(t)xm+ C(t)x, with n ≠ m and n, m ≥ 2 have at most three limit cycles. The novelty of our result is that, in contrast with other results of the literature, our hypotheses allow the functions A,B, and C to change sign. Finally we study in more detail the Abel equation x′ = A(t)x3+ B(t)x2, where the functions A and B are trigonometric polynomials of degree one.
CONTRITION DOES NOT ENSURE COOPERATION IN THE ITERATED PRISONER'S DILEMMA
Authors: HILBE CHRISTIAN
Published: February 2010

In search of strategies that boost cooperation in the iterated prisoner's dilemma game (IPD), Contrite Tit for Tat is a promising candidate. It combines the necessary rigor in handling selfish strategies with contrition whenever the player has exploited its coplayer inadvertently. This paper shows that, contrary to conventional wisdom, Contrite Tit for Tat is not evolutionarily stable in general. In a relatively noisy environment with a low benefit of mutual cooperation it pays to be a defector. Additionally, errors in perception impede altruism notably.
ON CONJUGATE PRIME IDEALS OF TENSOR PRODUCTS OF k-ALGEBRAS
Authors: BOUCHIBA SAMIR
Published: February 2010

The purpose of this paper is to explore new aspects of the prime ideal structure of tensor products of algebras over a field k. We prove that given a k-algebra A and a normal field extension K of k (in the sense of Galois theory), then for any prime ideals P1 and P2 of K ⊗k A lying over a fixed prime ideal p of A, there exists a k-automorphism σ of K such that (σ ⊗k id A)(P1) = P2. As an Application, we establish a result related to the dimension theory of tensor products stating that, for two arbitrary k-algebras A and B, the minimal prime ideals of p ⊗k B + Aσk q have the same height, for any prime ideals p and q of A and B, respectively.
THE HOCHSCHILD COHOMOLOGY RING OF A CLASS OF SPECIAL BISERIAL ALGEBRAS
Authors: SNASHALL NICOLE , TAILLEFER RACHEL
Published: February 2010

We consider a class of self-injective special biserial algebras ΛN over a field K and show that the Hochschild cohomology ring of dΛN is a finitely generated K-algebra. Moreover, the Hochschild cohomology ring of ΛN modulo nilpotence is a finitely generated commutative K-algebra of Krull dimension two. As a consequence the conjecture of [N. Snashall and Ø. Solberg, Support varieties and Hochschild cohomology rings, Proc. London Math. Soc.88 (2004) 705–732], concerning the Hochschild cohomology ring modulo nilpotence, holds for this class of algebras.
ON B(4,k) GROUPS
Authors: LI YUANLIN , TAN YILAN
Published: February 2010

A group G is said to be a B(n,k) group if for any n-element subset {a1,…, an} of G, |{aiaj | 1≤i, j≤n}|≤ k. In this paper, characterizations of B(4,11) groups, B(4,12) groups, and B(4,13) non-2-groups are given.
NeXCLass: A DECISION SUPPORT SYSTEM FOR NON-ORDERED MULTICRITERIA CLASSIFICATION
Authors: RIGOPOULOS GEORGE , ASKOUNIS DIMITRIOS TH. , METAXIOTIS KONSTANTINOS
Published: February 2010

This paper presents NexClass, a Decision Support System (DSS) which supports classification of alternatives into predefined non-ordered categories according to their performance on evaluation criteria and implements a novel classification algorithm based on multicriteria analysis and outranking relations. More detailed, assignment to classes is based on the concept of non-exclusivity, which defines at what degree an alternative can be included in a specific category. For each category, a threshold is defined by the decision maker, which indicates its limit with respect to the evaluation criteria. Alternatives are next evaluated according to the criteria and non-excluding degrees are calculated for each category. Finally, an alternative is assigned to the category for which non-excluding degree gets the lowest value. NexClass DSS implements the above classification algorithm, providing a user-friendly interface, which supports decision makers to formulate and solve classification problems. In addition to the methodology and the DSS, we present a real world application at a classification problem in banking environment. Our findings derived from evaluation experiments in the banking environment provide valid evidence that the proposed methodology and the DSS effectively support decision makers in classification decisions.
WEIGHTED AND CONTROLLED FRAMES: MUTUAL RELATIONSHIP AND FIRST NUMERICAL PROPERTIES
Authors: BALAZS PETER , ANTOINE JEAN-PIERRE , GRYBOŚ ANNA
Published: February 2010

