bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishment of In Vitro Susceptibility Testing Methodologies and Comparative Activities of Piperacillin in Combination with the Penem β-Lactamase Inhibitor BLI-489
Authors: Petersen Peter J. , Jones C. Hal , Venkatesan Aranapakam M. , Mansour Tarek S. , Projan Steven J. , Bradford Patricia A.
Published: November 2008

The novel bicyclic penem inhibitor BLI-489 has demonstrated activity as an inhibitor of class A, C, and D β-lactamases. To determine the combination of piperacillin and BLI-489 to be used in susceptibility testing that would most accurately identify susceptible and resistant isolates, a predictor panel of β-lactamase-producing bacteria was utilized to determine the reliability of the combination of piperacillin-BLI-489 at a constant inhibitor concentration of 2 or 4 μg/ml and at ratios of 1:1, 2:1, 4:1, and 8:1. There were a number of strains that would be falsely reported as susceptible or intermediate if tested with the ratios of 1:1 and 2:1, whereas the constant concentration of 2 μg/ml of BLI-489 and the ratio of 8:1 had a tendency to overpredict resistance. Similar MICs were obtained with piperacillin-BLI-489 in a 4:1 ratio and when BLI-489 was held constant at 4 μg/ml. Based on these results, an in vitro testing methodology employing a constant concentration of 4 μg/ml BLI-489 was used to evaluate the combination of piperacillin-BLI-489 against a larger panel of recently identified clinical isolates. Approximately 55% of all of the enteric bacilli tested were nonsusceptible to piperacillin alone (MIC ≥ 32 μg/ml). However, 92% of these piperacillin nonsusceptible strains were inhibited by ≤16 μg/ml piperacillin-BLI-489; in contrast, only 66% were inhibited by ≤16 μg/ml piperacillin-tazobactam. The combination of piperacillin-BLI-489 also demonstrated improved activity compared to that of piperacillin-tazobactam against the problematic extended-spectrum β-lactamase- and AmpC-expressing strains.
Vancomycin Ototoxicity: a Reevaluation in an Era of Increasing Doses
Authors: Forouzesh Avisheh , Moise Pamela A. , Sakoulas George
Published: November 2008

Nephrotoxicity and ototoxicity have historically been documented as relatively rare complications of vancomycin monotherapy. Recent reports have linked aggressive vancomycin dosing strategies to significant risks of nephrotoxicity. We evaluated the rate of high-frequency hearing loss detected by audiometry for patients on vancomycin therapy. For this purpose, we used retrospective case-control analysis of audiometry results for patients on vancomycin therapy for whom baseline and follow-up exams were available. Analysis of 89 patients for whom audiograms were performed after an average of 27 days of vancomycin therapy showed a 12% rate of high-frequency hearing loss, with a trend in univariate analysis toward a higher rate with advanced age. The mean of the highest vancomycin trough levels for both patients with worsening audiograms and those without worsening audiograms was 19 mg/liter. Regression tree modeling demonstrated that for patients <53 years old, the rate of high-frequency hearing loss detected by audiogram was 0%, while for patients >53 years old, the incidence was 19% (
P
= 0.008). We conclude that a significant rate of high-frequency hearing loss in older patients receiving vancomycin monotherapy was detected by audiometry. While these data urge caution against continued indiscriminate vancomycin dose escalation to treat infections caused by
Staphylococcus aureus
strains for which vancomycin MICs are 2 mg/liter, further prospective studies are needed to determine the clinical significance and reversibility of these effects.
Macrophage Uptake, Intracellular Localization, and Degradation of Poly-γ-
d
-Glutamic Acid, the Capsular Antigen of
Bacillus anthracis
Authors: Sutherland Marjorie D. , Kozel Thomas R.
Published: November 2008

Bacillus anthracis
is surrounded by a capsular polypeptide composed of poly-γ-
d
-glutamic acid (PGA). This antiphagocytic capsule is an essential virulence factor and is shed into body fluids during a murine model of pulmonary anthrax. Our previous studies of a murine model for antigen clearance showed that purified PGA accumulates in the liver and spleen, most notably in splenic macrophages and the Kupffer cells and sinusoidal endothelial cells of the liver. Although the tissue and cellular depots have been identified, there is little known about the uptake and intracellular fate of PGA. As a consequence, we examined the cellular uptake and organelle localization of PGA in the murine macrophage-like cell line J774.2. We found that PGA binds to and is internalized by J774.2 cells and accumulates in CD71 transferrin receptor-positive endosomes. The receptor-mediated endocytosis inhibitors amantadine and phenylarsine oxide inhibited the binding and uptake of PGA in these cells. Cytochalasin D and vinblastine, actin and microtubule inhibitors, respectively, failed to completely inhibit binding and uptake. Finally, we found that PGA is degraded in J774.2 cells starting 4 h after uptake, with continued degradation occurring for at least 24 h. This degradation of PGA may explain the rapid clearance of PGA that is observed in vivo compared to the slow clearance noted with capsular polysaccharides.
Characterization ofVibrio choleraeOuter Membrane Vesicles as a Candidate Vaccine for Cholera
Authors: Schild Stefan , Nelson Eric J. , Bishop Anne L. , Camilli Andrew
Published: November 2008

