bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional Synthesis of Mediterranean Atmospheric Circulation During the Last Glacial Maximum
Authors: Kuhlemann J. , Rohling E. J. , Krumrei I. , Kubik P. , Ivy-Ochs S. , Kucera M.
Published: August 2008

Atmospheric circulation leaves few direct traces in the geological record, making reconstructions of this crucial element of the climate system inherently difficult. We produced a regional Mediterranean synthesis of paleo-proxy data from the sea surface to alpine altitudes. This provides a detailed observational context for change in the three-dimensional structure of atmospheric circulation between the Last Glacial Maximum (LGM, ∼23,000 to 19,000 years ago) and the present. The synthesis reveals evidence for frequent cold polar air incursions, topographically channeled into the northwestern Mediterranean. Anomalously steep vertical temperature gradients in the central Mediterranean imply local convective precipitation. We find the LGM patterns to be analogous, though amplified, to previously reconstructed phases of enhanced meridional winter circulation during the Maunder Minimum (the Little Ice Age).
Dual Origin of Tissue-Specific Progenitor Cells in
Drosophila
Tracheal Remodeling
Authors: Weaver Molly , Krasnow Mark A.
Published: August 2008

During
Drosophila
metamorphosis, most larval cells die. Pupal and adult tissues form from imaginal cells, tissue-specific progenitors allocated in embryogenesis that remain quiescent during embryonic and larval life. Clonal analysis and fate mapping of single, identified cells show that tracheal system remodeling at metamorphosis involves a classical imaginal cell population and a population of differentiated, functional larval tracheal cells that reenter the cell cycle and regain developmental potency. In late larvae, both populations are activated and proliferate, spread over and replace old branches, and diversify into various stalk and coiled tracheolar cells under control of fibroblast growth factor signaling. Thus,
Drosophila
pupal/adult tissue progenitors can arise both by early allocation of multipotent cells and late return of differentiated cells to a multipotent state, even within a single tissue.
In Situ Formation of an Oxygen-Evolving Catalyst in Neutral Water Containing Phosphate and Co
2+
Authors: Kanan Matthew W. , Nocera Daniel G.
Published: August 2008

The utilization of solar energy on a large scale requires its storage. In natural photosynthesis, energy from sunlight is used to rearrange the bonds of water to oxygen and hydrogen equivalents. The realization of artificial systems that perform “water splitting” requires catalysts that produce oxygen from water without the need for excessive driving potentials. Here we report such a catalyst that forms upon the oxidative polarization of an inert indium tin oxide electrode in phosphate-buffered water containing cobalt (II) ions. A variety of analytical techniques indicates the presence of phosphate in an approximate 1:2 ratio with cobalt in this material. The pH dependence of the catalytic activity also implicates the hydrogen phosphate ion as the proton acceptor in the oxygen-producing reaction. This catalyst not only forms in situ from earth-abundant materials but also operates in neutral water under ambient conditions.
Preparation of Boc-Protected Cinnamyl-Type Alcohols: A Comparison of the Suzuki-Miyaura Coupling, Cross-Metathesis, and Horner-Wadsworth-Emmons Approaches and Their Merit in Parallel Synthesis
Authors: Štambaský Jan , Malkov Andrei V. , Kočovský Pavel
Published: August 2008

Three synthetic strategies for the construction of tert-butyl (E)-3-arylprop-2-en-1-ol carbonates are described. Complementary approaches employing Suzuki-Miyaura coupling and cross-metathesis reaction gave moderate yields of the title compounds in one-step, both methods are suitable for high-throughput and parallel chemistry. A detailed investigation into the Suzuki-Miyaura coupling reaction is provided along with the studies on the synthesis of pinacolyl 1-(tert-butyloxycarbonyl)propenol-3-ylboronate, the key building block. Conventional synthesis of the title compounds via the Horner-Wadsworth-Emmons reaction as a key step in a three-step-one-purification protocol was optimized and the results are compared with those of the latter reactions.
The burden of fatal and non-fatal injury in rural India
Authors: Cardona M , Joshi R , Ivers R Q , Iyengar S , Chow C K , Colman S , Ramakrishna G , Dandona R , Stevenson M R , Neal B C
Published: August 2008

Background:

Little is known about the burden or causes of injury in rural villages in India.