Weighted and controlled frames have been introduced recently to improve the numerical efficiency of iterative algorithms for inverting the frame operator. In this paper, we develop systematically these notions, including their mutual relationship. We will show that controlled frames are equivalent to standard frames and so this concept gives a generalized way to check the frame condition, while offering a numerical advantage in the sense of preconditioning. Next, we investigate weighted frames, in particular their relation to controlled frames. We consider the special case of semi-normalized weights, where the concepts of weighted frames and standard frames are interchangeable. We also make the connection with frame multipliers. Finally, we analyze weighted frames numerically. First, we investigate three possibilities for finding weights in order to tighten a given frame, i.e. decrease the frame bound ratio. Then, we examine Gabor frames and how well the canonical dual of a weighted frame is approximated by the inversely weighted dual frame.
INERTIA PARAMETERS ESTIMATION OF PLANAR OBJECT ON ROBOT PUSHING OPERATION
Authors: YU YONG , ARIMA TETSU , TSUJIO SHOWZOW
Published: February 2010

This paper proposes a technique that can estimate the inertia parameters of a graspless unknown object, which is pushed by robot fingers. Using the fingertip different accelerations (or angular accelerations), velocities (or angular velocities) and forces information measured in pushing operations, the algorithms to estimate the object mass (or moment of inertia) are described. Then, a line called C.M. Line, is defined in this paper. The line contains the center of mass and is between two fingertips which are in point-contact with an object side. By using two or more orientation-different C.M. lines, an algorithm to estimate the center of mass of the object is given. Lastly, experimental verification on the proposed approach is performed and its results are outlined.
Mice deficient in Group VIB phospholipase A2(iPLA2γ) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet
Authors: Song Haowei , Wohltmann Mary , Bao Shunzhong , Ladenson Jack H. , Semenkovich Clay F. , Turk John
Published: February 2010

Phospholipases A2(PLA2) play important roles in metabolic processes, and the Group VI PLA2family is comprised of intracellular enzymes that do not require Ca2+for catalysis. Mice deficient in Group VIA PLA2(iPLA2β) develop more severe glucose intolerance than wild-type (WT) mice in response to dietary stress. Group VIB PLA2(iPLA2γ) is a related enzyme distributed in membranous organelles, including mitochondria, and iPLA2γ knockout (KO) mice exhibit altered mitochondrial morphology and function. We have compared metabolic responses of iPLA2γ-KO and WT mice fed a Western diet (WD) with a high fat content. We find that KO mice are resistant to WD-induced increases in body weight and adiposity and in blood levels of cholesterol, glucose, and insulin, even though WT and KO mice exhibit similar food consumption and dietary fat digestion and absorption. KO mice are also relatively resistant to WD-induced insulin resistance, glucose intolerance, and altered patterns of fat vs. carbohydrate fuel utilization. KO skeletal muscle exhibits impaired mitochondrial β-oxidation of fatty acids, as reflected by accumulation of larger amounts of long-chain acylcarnitine (LCAC) species in KO muscle and liver compared with WT in response to WD feeding. This is associated with increased urinary excretion of LCAC and much reduced deposition of triacylglycerols in liver by WD-fed KO compared with WT mice. The iPLA2γ-deficient genotype thus results in a phenotype characterized by impaired mitochondrial oxidation of fatty acids and relative resistance to the metabolic abnormalities induced by WD.
Acute regulation of renal Na+/H+ exchanger NHE3 by dopamine: role of protein phosphatase 2A
Authors: Bobulescu I. Alexandru , Quiñones Henry , Gisler Serge M. , Di Sole Francesca , Hu Ming-Chang , Shi Mingjun , Zhang Jianning , Fuster Daniel G. , Wright Nancy , Mumby Marc , Moe Orson W.
Published: February 2010

Nephrogenic dopamine is a potent natriuretic paracrine/autocrine hormone that is central for mammalian sodium homeostasis. In the renal proximal tubule, dopamine induces natriuresis partly via inhibition of the sodium/proton exchanger NHE3. The signal transduction pathways and mechanisms by which dopamine inhibits NHE3 are complex and incompletely understood. This manuscript describes the role of the serine/threonine protein phosphatase 2A (PP2A) in the regulation of NHE3 by dopamine. The PP2A regulatory subunit B56δ (coded by the Ppp2r5d gene) directly associates with more than one region of the carboxy-terminal hydrophilic putative cytoplasmic domain of NHE3 (NHE3-cyto), as demonstrated by yeast-two-hybrid, coimmunoprecipitation, blot overlay, and in vitro pull-down assays. Phosphorylated NHE3-cyto is a substrate for purified PP2A in an in vitro dephosphorylation reaction. In cultured renal cells, inhibition of PP2A by either okadaic acid or by overexpression of the simian virus 40 (SV40) small T antigen blocks the ability of dopamine to inhibit NHE3 activity and to reduce surface NHE3 protein. Dopamine-induced NHE3 redistribution is also blocked by okadaic acid ex vivo in rat kidney cortical slices. These studies demonstrate that PP2A is an integral and critical participant in the signal transduction pathway between dopamine receptor activation and NHE3 inhibition.
Composite Modulatory Feedforward Loop Contributes to the Establishment of a Network State
Authors: Wu Jin-Sheng , Vilim Ferdinand S. , Hatcher Nathan G. , Due Michael R. , Sweedler Jonathan V. , Weiss Klaudiusz R. , Jing Jian
Published: February 2010