Outer membrane vesicles (OMVs) offer a new approach for an effective cholera vaccine. We recently demonstrated that immunization of female mice with OMVs induces a long-lasting immune response and results in protection of their neonatal offspring fromVibrio choleraeintestinal colonization. This study investigates the induced protective immunity observed after immunization with OMVs in more detail. Analysis of the stomach contents and sera of the neonates revealed significant amounts of anti-OMV immunoglobulins (Igs). Swapping of litters born to immunized and nonvaccinated control mice allowed us to distinguish between prenatal and neonatal uptakes of Igs. Transfer of Igs to neonates via milk was sufficient for complete protection of the neonates from colonization withV. cholerae, while prenatal transfer alone reduced colonization only. Detection of IgA and IgG1 in the fecal pellets of intranasally immunized adult mice indicates an induced immune response at the mucosal surface in the gastrointestinal tract, which is the site of colonization byV. cholerae. When a protocol with three intranasal immunizations 14 days apart was used, the OMVs proved to be efficacious at doses as low as 0.025 μg per immunization. This is almost equivalent to OMV concentrations found naturally in the supernatants of LB-grown cultures ofV. cholerae. Heterologous expression of the periplasmic alkaline phosphatase (PhoA) ofEscherichia coliresulted in the incorporation of PhoA into OMVs derived fromV. cholerae. Intranasal immunization with OMVs loaded with PhoA induced a specific immune response against this heterologous antigen in mice. The detection of an immune response against this heterologously expressed protein is a promising step toward the potential use of OMVs as antigen delivery vehicles in vaccine design.
The role of primary care in promoting children’s physical activity
Authors: Huang J S , Sallis J , Patrick K
Published: November 2008

Regular physical activity enhances health during childhood and adolescence and is important in setting the stage for participation in physical activity across the lifespan. Physician–patient interactions during childhood and adolescence provide important opportunities for clinicians to influence physical activity behaviours. This article reviews current physical activity recommendations for youth and the wide range of health benefits provided to youth from engaging in regular physical activity. It also outlines a practical counselling model, the 5As approach, that can guide clinical counselling for physical activity, and reviews how an increasingly important model of practice organisation, the Care Model, can be used to promote physical activity in children and adolescents. Family, social and environmental influences on child and adolescent physical activity are also addressed.
THE SURPRISING PHENOMENON OF LEVEL MERGING IN FINITE FERMI SYSTEMS
Authors: CLARK JOHN W. , KHODEL VICTOR A. , LI HAOCHEN , ZVEREV MIKHAIL V.
Published: November 2008

When applied to a finite Fermi system having a degenerate single-particle spectrum, the Landau-Migdal Fermi-liquid approach leaves room for the possibility that different single-particle energy levels merge with one another. It will be argued that the opportunity for this behavior exists over a wide range of strongly interacting quantum many-body systems. An inherent feature of the mergence phenomenon is the presence of nonintegral quasiparticle occupation numbers, which implies a radical modification of the standard quasiparticle picture. Consequences of this alteration are surveyed for nuclear, atomic, and solid-state systems.
DEPENDENCE OF NON-ABELIAN MATRIX BERRY PHASE OF A SEMICONDUCTOR QUANTUM DOT ON GEOMETRIC PROPERTIES OF ADIABATIC PATH
Authors: KIM S. C. , HWANG N. Y. , PARK P. S. , KIM Y. J. , LEE C. J. , YANG S. -R. ERIC
Published: November 2008

A matrix Berry phase can be generated and detected by all electric means in II-VI and III-V n-type semiconductor quantum dots by changing the shape of the confinement potential. This follows from general symmetry considerations in the presence of spin-orbit coupling terms. We explain these results and discuss how the matrix Berry phase depends on geometric properties of adiabatic paths. We suggest how the matrix Berry phase may be detected in transport measurements.
DILUTE ALPHA-PARTICLE CONDENSATION IN 12C AND 16O
Authors: YAMADA T. , FUNAKI Y. , HORIUCHI H. , TOHSAKI A. , RÖPKE G. , SCHUCK P.
Published: November 2008

Alpha particle condensation is studied in 12 C and 16 O with the orthogonality condition model (OCM). The OCM equation is an approximation of the equation of motion of α bosons based on microscopic theories. We demonstrate that 1) the Hoyle state (the [Formula: see text] state at 7.65 MeV in 12 C ), located just above the 3α disintegration threshold has a 3α-particle condensate character, in which 3α particles occupy an identical 0S orbit with 70 % occupancy, forming a dilute gas-like configuration, and 2) the [Formula: see text] state at Ex = 15.1 MeV in 16 O , appearing above the 4α breakup threshold, is a strong candidate with dilute 4α structure of the condensate-type.
OPTICAL AND TRANSPORT PROPERTIES IN DENSE PLASMAS COLLISION FREQUENCY FROM BULK TO CLUSTER
Authors: REINHOLZ H. , RAITZA T. , RÖPKE G. , MOROZOV I. V.
Published: November 2008

The dielectric function of dense plasmas is treated within a many-particle linear response theory beyond the RPA. In the long-wavelength limit, the dynamical collision frequency can be introduced which is expressed in terms of momentum and force auto-correlation functions (ACF). Analytical expressions for the collision frequency are considered for bulk plasmas, and reasonable agreement with MD simulations is found. Different applications such as Thomson scattering, reflectivity, electric and magnetic transport properties are discussed. In particular, experimental results for the static conductivity of inert gas plasmas are now well described.