Objective:

To examine injury-related mortality and morbidity in villages in the state of Andhra Pradesh, India.

Methods:

A verbal-autopsy-based mortality surveillance study was used to collect mortality data on all ages from residents in 45 villages in 2003–2004. In early 2005, a morbidity survey in adults was carried out using stratified random sampling in 20 villages. Participants were asked about injuries sustained in the preceding 12 months. Both fatal and non-fatal injuries were coded using classification methods derived from ICD-10.

Results:

Response rates for the mortality surveillance and morbidity survey were 98% and 81%, respectively. Injury was the second leading cause of death for all ages, responsible for 13% (95% CI 11% to 15%) of all deaths. The leading causes of fatal injury were self-harm (36%), falls (20%), and road traffic crashes (13%). Non-fatal injury was reported by 6.7% of survey participants, with the leading causes of injury being falls (38%), road traffic crashes (25%), and mechanical forces (16.1%). Falls were more common in women, with most (72.3%) attributable to slipping and tripping. Road traffic injuries were sustained mainly by men and were primarily the result of motorcycle crashes (48.8%).

Discussion:

Injury is an important contributor to disease burden in rural India. The leading causes of injury—falls, road traffic crashes, and suicides—are all preventable. It is important that effective interventions are developed and implemented to minimize the impact of injury in this region.
Analysis of 23 364 patient-generated, physician-reviewed malpractice claims from a non-tort, blame-free, national patient insurance system: lessons learned from Sweden
Authors: Pukk-Härenstam K , Ask J , Brommels M , Thor J , Penaloza R V , Gaffney F A
Published: August 2008

Context

In Sweden, patient malpractice claims are handled administratively and compensated if an independent physician review confirms patient injury resulting from medical error. Full access to all malpractice claims and hospital discharge data for the country provided a unique opportunity to assess the validity of patient claims as indicators of medical error and patient injury.

Objective

To determine: (1) the percentage of patient malpractice claims validated by independent physician review, (2) actual malpractice claims rates (claims frequency ÷ clinical volume) and (3) differences between Swedish and other national malpractice claims rates.

Design, setting and material

Swedish national malpractice claims and hospital discharge data were combined, and malpractice claims rates were determined by county, hospital, hospital department, surgical procedure, patient age and sex and compared with published studies on medical error and malpractice.

Results

From 1997 to 2004, there were 23 364 inpatient malpractice claims filed by Swedish patients treated at hospitals reporting 11 514 798 discharges. The overall claims rate, 0.20%, was stable over the period of study and was similar to that found in other tort and administrative compensation systems. Over this 8-year period, 49.5% (range 47.0–52.6%) of filed claims were judged valid and eligible for compensation. Claims rates varied significantly across hospitals; surgical specialties accounted for 46% of discharges, but 88% of claims. There were also large differences in claims rates for procedures.

Conclusions

Patient-generated malpractice claims, as collected in the Swedish malpractice insurance system and adjusted for clinical volumes, have a high validity, as assessed by standardised physician review, and provide unique new information on malpractice risks, preventable medical errors and patient injuries. Systematic collection and analysis of patient-generated quality of care complaints should be encouraged, regardless of the malpractice compensation system in use.
The effects of abiotic factors and intraspecific versus interspecific competition on the diel activity patterns of Atlantic salmon (Salmo salar) fry
Authors: Blanchet Simon , Loot Géraldine , Bernatchez Louis , Dodson Julian J.
Published: August 2008

We conducted semi-natural experiments to measure the relative contribution of various environmental factors and intraspecific and interspecific competition with an exotic invader on the daytime and crepuscular activity levels of Atlantic salmon ( Salmo salar ) fry. We demonstrated that interspecific competition with the exotic rainbow trout ( Oncorhynchus mykiss ) significantly increases the daytime activity of Atlantic salmon. The effect of intraspecific competition on the daytime activity of salmon was half that of interspecific competition. This indicates that the effect of rainbow trout was a combination of increasing density and the identity of the competitor. We also demonstrated that the effect of rainbow trout was probably the result of territorial interference between species. Moreover, we showed that water temperature simultaneously played an important role in explaining daytime activity of Atlantic salmon. During twilight, we observed no effect of competition on salmon activity, but environmental cues other than temperature (e.g., invertebrate drift, cloud cover) became significant predictors of activity. Feeding and growth rates of Atlantic salmon were not affected by the different levels of competition. Nevertheless, the exotic species may have a major impact by exposing the native species to increased risks of daytime predation.
Seasonal variation in size-dependent survival of juvenile Atlantic salmon (Salmo salar): performance of multistate capture–mark–recapture models
Authors: Letcher Benjamin H. , Horton Gregg E.
Published: August 2008