Feedforward loops (FFLs) are one of many network motifs identified in a variety of complex networks, but their functional role in neural networks is not well understood. We provide evidence that combinatorial actions of multiple modulators may be organized as FFLs to promote a specific network state in the Aplysia feeding motor network. The Aplysia feeding central pattern generator (CPG) receives two distinct inputs—a higher-order interneuron cerebral-buccal interneuron-2 (CBI-2) and the esophageal nerve (EN)—that promote ingestive and egestive motor programs, respectively. EN stimulation elicits a persistent egestive network state, which enables the network to temporarily express egestive programs following a switch of input from the EN to CBI-2. Previous work showed that a modulatory CPG element, B65, is specifically activated by the EN and participates in establishing the egestive state by enhancing activity of egestion-promoting B20 interneurons while suppressing activity and synaptic outputs of ingestion-promoting B40 interneurons. Here a peptidergic contribution is mediated by small cardioactive peptide (SCP). Immunostaining and mass spectrometry show that SCP is present in the EN and is released on EN stimulation. Importantly, SCP directly enhances activity and synaptic outputs of B20 and suppresses activity and synaptic outputs of B40. Moreover, SCP promotes B65 activity. Thus the direct and indirect (through B65) pathways to B20 and B40 from SCPergic neurons constitute two FFLs with one functioning to promote egestive output and the other to suppress ingestive output. This composite FFL consisting of the two combined FFLs appears to be an effective means to co-regulate activity of two competing elements that do not inhibit each other, thereby contributing to establish specific network states.
Human accelerated region 1 noncoding RNA is repressed by REST in Huntington's disease
Authors: Johnson Rory , Richter Nadine , Jauch Ralf , Gaughwin Philip M. , Zuccato Chiara , Cattaneo Elena , Stanton Lawrence W.
Published: February 2010

In the neurons of Huntington's disease (HD) patients, gene regulatory networks are disrupted by aberrant nuclear localization of the master transcriptional repressor REST. Emerging evidence suggests that, in addition to protein-coding genes, noncoding RNAs (ncRNAs) may also contribute to neurodegenerative processes. To discover ncRNAs that are involved in HD, we screened genome-wide data for novel, noncoding targets of REST. This identified human accelerated region 1 (HAR1), a rapidly evolving cis-antisense locus that is specifically transcribed in the nervous system. We show that REST is targeted to the HAR1 locus by specific DNA regulatory motifs, resulting in potent transcriptional repression. Consistent with other REST target genes, HAR1 levels are significantly lower in the striatum of HD patients compared with unaffected individuals. These data represent further evidence that noncoding gene expression changes accompany neurodegeneration in Huntington's disease.
Genetic Diversity and Population Structure of a Threatened African Tree Species,Milicia excelsa,Using Nuclear Microsatellites DNA Markers
Authors: Ouinsavi Christine , Sokpon Nestor , Khasa Damase P.
Published: February 2010

To accurately estimate the genetic diversity and population structure for improved conservation planning ofMilicia excelsatree, 212 individuals from twelve population samples covering the species' range in Benin were surveyed at seven specific microsatellite DNA loci. All loci were variable, with the mean number of alleles per locus ranging from 5.86 to 7.69. Considerable genetic variability was detected for all populations at the seven loci (AR=4.60;HE=0.811). Moderate but statistically significant genetic differentiation was found among populations considering bothFST(0.112) andRST(0.342). All of the populations showed heterozygosity deficits in test of Hardy-Weinberg Equilibrium and significantly positiveFISvalues due to inbreeding occurring in the species. PairwiseFSTvalues were positively and significantly correlated with geographical distances (r=0.432;P=.007, Mantel's test) indicating that populations are differentiated by “isolation by distance.” Bayesian analysis of population structure showed division of the genetic variation into four clusters revealing the existence of heterogeneity in population genetic structure. Altogether, these results indicate that genetic variation inMilicia excelsais geographically structured. Information gained from this study also emphasized the need for in situ conservation of the relict populations and establishment of gene flow corridors through agroforestry systems for interconnecting these remnant populations.
A Novel Method for High‐Level Production of TEV Protease by Superfolder GFP Tag
Authors: Wu Xudong , Wu Di , Lu Zhisheng , Chen Wentao , Hu Xiaojian , Ding Yu
Published: February 2010

Because of its stringent sequence specificity, tobacco etch virus (TEV) protease is widely used to remove fusion tags from recombinant proteins. Due to the poor solubility of TEV protease, many strategies have been employed to increase the expression level of this enzyme. In our work, we introduced a novel method to produce TEV protease by using visible superfolder green fluorescent protein (sfGFP) as the fusion tag. The soluble production and catalytic activity of six variants of sfGFP‐TEV was examined, and then the best variant was selected for large‐scale production. After purified by Ni‐NTA affinity chromatography and Q anion exchange chromatography, the best variant of sfGFP‐TEV fusion protease was obtained with purity of over 98% and yield of over 320 mg per liter culture. The sfGFP‐TEV had a similar catalytic activity to that of the original TEV protease. Our research showed a novel method of large‐scale production of visible and functional TEV protease for structural genomics research and other applications.
Analysis and Compensation of the AM-AM and AM-PM Distortion for CMOS Cascode Class-E Power Amplifier
Authors: Tsou Wen An , Wuen Wen Shen , Yang Tzu Yi , Wen Kuei Ann
Published: February 2010