The transition from bulk properties to finite cluster properties is of particular interest. Within semiclassical MD simulations, single-time characteristics as well as two-time correlation functions are evaluated and analyzed. In particular, the Laplace transform of current and force ACFs show typical structures which are interpreted as collective modes of the microplasma. The damping rates of these modes are size dependent. They increase for the transition from small clusters to bulk plasmas.
EFFECTS OF HEAT TREATMENT ON SPIN HAMILTONIAN PARAMETERS OF Cr3+ IONS IN NATURAL PINK SAPPHIRE
Authors: KITTIAUCHAWAL T. , LIMSUWAN P. , EITSSAYEAM SUKUM , TUNKASIRI TAWEE
Published: November 2008

The purpose of this research work is to investigate the effects of heat treatment on spin Hamiltonian parameters of Cr 3+ ions in natural pink sapphire sample. The pink sapphire were heated at different temperatures of 1200, 1300, 1400, 1500 and 1600°C in oxygen atmosphere for 12 h, respectively. Electron Spin Resonance (ESR) spectra of pink sapphire samples before and after heat treatment were recorded in X-band frequency by mounting the crystal sample with the c-axis perpendicular to the applied magnetic field direction. The spectra were recorded in the range of 0-180 degrees for every 15 degrees of rotation angle (φ). It was found that, five strong ESR absorption peaks at the magnetic fields of 97, 163, 312, 519 and 724 mT were obtained. The magnetic fields of 163 and 519 mT corresponding to Cr 3+ ions replacing the Al 3+ ions site of corundum structure (α- Al 2 O 3), and those of 97, 312, and 724 mT were assigned to Fe 3+ ions. Some conspicuous peaks of Cr 3+ ion at various rotation angles were used to calculate the spin Hamiltonian parameters by least-squares fit method with the help of a computer program. The optimum spin Hamiltonian parameters of Cr 3+ ions were then used to simulate the energy levels diagram of Cr 3+ ions in sample before and after heat treatment.
QUANTUM BROWNIAN AND THE CONSTRAINED PATH INTEGRAL
Authors: BOONCHUI S. , SA-YAKANIT V. , PALOTAIDAMKERNG P.
Published: November 2008

We show that the environment affects a quantum system in the form of the constrained trajectory. Our result allows one to describe the quantum system in terms of stochastic state vector rather than quantum history. Moreover we can alternatively reduce the time evolution operator. Then the trajectory of system is constrained.
Mobio threat
Authors: Segatto Wilian , Herzer Eduardo , Mazzotti Cristiano L. , Bittencourt João R. , Barbosa Jorge
Published: November 2008

Pervasive gaming is a new genre that became possible due to the development of communication technologies, especially wireless ones. In this area of gaming, players must physically walk to certain places of the game area to reach their objectives and missions. They may also interact with the environment and with real objects. Nowadays, there are just a few pervasive games developed, and all of them have limitations concerning localization tracking, hardware flexibility, signal coverage, and cheap setup. In this context, an innovative game, called
moBIO Threat // Disease Control
, was developed on the basis of the integration of multiple wireless technologies, mixing their capabilities and neutralizing their limitations. It utilizes RFID, IrDA, and QR Code technologies for object interaction, Bluetooth for exchanging information between players who are physically close and the IEEE 802.11 Wi-Fi protocol to connect all of the players with the game server. From what we observed,
moBIO Threat
provides a completely different game experience, with social gaming and collaboration being strong attributes of the game. This article describes the development of the game and other details about the project and about pervasive gaming.
Evaluating a middleware for crossmedia games
Authors: Trinta Fernando , Pedrosa Davi , Ferraz Carlos , Ramalho Geber
Published: November 2008

Crossmedia games are a genre of pervasive gaming where a single game instance can be played with a variety of heterogeneous devices that support different forms of players' participation and deliver different game experiences. In this article we present the PM2G initiative, a service-oriented architecture aiming to support crossmedia game development and execution. Due to their relevance in this document, content adaptation and interaction adaptation services are discussed in detail. We also present, as a case study, a game called
Pervasive Wizards
, which is used to validate our architecture. Finally, we present some performance results obtained in our experiments.
Providing expressive gaze to virtual animated characters in interactive applications
Authors: Queiroz Rossana B. , Barros Leandro M. , Musse Soraia R.
Published: November 2008

Eyes play an important role in communication among people. Motions of the eye express emotions and regulate the flow of conversation. Hence we consider fundamental that virtual humans or other characters present convincing and expressive gaze in applications such as Embodied Conversational Agents (ECAs), games and movies. However, we perceive that in many applications that require automatic generation of facial movements, such as ECA, character's eye motion does not carry meaning related to its expressiveness. This work proposes a model for the automatic generation of expressive gaze by examining eye behavior in different affective states. To collect data related to gaze and expressiveness, we looked at Computer Graphics movies. This data was used as a basis to describe gaze expressions in the proposed model. We also implemented a prototype and performed some tests with users in order to observe the impact of eye behavior during some expressions of emotion. The results show that the model is capable of generating eye motions that are coherent with the affective states of the virtual character.
A game loop architecture for the GPU used as a math coprocessor in real-time applications
Authors: Zamith Marcelo P. M. , Clua Esteban W. G. , Conci Aura , Montenegro Anselmo , Leal-Toledo Regina C. P. , Pagliosa Paulo A. , Valente Luis , Feij Bruno
Published: November 2008

This article concerns the use of a graphics processor unit (GPU) as a math co-processor in real-time applications in special games and physics simulations. To validate this approach, we present a new game loop architecture that employs GPUs for general-purpose computations (GPGPUs). A critical issue here is the process distribution between the CPU and the GPU. The architecture consists of a model for distribution, and our implementation offers many advantages in comparison to other approaches without the GPGPU stage. This architecture can be used either by a general-purpose language such as the Compute Unified Device Architecture (CUDA), or shader languages such as the High-Level Shader Language (HLSL) and the OpenGL Shading Language (GLSL).