We estimated the magnitude and shape of size-dependent survival (SDS) across multiple sampling intervals for two cohorts of stream-dwelling Atlantic salmon ( Salmo salar ) juveniles using multistate capture–mark–recapture (CMR) models. Simulations designed to test the effectiveness of multistate models for detecting SDS in our system indicated that error in SDS estimates was low and that both time-invariant and time-varying SDS could be detected with sample sizes of >250, average survival  of >0.6, and average probability of capture of >0.6, except for cases of very strong SDS. In the field (N ∼750, survival 0.6–0.8 among sampling intervals, probability of capture 0.6–0.8 among sampling occasions), about one-third of the sampling intervals showed evidence of SDS, with poorer survival of larger fish during the age-2+ autumn and quadratic survival (opposite direction between cohorts) during age-1+ spring. The varying magnitude and shape of SDS among sampling intervals suggest a potential mechanism for the maintenance of the very wide observed size distributions. Estimating SDS using multistate CMR models appears complementary to established approaches, can provide estimates with low error, and can be used to detect intermittent SDS.
Taste and odour and cyanobacterial toxins: impairment, prediction, and management in the Great Lakes
Authors: Watson Susan B. , Ridal Jeff , Boyer Gregory L.
Published: August 2008

This paper reviews the issues associated with algal–cyanobacterial taste–odour (T&O) compounds and toxins in the Great Lakes. As with other remediated water bodies, the Great Lakes have undergone significant shifts in nutrient and food-web regimes and are exhibiting erratic blooms and noxious algal metabolite (NAM) outbreaks, despite reduced offshore nutrient levels. We appraise the chemistry, biota, and distribution of NAM impairments and conclude that management strategies based on lakewide monitoring and remedial action plans are often unsuccessful because they attempt NAM control through an unsustainable reliance on water treatment and broad-scale nutrient–biomass models. This approach is undermined by several factors: (i) only some species produce NAMs; (ii) different taxa show disparate patterns across nutrient and mixing regimes; (iii) nuisance species may be planktonic or benthic and located outside remedial boundaries; and (iv) species differ significantly in NAM biochemistry and release. Thus, there are no robust relationships between total plankton biomass, toxins, and T&O compounds in these and other source waters. Given the potential ecological and socioeconomic threats posed by NAM outbreaks, there is a critical need to develop a multistep management framework based on more stringent restoration targets, combining broad-scale screening and nutrient management with system and taxa-specific approaches.
A preliminary national analysis of some key characteristics of Canadian lakes
Authors: Minns Charles K. , Moore James E. , Shuter Brian J. , Mandrak Nicholas E.
Published: August 2008

Knowledge of Canada’s lakes is needed to manage environmental stresses. Lake inventory and lake feature databases were used to build a national impact assessment template and assess regional typology. There are ~910 400 lakes with area ≥ 0.1 km2(10 ha), 37% of the Earth’s total. Lake features (number of lakes by size class, maximum depth, mean–maximum depth ratio, Secchi depth, pH, and total dissolved solids) were modeled regionally by secondary watershed (SWS) using linear regression models. Lake trout ( Salvelinus namaycush ) occurrence was analyzed as a cofactor to highlight regional links between lake characteristics and aquatic biota. Significant (R2from 0.231 to 0.492) regional models were obtained using area or maximum depth, lake trout occurrence, and their cross products as covariates. Analyses of fitted SWS coefficients showed that ecozones were a better predictor of lake characteristics than primary watersheds. The national typology was consistent with previous regional assessments. The regional models were used to estimate the number, area, and volume of lake trout lakes by size class and ecozone. There are ~66 500 lake trout lakes covering ~3 510 000 km2primarily on Boreal and Taiga Shield areas. Regional lake resource models will enable national assessment of stresses such as climate change and invasive species.
Development of an NEHRP map for the Orleans suburb of Ottawa, Ontario
Authors: Motazedian Dariush , Hunter James
Published: August 2008