Analysis and compensation methodology of the AM-AM and AM-PM distortion of cascode class-E power amplifiers are presented. A physical-based model is proposed to illustrate that the nonlinear capacitance and transconductance cause the AM-AM and AM-PM distortion when modulating the supply voltage of the PA. A novel methodology that can reduce the distortion is also proposed. By degenerating common-gate transistor into a resistor, the constant equivalent impedance is obtained so that the AM-AM and AM-PM distortion is compensated. An experimental prototype of 2.6 GHz cascode class-E power amplifier with the AM-AM and AM-PM compensation has been integrated in a 0.18 μm CMOS technology, occupies a total die area of 1.6 mm2. It achieves a drain efficiency of 17.8% and a power-added efficiency of 16.6% while delivering 12 dBm of linear output power and drawing 31 mA from a 1.8 V supply. Finally, a co-simulation result demonstrated that, when the distortion of the PA has been compensated, the EVM is improved from −17 dB to −19 dB with an IEEE802.11a-like signal source.
A Simulation Tool for Hurricane Evacuation Planning
Authors: Fonseca Daniel J. , Moynihan Gary P. , Johnston Jordan , Jennings Jordan
Published: February 2010

Atlantic hurricanes and severe tropical storms are a serious threat for the communities in the Gulf of Mexico region. Such storms are violent and destructive. In response to these dangers, coastal evacuation may be ordered. This paper describes the development of a simulation model to analyze the movement of vehicles through I-65, a major US Interstate highway that runs north off the coastal City of Mobile, Alabama, towards the State of Tennessee, during a massive evacuation originated by a disastrous event such a hurricane. The constructed simulation platform consists of a primary and two secondary models. The primary model is based on the entry of vehicles from the 20 on-ramps to I-65. The two secondary models assist the primary model with related traffic events such as car breakdowns and accidents, traffic control measures, interarrival signaling, and unforeseen emergency incidents, among others. Statistical testing was performed on the data generated by the simulation model to indentify variation in relevant traffic variables affecting the timely flow of vehicles travelling north. The performed statistical analysis focused on the closing of alternative on-ramps throughout the Interstate.
Hypersensitivity Vasculitis with Leukocytoclastic Vasculitis Associated with Alpha-1-Proteinase Inhibitor
Authors: Mwirigi Nicola W. , Thomas Charles F.
Published: February 2010

Prolastin is a commercially available form of alpha-1-antitrypsin (AAT) that is derived from pooled human plasma and used for treatment of severe alpha-1-antitrypsin deficiency (AATD). We describe a patient with AATD who developed presumed hypersensitivity vasculitis (HV) following a Prolastin infusion. Hypersensitivity vasculitis (HV), or cutaneous vasculitis, is characterized by inflammation of the small vessels of the skin with resultant ischemia to the distally supplied areas. To our knowledge, this is the first reported case of presumed hypersensitivity vasculitis following Prolastin infusion.
Higher‐Order Equations of the KdV Type are Integrable
Authors: Marinakis V.
Published: February 2010

We show that a nonlinear equation that represents third‐order
approximation of long wavelength, small amplitude waves of inviscid and incompressible
fluids is integrable for a particular choice of its parameters, since in this
case it is equivalent with an integrable equation which has recently appeared in
the literature. We also discuss the integrability of both second‐ and third‐order
approximations of additional cases.
Neuroendocrine Alterations in Obese Patients with Sleep Apnea Syndrome
Authors: Lanfranco Fabio , Motta Giovanna , Minetto Marco Alessandro , Baldi Matteo , Balbo Marcella , Ghigo Ezio , Arvat Emanuela , Maccario Mauro
Published: February 2010

Obstructive sleep apnea syndrome (OSAS) is a serious, prevalent condition that has significant morbidity and mortality when untreated. It is strongly associated with obesity and is characterized by changes in the serum levels or secretory patterns of several hormones. Obese patients with OSAS show a reduction of both spontaneous and stimulated growth hormone (GH) secretion coupled to reduced insulin-like growth factor-I (IGF-I) concentrations and impaired peripheral sensitivity to GH. Hypoxemia and chronic sleep fragmentation could affect the sleep-entrained prolactin (PRL) rhythm. A disrupted Hypothalamus-Pituitary-Adrenal (HPA) axis activity has been described in OSAS. Some derangement in Thyroid-Stimulating Hormone (TSH) secretion has been demonstrated by some authors, whereas a normal thyroid activity has been described by others. Changes of gonadal axis are common in patients with OSAS, who frequently show a hypogonadotropic hypogonadism. Altogether, hormonal abnormalities may be considered as adaptive changes which indicate how a local upper airway dysfunction induces systemic consequences. The understanding of the complex interactions between hormones and OSAS may allow a multi-disciplinary approach to obese patients with this disturbance and lead to an effective management that improves quality of life and prevents associated morbidity or death.
Investigating the Underlying Intelligence Mechanisms of the Biological Olfactory System
Authors: Makino Yoshinari , Yano Masafumi
Published: February 2010