Although the architecture proposed here aims at supporting mathematics and physics on the GPU, it is possible to adapt any kind of generic computation. This article discusses the model implementation in an open-source game engine and presents the results of using this platform.
Controlling Chemistry by Geometry in Nanoscale Systems
Authors: Lizana L. , Konkoli Z. , Bauer B. , Jesorka A. , Orwar O.
Published: November 2008

Scientific literature dealing with the rates, mechanisms, and thermodynamic properties of chemical reactions in condensed media almost exclusively assumes that reactions take place in volumes that do not change over time. The reaction volumes are compact (such as a sphere, a cube, or a cylinder) and do not vary in shape. In this review article, we discuss two important systems at small length scales (∼10 nm to 5 μm), in which these basic assumptions are violated. The first system exists in cell biology and is represented by the tiniest functional components (i.e., single cells, organelles, and other physically delineated cellular microenvironments). The second system comprises nanofluidic devices, in particular devices made from soft-matter materials such as lipid nanotube-vesicle networks. In these two systems, transport, mixing, and shape changes can be achieved at or very close to thermal energy levels. In further contrast to macroscopic systems, mixing by diffusion is extremely efficient, and kinetics can be controlled by shape and volume changes.
Principles and Progress in Ultrafast Multidimensional Nuclear Magnetic Resonance
Authors: Mishkovsky Mor , Frydman Lucio
Published: November 2008

Multidimensional acquisitions play a central role in the progress and applications of nuclear magnetic resonance (NMR) spectroscopy. Such experiments have been collected traditionally as an array of one-dimensional scans, with suitably incremented delay parameters that encode along independent temporal domains the nD spectral distribution being sought. During the past few years, an ultrafast approach to nD NMR has been introduced that is capable of delivering any type of multidimensional spectrum in a single transient. This method operates by departing from the canonical nD NMR scheme and by replacing its temporal encoding with a series of spatial manipulations derived from magnetic resonance imaging. The present survey introduces the main principles of this subsecond approach to spectroscopy, focusing on the applications that have hitherto been demonstrated for single-scan two-dimensional NMR in different areas of chemistry.
Light Switching of Molecules on Surfaces
Authors: Browne Wesley R. , Feringa Ben L.
Published: November 2008

Smart surfaces, surfaces that respond to an external stimulus in a defined manner, hold considerable potential as components in molecular-based devices, not least as discrete switching elements. Many stimuli can be used to switch surfaces between different states, including redox, light, pH, and ion triggers. The present review focuses on molecular switching through the electronic excitation of molecules on surfaces with light. In developing light-responsive surfaces, investigators face several challenges, not only in achieving high photostationary states and fully reversible switching, but also in dealing with fatigue resistance and the effect of immobilization itself on molecular properties. The immobilization of light-responsive molecules requires the design and synthesis of functional molecular components both to achieve light switching and to anchor the molecular entity onto a surface. This review discusses several demonstrative examples of photoswitchable molecular systems in which the photochemistry has been explored in the immobilized state under ambient conditions and especially on electroactive surfaces, including self-assembled monolayers, bilayers, and polymer films.
Physical Chemistry of DNA Viruses
Authors: Knobler Charles M. , Gelbart William M.
Published: November 2008

The relative simplicity of viruses makes it possible to apply generic physical approaches to the understanding of their structure and function. We focus here on viruses that have double-stranded (ds)DNA genomes that are enclosed in a protein container called the capsid. Their structures are now known in precise detail from cryo-electron microscopy. dsDNA is a stiff, highly charged polymer, and typical viral DNAs have contour lengths 1000 times longer than the radius of the capsid into which they are introduced in the assembly process, which is driven by a biological motor. As a result, the confined DNA is highly stressed. The energy stored in the dsDNA, which is compressed to crystalline densities, drives the ejection of the genome into the host at the start of an infection. Experiments have examined the packaging and ejection of the genomes, which have also been the subject of analytic theories and simulations.
A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death
Authors: Wood Tabitha E. , Dalili Shadi , Simpson Craig D. , Hurren Rose , Mao Xinliang , Saiz Fernando Suarez , Gronda Marcela , Eberhard Yanina , Minden Mark D. , Bilan Philip J. , Klip Amira , Batey Robert A. , Schimmer Aaron D.
Published: November 2008