The average shear-wave velocity to a depth of 30 m (Vs30) has been obtained for 73 sites in the Orleans area in the northeast part of the City of Ottawa. Measurements of Vs30 were made using both ground surface reflection and refraction methods. In addition, borehole data was used to estimate Vs versus depth profiles using average Vs values assigned to distinct geological units. High values of Vs (>1500 m/s) were obtained in areas of thin surficial sediments overlying Paleozoic bedrock, and low Vs values (<180 m/s) were calculated in areas of thick late–post-glacial clay. The Vs30 values have been used to prepare an NEHRP map for the study area. Much of the suburb of Orleans is classified as NEHRP zone E, whereas the perimeter areas and some isolated central areas are classified as zones ranging from zone D to zone A. The presence of thick unconsolidated late–post-glacial sediments deposited in the Champlain Sea is the main contributing factor to the wide range of average shear-wave velocities in the study area.
A NEW APPROACH TO THE RELATIVISTIC TREATMENT OF THE FERMION–BOSON SYSTEM, BASED ON THE EXTENSION OF THE SL(2, C) GROUP
Authors: KULIKOV D. A. , TUTIK R. S.
Published: August 2008

A new technique for constructing the relativistic wave equation for the two-body system composed of the spin-1/2 and spin-0 particles is proposed. The method is based on the extension of the SL (2, C) group to the Sp (4, C) one. The obtained equation includes the interaction potentials, having both the Lorentz-vector and Lorentz-tensor structure, exactly describes the relativistic kinematics and possesses the correct one-particle limits. The comparison with results of other approaches to this problem is discussed.
THE LOVELOCK BLACK HOLES
Authors: GARRAFFO CECILIA , GIRIBET GASTON
Published: August 2008

Lovelock theory is a natural extension of Einstein theory of gravity to higher dimensions, and it is of great interest in theoretical physics as it describes a wide class of models. In particular, it describes string theory inspired ultraviolet corrections to Einstein–Hilbert action, while admits the Einstein general relativity and the so-called Chern–Simons theories of gravity as particular cases. Here, we give an introduction to the black hole solutions of Lovelock theory and analyze their most important properties. These solutions can be regarded as generalizations of the Boulware–Deser solution of Einstein–Gauss–Bonnet gravity, which we discuss in detail here. We briefly discuss some recent progress in understanding these and other solutions, like topological black holes that represent black branes of the theory, and vacuum thin-shell wormhole-like geometries that connect two different asymptotically de Sitter spaces. We also make some comments on solutions with time-like naked singularities.
POSTBUCKLING OF SHEAR-DEFORMABLE ANISOTROPIC LAMINATED CYLINDRICAL SHELLS UNDER AXIAL COMPRESSION
Authors: LI ZHI-MIN , SHEN HUI-SHEN
Published: August 2008

A postbuckling analysis is presented for a shear-deformable anisotropic laminated cylindrical shell of finite length subjected to axial compression. The material of each layer of the shell is assumed to be linearly elastic, anisotropic and fiber-reinforced. The governing equations are based on a higher order shear-deformable shell theory with the von Kármán–Donnell type of kinematic nonlinearity and including the extension/twist, extension/flexural and flexural/twist couplings. The nonlinear prebuckling deformations and initial geometric imperfections of the shell are both taken into account. A singular perturbation technique is employed to determine the buckling loads and postbuckling equilibrium paths. The numerical illustrations concern the postbuckling response of perfect and imperfect, moderately thick, anisotropic laminated cylindrical shells with different values of shell parameters and stacking sequence. The results confirm that there exists a compressive stress along with an associate shear stress and twisting when the anisotropic shell is subjected to axial compression. The postbuckling equilibrium path is unstable for the moderately thick cylindrical shell under axial compression and the shell structure is imperfection-sensitive.
STABILITY ANALYSIS OF A CIRCULAR CYLINDRICAL SHELL BY THE EQUILIBRIUM METHOD
Authors: TZENG YUH-CHYUN , CHERN CHING-CHURN
Published: August 2008