The brain is the center of intelligence that biological systems have acquired during their evolutionary history. In unpredictably changing environments, animals use it to recognize the external world and to make appropriate behavioral decisions. Understanding the mechanisms underlying biological intelligence is important for the development of artificial intelligence. Olfaction is one of the sensory modalities that animals use to locate distant objects. Because of its relative simplicity compared with other sensory modalities and the wealth of knowledge at cellular, network, system, and psychophysical levels, it is possible that the biological olfactory system would be understood comprehensively. This paper reviews our biological and computational works with a focus on the temporal aspects of olfactory information processing. In addition, the paper highlights that the “time” dimension is essential for the functioning of the olfactory information processing system in the real world.
Synchronization of Dissipative Dynamical Systems Driven by Non‐Gaussian Lévy Noises
Authors: Liu Xianming , Duan Jinqiao , Liu Jicheng , Kloeden Peter E.
Published: February 2010

Dynamical systems driven by Gaussian noises have been considered
extensively in modeling, simulation, and theory. However, complex systems
in engineering and science are often subject to non‐Gaussian fluctuations
or uncertainties. A coupled dynamical system under a class of Lévy noises is considered. After discussing cocycle property, stationary orbits, and random attractors, a synchronization phenomenon
is shown to occur, when the drift terms of the coupled system satisfy
certain dissipativity and integrability conditions. The synchronization
result implies that coupled dynamical systems share a dynamical
feature in some asymptotic sense.
Isotope Effect on Eutectic and Hydrate Melting Temperatures in the Water-THF System
Authors: Jones C. Y. , Zhang J. S. , Lee J. W.
Published: February 2010

Differential scanning calorimetry was used to study the effect of isotopic substitution on the eutectic and melting temperatures in the water-tetrahydrofuran (THF) system with THF molar fractions near the stoichiometry of the hydrate phase. Deuteration of the host causes an opposite effect from that of the guest with respect to the hydrate liquidus curve and eutectic melting temperature. The eutectic temperature in D2O-containing systems is approximately 3.7 K higher than that in H2O-containing systems. The melting temperatures of THF and deuterated THF hydrates increase by roughly 3.5 K with heavy water. The inclusion of deuterated THF causes a depression of the hydrate liquidus temperatures and a small but measurable effect on the eutectic temperature.
Animal Models of CNS Viral Disease: Examples from Borna Disease Virus Models
Authors: Solbrig Marylou V.
Published: February 2010

Borna disease (BD), caused by the neurotropic RNA virus, Borna Disease virus, is an affliction ranging from asymptomatic to fatal meningoencephalitis across naturally and experimentally infected warmblooded (mammalian and bird) species. More than 100 years after the first clinical descriptions of Borna disease in horses and studies beginning in the 1980's linking Borna disease virus to human neuropsychiatric diseases, experimentally infected rodents have been used as models for examining behavioral, neuropharmacological, and neurochemical responses to viral challenge at different stages of life. These studies have contributed to understanding the role of CNS viral injury in vulnerability to behavioral, developmental, epileptic, and neurodegenerative diseases and aided evaluation of the proposed and still controversial links to human disease.
Surfactant‐Templated Mesoporous Metal Oxide Nanowires
Authors: Luo Hongmei , Lin Qianglu , Baber Stacy , Naalla Mahesh
Published: February 2010

We demonstrate two approaches to prepare mesoporous metal oxide nanowires by surfactant assembly and nanoconfinement via sol‐gel or electrochemical deposition. For example, mesoporous Ta2O5 and zeolite nanowires are prepared by block copolymer Pluronic 123‐templated sol‐gel method, and mesoporous ZnO nanowires are prepared by electrodeposition in presence of anionic surfactant sodium dodecyl sulfate (SDS) surfactant, in porous membranes. The morphologies of porous nanowires are studied by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses.
A Hybrid Approach to Assess the Network Awareness of P2P-TV Applications
Authors: Rossi Dario , Veglia Paolo
Published: February 2010