Evasion of death receptor ligand-induced apoptosis is an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule N-[4-chloro-3-(trifluoromethyl)phenyl]-3-oxobutanamide (fasentin) was identified as a chemical sensitizer to the death receptor stimuli FAS and tumor necrosis factor apoptosis-inducing ligand, but its mechanism of action was unknown. Here, we determined that fasentin alters expression of genes associated with nutrient and glucose deprivation. Consistent with this finding, culturing cells in low-glucose medium recapitulated the effects of fasentin and sensitized cells to FAS. Moreover, we showed that fasentin inhibited glucose uptake. Using virtual docking studies with a homology model of the glucose transport protein GLUT1, fasentin interacted with a unique site in the intracellular channel of this protein. Additional chemical studies with other GLUT inhibitors and analogues of fasentin supported a role for partial inhibition of glucose transport as a mechanism to sensitize cells to death receptor stimuli. Thus, fasentin is a novel inhibitor of glucose transport that blocks glucose uptake and highlights a new mechanism to sensitize cells to death ligands. [Mol Cancer Ther 2008;7(11):3546–55]
Activation of toll-like receptors 2, 3, and 4 on human melanoma cells induces inflammatory factors
Authors: Goto Yasufumi , Arigami Takaaki , Kitago Minoru , Nguyen Sandy L. , Narita Norihiko , Ferrone Soldano , Morton Donald L. , Irie Reiko F. , Hoon Dave S.B.
Published: November 2008

Toll-like receptors (TLR) have been shown to be expressed on various types of cancers; however, their functional activity is not known. We examined TLR profiles of human melanoma cells and showed that TLR2, TLR3, and TLR4 were found to be highly expressed. By PCR array analysis, specific stimulation of TLR2, TLR3, and TLR4 on melanoma cells showed significant activation of the adaptor protein MyD88, as well as downstream signal transduction factors nuclear factor-κB and inflammatory response–related factors. Specific ligand activation of TLR2, TLR3, and TLR4 was shown to induce cell migration. Peripheral blood lymphocytes and melanoma purified RNA was shown to activate TLR3 on melanoma cells. These studies show expression and functional activity of specific TLRs on melanoma cells and as potential therapeutic targets to control tumor progression. [Mol Cancer Ther 2008;7(11):3642–53]
Dithiolethiones for cancer chemoprevention: where do we stand?
Authors: Zhang Yuesheng , Munday Rex
Published: November 2008

Dithiolethiones are a well-known class of cancer chemopreventive agents; the key mechanism of action of dithiolethiones involves activation of Nrf2 signaling and induction of phase II enzymes. In the past, attention has been focused mainly on 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz), which showed ability as a wide-spectrum inhibitor of chemical carcinogenesis in preclinical models. However, clinical trials of oltipraz have shown questionable efficacy, and at the high doses employed in such studies, significant side effects were observed. Dithiolethiones that are markedly more effective and potent than oltipraz in both induction of phase II enzymes and inhibition of chemical carcinogenesis in preclinical studies have been identified, and these compounds have shown pronounced organ specificity in vivo. Further investigation of these compounds may lead to development of effective and safe agents for cancer prevention in humans. [Mol Cancer Ther 2008;7(11):3470–9]
Involvement of c-FLIP and survivin down-regulation in flexible heteroarotinoid-induced apoptosis and enhancement of TRAIL-initiated apoptosis in lung cancer cells
Authors: Lin Yidan , Liu Xiangguo , Yue Ping , Benbrook Doris M. , Berlin K. Darrell , Khuri Fadlo R. , Sun Shi-Yong
Published: November 2008

The flexible heteroarotinoid, SHetA2, is a novel compound with apoptosis-inducing and anticancer activities in vitro and in vivo. Our previous research showed that up-regulation of death receptor 5 plays a critical role in the mechanism of SHetA2-induced apoptosis in human lung cancer cells. The hypothesis of this study was that the mechanism of SHetA2-induced apoptosis requires modulation of additional proteins critical for regulation of apoptosis, including cellular FLICE-inhibitory protein (c-FLIP), survivin, X-linked inhibitor of apoptosis, Bcl-2, Bcl-XL, Bax, and Bim. Western blot analysis showed that c-FLIP and survivin were substantially reduced in all of the tested cell lines exposed to SHetA2 compared with other proteins that were reduced only in a subset of the cell lines tested. Strikingly, overexpression of c-FLIP, but not survivin, protected cells from SHetA2-induced apoptosis and enhancement of TRAIL-initiated apoptosis, although knockdown of endogenous survivin did slightly sensitize cells to SHetA2-induced apoptosis. Consistent with these results, small interfering RNA-mediated reduction of c-FLIP was more effective than survivin down-regulation in triggering apoptosis in these cell lines. SHetA2 increased ubiquitination of c-FLIP and the consequent degradation was abrogated by the proteasome inhibitor MG132. Although SHetA2 treatment led to increased c-Jun phosphorylation, the JNK inhibitor SP600125 did not prevent c-FLIP down-regulation by SHetA2. Thus, it appears that SHetA2 down-regulates c-FLIP levels by facilitating its ubiquitin/proteasome-mediated degradation independent of JNK activation. Collectively, the present study indicates that, in addition to death receptor 5 up-regulation, c-FLIP down-regulation is another important component of flexible heteroarotinoid (SHetA2)-induced apoptosis as well as enhancement of TRAIL-induced apoptosis. [Mol Cancer Ther 2008;7(11):1–10] [Mol Cancer Ther 2008;7(11):3556–65]
Gene silencing for epidermal growth factor receptor variant III induces cell-specific cytotoxicity
Authors: Yamoutpour Farnaz , Bodempudi Vidya , Park Shay E. , Pan Weihong , Mauzy Mary Jean , Kratzke Robert A. , Dudek Arkadiusz , Potter David A. , Woo Richard A. , O'Rourke Donald M. , Tindall Donald J. , Farassati Faris
Published: November 2008

Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active mutant form of EGFR that is expressed in 40% to 50% of gliomas and several other malignancies. Here, we describe the therapeutic effects of silencing EGFRvIII on glioma cell lines in vitro and in vivo. A small interfering RNA molecule against EGFRvIII was introduced into EGFRvIII-expressing glioma cells (U87Δ) by electroporation resulting in complete inhibition of expression of EGFRvIII as early as 48 h post-treatment. During EGFRvIII silencing, a decrease in the proliferation and invasiveness of U87Δ cells was accompanied by an increase in apoptosis (P < 0.05). Notably, EGFRvIII silencing inhibited the signal transduction machinery downstream of EGFRvIII as evidenced by decreases in the activated levels of Ras and extracellular signal-regulated kinase. A lentivirus capable of expressing anti-EGFRvIII short hairpin RNA was also able to achieve progressive silencing of EGFRvIII in U87Δ cells in addition to inhibiting cell proliferation, invasiveness, and colony formation in a significant manner (P < 0.05). Silencing EGFRvIII in U87Δ cultures with this virus reduced the expression of factors involved in epithelial-mesenchymal transition including N-cadherin, β-catenin, Snail, Slug, and paxillin but not E-cadherin. The anti-EGFRvIII lentivirus also affected the cell cycle progression of U87Δ cells with a decrease in G1 and increase in S and G2 fractions. In an in vivo model, tumor growth was completely inhibited in severe combined immunodeficient mice (n = 10) injected s.c. with U87Δ cells treated with the anti-EGFRvIII lentivirus (P = 0.005). We conclude that gene specific silencing of EGFRvIII is a promising strategy for treating cancers that contain this mutated receptor. [Mol Cancer Ther 2008;7(11):3586–97]
Identification of a nonkinase target mediating cytotoxicity of novel kinase inhibitors
Authors: Ross-Macdonald Petra , de Silva Heshani , Guo Qi , Xiao Hong , Hung Chen-Yi , Penhallow Becky , Markwalder Jay , He Liqi , Attar Ricardo M. , Lin Tai-an , Seitz Steven , Tilford Charles , Wardwell-Swanson Judith , Jackson Donald
Published: November 2008

In developing inhibitors of the LIM kinases, the initial lead molecules combined potent target inhibition with potent cytotoxic activity. However, as subsequent compounds were evaluated, the cytotoxic activity separated from inhibition of LIM kinases. A rapid determination of the cytotoxic mechanism and its molecular target was enabled by integrating data from two robust core technologies. High-content assays and gene expression profiling both indicated an effect on microtubule stability. Although the cytotoxic compounds are still kinase inhibitors, and their structures did not predict tubulin as an obvious target, these results provided the impetus to test their effects on microtubule polymerization directly. Unexpectedly, we confirmed tubulin itself as a molecular target of the cytotoxic kinase inhibitor compounds. This general approach to mechanism of action questions could be extended to larger data sets of quantified phenotypic and gene expression data. [Mol Cancer Ther 2008;7(11):3490–8]
Association Between Intraoperative and Early Postoperative Glucose Levels and Adverse Outcomes After Complex Congenital Heart Surgery
Authors: Polito Angelo , Thiagarajan Ravi R. , Laussen Peter C. , Gauvreau Kimberlee , Agus Michael S.D. , Scheurer Mark A. , Pigula Frank A. , Costello John M.
Published: November 2008

Background—

This study sought to determine whether associations exist between perioperative glucose exposure, prolonged hospitalization, and morbid events after complex congenital heart surgery.

Methods and Results—

Metrics of glucose control, including average, peak, minimum, and SD of glucose levels, and duration of hyperglycemia were determined intraoperatively and for 72 hours after surgery for 378 consecutive high-risk cardiac surgical patients. Multivariable regression analyses were used to determine relationships between these metrics of glucose control, hospital length of stay, and a composite morbidity-mortality outcome after controlling for multiple variables known to influence early outcomes after congenital heart surgery. Intraoperatively, a minimum glucose ≤75 mg/dL was associated with greater adjusted odds of reaching the composite morbidity-mortality end point (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.49 to 6.48), but other metrics of glucose control were not associated with the composite end point or length of stay. Greater duration of hyperglycemia (glucose >126 mg/dL) during the 72 postoperative hours was associated with longer duration of hospitalization (
P
<0.001). In the 72 hours after surgery, average glucose <110 mg/dL (OR, 7.30; 95% CI, 1.95 to 27.25) or >143 mg/dL (OR, 5.21; 95% CI, 1.37 to 19.89), minimum glucose ≤75 mg/dL (OR, 2.85; 95% CI, 1.38 to 5.88), and peak glucose level ≥250 mg/dL (OR, 2.55; 95% CI, 1.20 to 5.43) were all associated with greater adjusted odds of reaching the composite morbidity-mortality end point.