Presented herein is a formulation for the buckling of a cylindrical shell subjected to external loads using an infinitesimal shell element defined in a convenient coordinate system. The governing equation in terms of the radial deflection is derived for the element by adopting an operator. The eighth order partial differential equation derived can be applied for cylindrical shells with various boundary conditions. For illustration, simply supported cylindrical shells subjected to axial compressive forces are studied using either a one-variable or a two-variable shape function. The critical stresses obtained for the buckling of cylindrical shells are compared with those by the finite element program SAP2000. The critical stress of the cylindrical shell is similar to that of the column, in that the critical stress decreases as the thickness ratio (the ratio of R/h) or the slenderness ratio increases. Good agreement has been obtained for most of the comparative cases, while the finite element results appear to be slightly higher for some cases.
NONLINEAR TRANSIENT ANALYSIS OF A RAILWAY CONCRETE SLEEPER IN A TRACK SYSTEM
Authors: KAEWUNRUEN SAKDIRAT , REMENNIKOV ALEX M.
Published: August 2008

Railway sleepers in a track system are usually subjected to a wide range of loading conditions. A critical type of loading condition that causes cracking in the railway concrete sleepers is the dynamic transient wheel force. The transient wheel forces are often due to wheel or rail abnormalities. This paper presents a dynamic finite element model of a railway concrete sleeper in a track system, aimed at raising the consideration of dynamic effects in sleeper design. The railway concrete sleeper is modeled using the beam-on-elastic-foundation theory. Since in the actual tracks the ballast underneath does not provide any tensile resistance, the finite beam elements employed in this investigation take into account the bending and shear deformations, together with the tensionless nature of the elastic support. This paper places emphasis on the effect of the transient periods on the flexural responses of railway sleepers in track systems. Using the robust finite element software STRAND7, the finite element model of the railway concrete sleeper was previously established and validated against experimental data by the authors. The numerical analyses present the ratio between the dynamic and the static bending moment resultants, the dynamic magnification factor, of the railway concrete sleeper under different sinusoidal pulse durations.
POLARIZATION ENTANGLEMENT THROUGH NOISE
Authors: BENATTI F. , FLOREANINI R. , ROSINI P.
Published: August 2008

We show that a suitably engineered external non-Gaussian noise can entangle a class of initially separable, polarized two-photon coherent states.
FIDELITY AND ENTANGLEMENT OF A SPATIALLY EXTENDED LINEAR THREE-QUBIT REGISTER
Authors: DOLL ROLAND , WUBS MARTIJN , KOHLER SIGMUND , HÄNGGI PETER
Published: August 2008

We study decoherence of a three-qubit array coupled to substrate phonons. Assuming an initial three-qubit entangled state that would be decoherence-free for identical qubit positions, allows us to focus on non-Markovian effects of the inevitable spatial qubit separation. It turns out that the coherence is most affected when the qubits are regularly spaced. Moreover, we find that up to a constant scaling factor, two-qubit entanglement is not influenced by the presence of the third qubit, even though all qubits interact via the phonon field.
PROPERTIES OF COMPLEX CHAOS IN CONDITIONAL QUBIT DYNAMICS
Authors: KISS T. , JEX I. , ALBER G. , KOLLÁR E.
Published: August 2008

Complex chaos is specified by an iterated mapping on complex numbers. It has recently been found in the dynamics of qubits where each time step is conditioned on a measurement result on part of the system. We analyse the simplest case of one qubit dynamics with one complex parameter in some detail. We point out that two attractive cycles can exist and provide examples how the fractal like Julia set divides the areas of corresponding initial states. We show how to determine the set of parameters for which one, two or no stable fixed cycles exists and provide the numerically calculated images of the sets. The results can be relevant for the quantum state purification protocol based on the similar dynamics of two or more qubits and in general for any protocol based on conditioned nonlinear dynamics where truly chaotic behavior may occur.
ENVIRONMENTALLY INDUCED CORRECTIONS TO THE GEOMETRIC PHASE IN A TWO-LEVEL SYSTEM
Authors: LOMBARDO FERNANDO C. , VILLAR PAULA I.
Published: August 2008