In this work, we develop a general methodology to assess the level of network awareness and friendliness of P2P-TV applications. The methodology is based on a combination of active and passive measurement techniques and can be applied to any P2P-TV system since it is designed to work considering such systems as a black-boxes. As an interesting case study, we then apply this methodology to PPLive, one of the most popular P2P-TV systems nowadays. Focusing on the video content distribution, we consider several per-path and per-peer metrics, investigating which of them mostly biases PPLive download preferences. Furthermore, in order to refine the picture of PPLive peer selection policy, we not only study the impact of different metrics in isolation, but also assess the joint impact of different metrics at the same time. Our main finding is that PPLive seems mainly bandwidth greedy, but does not show any preference toward peer proximity based on RTT delay; at the same time, our results also suggest that this choice alone may provide a nonnegligible level of geographical clustering among peers as a beneficial side effect.
Cyclin D1/Cyclin-Dependent Kinase 4 Interacts with Filamin A and Affects the Migration and Invasion Potential of Breast Cancer Cells
Authors: Zhong Zhijiu , Yeow Wen-Shuz , Zou Chunhua , Wassell Richard , Wang Chenguang , Pestell Richard G. , Quong Judy N. , Quong Andrew A.
Published: February 2010

Cyclin D1 belongs to a family of proteins that regulate progression through the G1-S phase of the cell cycle by binding to cyclin-dependent kinase (cdk)-4 to phosphorylate the retinoblastoma protein and release E2F transcription factors for progression through cell cycle. Several cancers, including breast, colon, and prostate, overexpress the cyclin D1 gene. However, the correlation of cyclin D1 overexpression with E2F target gene regulation or of cdk-dependent cyclin D1 activity with tumor development has not been identified. This suggests that the role of cyclin D1 in oncogenesis may be independent of its function as a cell cycle regulator. One such function is the role of cyclin D1 in cell adhesion and motility. Filamin A (FLNa), a member of the actin-binding filamin protein family, regulates signaling events involved in cell motility and invasion. FLNa has also been associated with a variety of cancers including lung cancer, prostate cancer, melanoma, human bladder cancer, and neuroblastoma. We hypothesized that elevated cyclin D1 facilitates motility in the invasive MDA-MB-231 breast cancer cell line. We show that MDA-MB-231 motility is affected by disturbing cyclin D1 levels or cyclin D1-cdk4/6 kinase activity. Using mass spectrometry, we find that cyclin D1 and FLNa coimmunoprecipitate and that lower levels of cyclin D1 are associated with decreased phosphorylation of FLNa at Ser2152 and Ser1459. We also identify many proteins related to cytoskeletal function, biomolecular synthesis, organelle biogenesis, and calcium regulation whose levels of expression change concomitant with decreased cell motility induced by decreased cyclin D1 and cyclin D1-cdk4/6 activities. Cancer Res; 70(5); 2105–14
Reexpression of hSNF5 in Malignant Rhabdoid Tumor Cell Lines Causes Cell Cycle Arrest through a p21CIP1/WAF1-Dependent Mechanism
Authors: Kuwahara Yasumichi , Charboneau Aubri , Knudsen Erik S. , Weissman Bernard E.
Published: February 2010

Loss of hSNF5 function is usually observed in malignant rhabdoid tumor (MRT), a highly aggressive pediatric neoplasm. Previous studies have shown that reexpression of hSNF5 in MRT cell lines causes G1 cell cycle arrest with p16INK4A, p21CIP1/WAF1, and cyclin D1 playing key roles in MRT cell growth control. However, we have shown that reexpression of hSNF5 induced cell cycle arrest in the absence of p16INK4A expression. These results indicate that the mechanism of hSNF5-induced cell cycle arrest is context dependent. Here, we investigated the relationship between p21CIP1/WAF1 and hSNF5 in the regulation of growth using several MRT cell lines. We found that G1 cell cycle arrest occurred concomitant with an increase in p21CIP1/WAF1 mRNA and protein levels and preceded p16INK4A mRNA and protein upregulation. Chromatin immunoprecipitation data confirmed that hSNF5 appeared at both p21CIP1/WAF1 and p16INK4A promoters after reexpression. We further showed that p21CIP1/WAF1 induction showed both p53-dependent and p53-independent mechanisms. We also showed that reduction of p21CIP1/WAF1 expression by RNAi significantly inhibited hSNF5-induced G1 arrest. Our results show that both p21CIP1/WAF1 and p16INK4A are targets for hSNF5 and that p21CIP1/WAF1 upregulation during hSNF5-induced G1 arrest precedes p16INK4A upregulation. These findings indicate that SNF5 mediates a temporally controlled program of cyclin-dependent kinase inhibition to restrict aberrant proliferation in MRT cells. Cancer Res; 70(5); 1854–65
CD73 on Tumor Cells Impairs Antitumor T-Cell Responses: A Novel Mechanism of Tumor-Induced Immune Suppression
Authors: Jin Dachuan , Fan Jie , Wang Long , Thompson Linda F. , Liu Aijie , Daniel Benjamin J. , Shin Tahiro , Curiel Tyler J. , Zhang Bin
Published: February 2010