Conclusions—

In children undergoing complex congenital heart surgery, the optimal postoperative glucose range may be 110 to 126 mg/dL. Randomized trials of strict glycemic control achieved with insulin infusions in this patient population are warranted.
Somatostatin 2A Receptor-Expressing Presympathetic Neurons in the Rostral Ventrolateral Medulla Maintain Blood Pressure
Authors: Burke Peter G.R. , Li Qun , Costin Monique L. , McMullan Simon , Pilowsky Paul M. , Goodchild Ann K.
Published: November 2008

Bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are critical for the maintenance of sympathetic vasomotor tone and normal cardiovascular reflex function. So far, selectively eliminating/inhibiting distinct subpopulations of RVLM neurons has not significantly altered arterial pressure. Here we show that RVLM presympathetic neurons that express somatostatin 2A receptors are essential for maintaining and potentially generating sympathetic vasomotor tone. Combined immunocytochemistry and in situ hybridization were used to map the expression of somatostatin receptors 1, 2A, 2B, 3, and 4 (sst1 through 4, respectively) in the rat RVLM. sst1 and sst2B were absent; sst3 and sst4 were sparse. However, sst2A was found postsynaptically and detected in 35±5% of bulbospinal RVLM neurons a population that included 54±4% of catecholaminergic and 30±3% of enkephalinergic neurons. Bilateral microinjection into the RVLM of either somatostatin or the receptor-selective agonist lanreotide evoked dramatic, dose-dependent sympathoinhibition, hypotension, and bradycardia that were blocked by the sst2 receptor antagonist BIM-23627 in anesthetized rats. Bilateral RVLM microinjection of somatostatin also attenuated chemoreceptor and somatosympathetic reflex function. Somatostatin only eliminated the first sympathoexcitatory peak evoked by somatosympathetic reflex activation, whereas muscimol abolished both excitatory peaks providing functional evidence that the activity of only a subpopulation of RVLM presympathetic neurons is inhibited by somatostatin. We suggest that the subpopulation of bulbospinal RVLM neurons that expresses the sst2A receptor sets sympathetic vasomotor output. These neurons are essential for maintaining resting blood pressure under anesthesia and contribute to adaptive reflexes mediated through the RVLM.
Influence of Cloud Condensation Nuclei on Orographic Snowfall
Authors: Saleeby Stephen M. , Cotton William R. , Lowenthal Douglas , Borys Randolph D. , Wetzel Melanie A.
Published: November 2008

Pollution aerosols acting as cloud condensation nuclei (CCN) have the potential to alter warm rain clouds via the aerosol first and second indirect effects in which they modify the cloud droplet population, cloud lifetime and size, rainfall efficiency, and radiation balance from increased albedo. For constant liquid water content, an increase in CCN concentration (NCCN) tends to produce an increased concentration of droplets with smaller diameters. This reduces the collision and coalescence rate, and thus there is a local reduction in rainfall. While this process applies to warm clouds, it does not identically carry over to mixed-phase clouds in which crystal nucleation, crystal riming, crystal versus droplet fall speed, and collection efficiency play active roles in determining precipitation amount. Sulfate-based aerosols serve as very efficient cloud nuclei but are not effective as ice-forming nuclei. In clouds where precipitation formation is dominated by the ice phase, NCCN influences precipitation growth by altering the efficiency of droplet collection by ice crystals and the fall trajectories of both droplet and crystal hydrometeors. The temporal and spatial variation in both crystal and droplet populations determines the resultant snowfall efficiency and distribution. Results of numerical simulations in this study suggest that CCN can play a significant role in snowfall production by winter, mixed-phase, cloud systems when liquid and ice hydrometeors coexist. In subfreezing conditions, a precipitating ice cloud overlaying a supercooled liquid water cloud allows growth of precipitation particles via the seeder–feeder process, in which nucleated ice crystals fall through the supercooled liquid water cloud and collect droplets. Enhanced NCCN from sulfate pollution by fossil fuel emissions modifies the droplet distribution and reduces crystal riming efficiency. Reduced riming efficiency inhibits the rate of snow growth, producing lightly rimed snow crystals that fall slowly and advect farther downstream prior to surface deposition. Simulations indicate that increasing NCCN along the orographic barrier of the Park Range in north-central Colorado results in a modification of the orographic cloud such that the surface snow water equivalent amounts are reduced on the windward slopes and enhanced on the leeward slopes. The inhibition of snowfall by pollution aerosols (ISPA) effect has significant implications for water resource distribution in mountainous terrain.
Generation and Propagation of Inertia–Gravity Waves from Vortex Dipoles and Jets
Authors: Wang Shuguang , Zhang Fuqing , Snyder Chris
Published: November 2008

This study investigates gravity wave generation and propagation from jets within idealized vortex dipoles using a nonhydrostatic mesoscale model. Two types of initially balanced and localized jets induced by vortex dipoles are examined here. These jets have their maximum strength either at the surface or in the middle levels of a uniformly stratified atmosphere. Within these dipoles, inertia–gravity waves with intrinsic frequencies 1–2 times the Coriolis parameter are simulated in the jet exit region. These gravity waves are nearly phase locked with the jets as shown in previous studies, suggesting spontaneous emission of the waves by the localized jets. A ray tracing technique is further employed to investigate the propagation effects of gravity waves. The ray tracing analysis reveals strong variation of wave characteristics along ray paths due to variations (particularly horizontal variations) in the propagating environment.