CD73, originally defined as a lymphocyte differentiation antigen, is thought to function as a cosignaling molecule on T lymphocytes and an adhesion molecule that is required for lymphocyte binding to endothelium. We show here that CD73 is widely expressed on many tumor cell lines and is upregulated in cancerous tissues. Because the ecto-5′-nucleotidase activity of CD73 catalyzes AMP breakdown to immunosuppressive adenosine, we hypothesized that CD73-generated adenosine prevents tumor destruction by inhibiting antitumor immunity. We confirmed this hypothesis by showing that combining tumor CD73 knockdown and tumor-specific T-cell transfer cured all tumor-bearing mice. In striking contrast, there was no therapeutic benefit of adoptive T-cell immunotherapy in mice bearing tumors without CD73 knockdown. Moreover, blockade of the A2A adenosine receptor with a selective antagonist also augmented the efficacy of adoptive T-cell therapy. These findings identify a potential mechanism for CD73-mediated tumor immune evasion and point to a novel cancer immunotherapy strategy by targeting the enzymatic activity of tumor CD73. Cancer Res; 70(6); 2245–55
Bitter Melon (Momordica charantia) Extract Inhibits Breast Cancer Cell Proliferation by Modulating Cell Cycle Regulatory Genes and Promotes Apoptosis
Authors: Ray Ratna B. , Raychoudhuri Amit , Steele Robert , Nerurkar Pratibha
Published: February 2010

Breast cancer is one of the most common cancers among women in the United States. Although there are effective drugs for treating advanced stages of breast cancers, women eventually develop resistance. One of the approaches to control breast cancer is prevention through diet, which inhibits one or more neoplastic events and reduces cancer risk. In this study, we have used human breast cancer cells, MCF-7 and MDA-MB-231, and primary human mammary epithelial cells as an in vitro model to assess the efficacy of bitter melon (Momordica charantia) extract (BME) as an anticancer agent. BME treatment of breast cancer cells resulted in a significant decrease in cell proliferation and induced apoptotic cell death. Apoptosis of breast cancer cells was accompanied by increased poly(ADP-ribose) polymerase cleavage and caspase activation. Subsequent studies showed that BME treatment of breast cancer cells inhibited survivin and claspin expression. Fluorescence-activated cell sorting analysis suggested that MCF-7 cells treated with BME accumulated during the G2-M phase of the cell cycle. Further studies revealed that BME treatment enhanced p53, p21, and pChk1/2 and inhibited cyclin B1 and cyclin D1 expression, suggesting an additional mechanism involving cell cycle regulation. Together, these results show that BME modulates signal transduction pathways for inhibition of breast cancer cell growth and can be used as a dietary supplement for prevention of breast cancer. Cancer Res; 70(5); 1925–31
Drugging the PI3 Kinome: From Chemical Tools to Drugs in the Clinic
Authors: Workman Paul , Clarke Paul A. , Raynaud Florence I. , van Montfort Rob L.M.
Published: February 2010

The phosphatidylinositide 3-kinase (PI3K) pathway is very commonly activated in a wide range of human cancers and is a major driving force in oncogenesis. One of the class I lipid kinase members of the PI3K family, p110α, is probably the most commonly mutated kinase in the human genome. Alongside genetic, molecular biological, and biochemical studies, chemical inhibitors have been extremely helpful tools in understanding the role of PI3K enzymes in signal transduction and downstream physiological and pathological processes, and also in validating PI3Ks as therapeutic targets. Although they have been valuable in the past, the early and still frequently employed inhibitors, wortmannin and LY294002, have significant limitations as chemical tools. Here, we discuss the case history of the discovery and properties of an increasingly used chemical probe, the pan-class I PI3K and mammalian target of rapamycin (mTOR) inhibitor PI-103 (a pyridofuropyrimidine), and its very recent evolution into the thienopyrimidine drug GDC-0941, which exhibits excellent oral anticancer activity in preclinical models and is now undergoing phase I clinical trials in cancer patients. We also illustrate the impact of structural biology on the design of PI3K inhibitors and on the interpretation of their effects. The challenges and outlook for drugging the PI3 kinome are discussed in the more general context of the role of structural biology and chemical biology in innovative drug discovery. Cancer Res; 70(6); 2146–57
HER3 Comes of Age: New Insights into Its Functions and Role in Signaling, Tumor Biology, and Cancer Therapy
Authors: Campbell Marcia R. , Amin Dhara , Moasser Mark M.
Published: February 2010