The dependence of wave amplitude on the jet strength (and thus on the Rossby number of the flow) is examined through experiments in which the two vortices are initially separated by a large distance but subsequently approach each other and form a vortex dipole with an associated amplifying localized jet. The amplitude of the stationary gravity waves in the simulations with 90-km grid spacing increases as the square of the Rossby number (Ro), when Ro falls in a small range of 0.05–0.15, but does so significantly more rapidly when a smaller grid spacing is used.
An Intercomparison of Observational, Reanalysis, Satellite, and Coupled Model Data on Mean Rainfall in the Caribbean
Authors: Jury Mark R.
Published: November 2008

This study examines the spatial variability of mean annual rainfall in the Caribbean in the satellite era 1979–2000. Intercomparisons of gridded rainfall fields from conventional stations, satellite estimators, reanalysis products, and coupled general circulation models (CGCMs) are made, with a focus on the Antilles island chain and their land–sea transitions. The rainfall products are rated for their ability to capture a number of key features, including (i) topographically enhanced precipitation over the larger western Antilles islands of Cuba, Jamaica, Hispanola, and Puerto Rico; (ii) the rain shadow west of Hispanola; (iii) the two dry zones where SSTs are low: north of Venezuela and north of the Lesser Antilles; and (iv) the wet axis extending north of Trinidad. The various monitoring and modeling systems produce gridded rainfall fields at resolutions from 50 to 280 km, from station reconstructions, satellite estimates, blended and reanalysis products, and CGCM climatologies with respect to surface forcing fields. Wet and dry biases were found in many of the reanalysis and satellite products, respectively—either over the whole Caribbean or in a certain sector. The intercomparison found some measure of consensus, but no single product is without discrepancy. High-resolution passive microwave satellite rainfall estimates [Climate Prediction Center’s multisaltellite passive microwave, IR morphed product (cMOR)] appear “most representative”; however, the climatology is short (2003–07) and the field is generally drier than the consensus. Of the conventional products, decadal variability of climate interpolated rain gauges (DEKL), World Climate Research Programme’s (WCRP) blended rain gauges, the Comprehensive Ocean–Atmosphere Data Set (COADS), and an operational climate anomaly monitoring system of NCEP (CAMS) perform well. Among the satellite estimators, the Global Precipitation Climatology Project’s blended gauge and IR satellite (GPCP) and outgoing longwave radiation (OLR) capture the key features and ocean–island transitions. The Center for Ocean–Land–Atmosphere Studies [COLA; the coupled model, part of the Coupled Model Intercomparison Project (CMIP, phase 3)] and the climate forecast system of the NCEP (CFS) models perform reasonably, but NCAR’s Parallel Climate Model (PCM; the CGCM’s historical run of CMIP3) fares poorly. The version 2 hindcast of the operational Medium-Range Forecast (MRF) weather prediction model (REAN) captures the smaller wet zones and topographically enhanced features, but it does not handle the broad oceanic dry zones well, as the input from the operational climate data assimilation system of NCEP (CDAS) has a wet bias. Of the various key rainfall features, high rainfall over southern Cuba and the rain shadow west of Hispanola are poorly handled by most products. The wet axis north of Trinidad and the dry zone north of Venezuela are well represented in many climatologies.
Impact of Satellite-Derived Rapid-Scan Wind Observations on Numerical Model Forecasts of Hurricane Katrina
Authors: Langland Rolf H. , Velden Christopher , Pauley Patricia M. , Berger Howard
Published: November 2008

The impacts of special Geostationary Operational Environmental Satellite (GOES) rapid-scan (RS) wind observations on numerical model 24–120-h track forecasts of Hurricane Katrina are examined in a series of data assimilation and forecast experiments. The RS wind vectors are derived from geostationary satellites by tracking cloud motions through successive 5-min images. In these experiments, RS wind observations are added over the area 15°–60°N, 60°–110°W, and they supplement the observations used in operational forecasts. The inclusion of RS wind observations reduces errors in numerical forecasts of the Katrina landfall position at 1200 UTC 29 August 2005 by an average of 12% compared to control cases that include “targeted” dropsonde observations in the Katrina environment. The largest average improvements are made to the 84- to 120-h Katrina track forecasts, rather than to the short-range track forecasts. These results suggest that RS wind observations can potentially be used in future cases to improve track forecasts of tropical cyclones.
Presentation Names: Their Distribution in Space and Time
Authors: Callary Edward
Published: November 2008

AbstractThe name forms by which we present ourselves publicly are shown to be sociolinguistic variables. A 1996 study of the preferred name forms of state legislators in the US found that informal presentation names were common in much of the south and west of the country, and generally absent in the northeast. A 2007 replication of that study both confirmed the earlier findings and showed that the public use of informal name forms had increased. The practice of using informal presentation names originated in the south and northwest and spread to all parts of the country except the northeast. The increasing use of informal names is seen as part of a general societal shift toward greater informality.
Nicknames, Interpellation, and Dubya's Theory of the State
Authors: Adams Michael
Published: November 2008

AbstractGeorge W. Bush freely assigns nicknames to political aides, cabinet secretaries, legislators, reporters, and others who cross his presidential path. Nicknaming seems an innocuous, playful social behavior, but it is a more complex onomastic maneuvre than it seems, and more significant: it is a species of Althusserian interpellation, a means of 'hailing' actors within the state and converting them into subjects of state ideology, which, on one construction (the one operating here), collapses state authority and the executive power of the American presidency. Nicknaming, then, is evidence of a theory of state and an instrument of its institution.