The human epidermal growth family (HER) of tyrosine kinase receptors underlies the pathogenesis of many types of human cancer. The oncogenic functions of three of the HER proteins can be unleashed through amplification, overexpression, or mutational activation. This has formed the basis for the development of clinically active targeted therapies. However, the third member HER3 is catalytically inactive, not found to be mutated or amplified in cancers, and its role and functions have remained shrouded in mystery. Recent evidence derived primarily from experimental models now seems to implicate HER3 in the pathogenesis of several types of cancer. Furthermore, the failure to recognize the central role of HER3 seems to underlie resistance to epidermal growth factor receptor (EGFR)- or HER2-targeted therapies in some cancers. Structural and biochemical studies have now greatly enhanced our understanding of signaling in the HER family and revealed the previously unrecognized activating functions embodied in the catalytically impaired kinase domain of HER3. This renewed interest and mechanistic basis has fueled the development of new classes of HER3-targeting agents for cancer therapy. However, identifying HER3-dependent tumors presents a formidable challenge and the success of HER3-targeting approaches depends entirely on the development and power of predictive tools. Clin Cancer Res; 16(5); 1373–83
Phase 1 Experience with an Anti-Glycotope Monoclonal Antibody, RAV12, in Recurrent Adenocarcinoma
Authors: Burris Howard A. , Rosen Lee S. , Rocha-Lima Caio M. , Marshall John , Jones Suzanne , Cohen Roger B. , Kunkel Lori A. , Loo Deryk , Baughman Jan , Stewart Stanford J. , Lewis Nancy
Published: February 2010

Purpose: RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell surface proteins. RAAG12 is highly expressed on many adenocarcinomas, particularly those of gastrointestinal origin. A phase 1 dose-escalation safety and pharmacokinetics trial was conducted in patients with metastatic or recurrent adenocarcinomas.

Experimental Design: RAV12 was initially given i.v. weekly ×4, then by fractionated dosing twice or thrice weekly. Thirty-three patients were treated in the dose escalation segment of the trial in the following cohorts: 0.3 mg/kg qw (6), 1.0 mg/kg qw (8), 1.5 mg/kg qw (7); and 0.5 mg/kg biw (3), 0.75 mg/kg biw (3), and 0.5 mg/kg tiw (6). Twenty patients were enrolled in a maximum tolerated dose cohort expansion at 0.75 mg/kg biw.

Results: Two clinical syndromes were associated with drug administration: abdominal cramping pain with diarrhea, and asymptomatic, self-limited increases of liver function tests. These effects were partially ameliorated with fractionated dosing. Pharmacokinetics was dose dependent. Maximum concentration was reduced, whereas area under the concentration versus time curve was maintained with fractionated dosing. One patient with colorectal cancer experienced a durable partial remission, with a time to progression (TTP) of >8 months. Three additional patients experienced a TTP of >4 months.

Conclusions: RAV12 has activity in recurrent adenocarcinomas. However, the safety profile of the antibody seems to preclude the delivery of highly efficacious doses. Re-engineering the molecule to remove FcRn binding (while maintaining FcγR binding) and to humanize it may improve the toxicity profile and efficacy. Clin Cancer Res; 16(5); 1673–81
Low Level Her2 Overexpression Is Associated with Rapid Tumor Cell Proliferation and Poor Prognosis in Prostate Cancer
Authors: Minner Sarah , Jessen Birte , Stiedenroth Lars , Burandt Eike , Köllermann Jens , Mirlacher Martina , Erbersdobler Andreas , Eichelberg Christian , Fisch Margit , Brümmendorf Tim Henrik , Bokemeyer Carsten , Simon Ronald , Steuber Thomas , Graefen Markus , Huland Hartwig , Sauter Guido , Schlomm Thorsten
Published: February 2010

Purpose: The HER2 oncogene is involved in the biology of many different tumor types and serves as a prognostic marker and a therapeutic target in breast cancer. In contrast to breast cancer, studies on Her2 overexpression and gene amplification in prostate cancer have yielded different results. The purpose of this study was to learn more on the prevalence and clinical significance of HER2 amplification and overexpression in prostate cancer.

Experimental Design: A tissue microarray containing >2,000 prostate cancers with follow-up data was used. Tissue microarray sections were analyzed on protein and DNA level using two different antibodies (HercepTest, DAKO; Novocastra NCL-CB11) and fluorescence in situ hybridization.

Results: Immunohistochemical analyses showed highly similar results for both antibodies. Detectable Her2 immunostaining was observed in 17.2% for the HercepTest and in 22.5% for the Novocastra antibody with the vast majority of cases showing 1+ or 2+ staining. For both antibodies (HercepTest/Novocastra), significant associations were found between positive staining and high Gleason grade (P < 0.0001, both), advanced pT stage (P < 0.0001/P = 0.0015), rapid tumor cell proliferation (P = 0.0004/P = 0.0071), and tumor recurrence (P < 0.0001, both). HER2 amplification was only found in 1 of 2,525 analyzable cases (0.04%).

Conclusions: Low-level Her2 overexpression occurs at relevant frequency in prostate cancer and in the absence of gene amplification. Increased Her2 expression may potentially lead to an aggressive behavior of tumor cells through the stimulation of tumor cell proliferation because Her2 staining was shown to be significantly associated with Ki67 labeling index. These data argue for reconsidering anti-Her2 therapy, possibly with modified approaches. Clin Cancer Res; 16(5); 1553–60