We calculate the geometric phase for different open systems (spin-boson and spin-spin models). We study not only how they are corrected by the presence of the different type of environments but also discuss the appearence of decoherence effects. These should be taken into account when planning experimental setups to study the geometric phase in the nonunitary regime. We propose a model with slow decoherence rate in which the geometric phase is still modified and might be measured.
Design Features of a Mitotic Spindle: Balancing Tension and Compression at a Single Microtubule Kinetochore Interface in Budding Yeast
Authors: Bouck David C. , Joglekar Ajit P. , Bloom Kerry S.
Published: August 2008

Accurate segregation of duplicated chromosomes ensures that daughter cells get one and only one copy of each chromosome. Errors in chromosome segregation result in aneuploidy and have severe consequences on human health. Incorrect chromosome number and chromosomal instability are hallmarks of tumor cells. Hence, segregation errors are thought to be a major cause of tumorigenesis. A study of the physical mechanical basis of chromosome segregation is essential to understand the processes that can lead to errors. Tremendous progress has been made in recent years in identifying the proteins necessary for chromosome movement and segregation, but the mechanism and structure of critical force generating components and the molecular basis of centromere stiffness remain poorly understood.
Insect Vector Interactions with Persistently Transmitted Viruses
Authors: Hogenhout Saskia A. , Ammar El-Desouky , Whitfield Anna E. , Redinbaugh Margaret G.
Published: August 2008

The majority of described plant viruses are transmitted by insects of the Hemipteroid assemblage that includes aphids, whiteflies, leafhoppers, planthoppers, and thrips. In this review we highlight progress made in research on vector interactions of the more than 200 plant viruses that are transmitted by hemipteroid insects beginning a few hours or days after acquisition and for up to the life of the insect, i.e., in a persistent-circulative or persistent-propagative mode. These plant viruses move through the insect vector, from the gut lumen into the hemolymph or other tissues and finally into the salivary glands, from which these viruses are introduced back into the plant host during insect feeding. The movement and/or replication of the viruses in the insect vectors require specific interactions between virus and vector components. Recent investigations have resulted in a better understanding of the replication sites and tissue tropism of several plant viruses that propagate in insect vectors. Furthermore, virus and insect proteins involved in overcoming transmission barriers in the vector have been identified for some virus-vector combinations.
Siderophores in Fungal Physiology and Virulence
Authors: Haas Hubertus , Eisendle Martin , Turgeon B. Gillian
Published: August 2008

Maintaining the appropriate balance of iron between deficiency and toxicity requires fine-tuned control of systems for iron uptake and storage. Both among fungal species and within a single species, different systems for acquisition, storage, and regulation of iron are present. Here we discuss the most recent findings on the mechanisms involved in maintaining iron homeostasis with a focus on siderophores, low-molecular-mass iron chelators, employed for iron uptake and storage. Recently siderophores have been found to be crucial for pathogenicity of animal, as well as plant-pathogenic fungi and for maintenance of plant-fungal symbioses.
The Phenotypic Expression of a Genotype: Bringing Muddy Boots and Micropipettes Together
Authors: Hull Roger
Published: August 2008

Starting with the influences of having a father who was an agricultural plant pathologist, I sketch my career through university and research institute from field epidemiology, basic virus characterization to molecular biology. I note what I consider to be the highlights of my scientific career and the events that shaped the development of my thinking. These include secondment to teach in a university in Uganda, a sabbatical year in the University of California, Davis, where I became aware of the emerging DNA technology, studying the molecular biology of Cauliflower mosaic virus, rice tungro viruses, and Banana streak virus with the aim of developing diagnostics and approaches to control of viruses. Bringing these experiences together, I am now involved in facilitating the uptake of the application of biotechnology to crop improvement in developing countries. I conclude with some thoughts on opportunities for young plant pathologists over the next years of rapid change. As I am one of the few British scientists who have had the honor of writing such an article, I also note some of the vagaries of the British system.
Ether-a-go-go-related gene 3 is the main candidate for the E-4031-sensitive potassium current in the pacemaker interstitial cells of Cajal
Authors: White Elizabeth J. , Park Sung Jin , Foster Jane A. , Huizinga Jan D.
Published: August 2008

The interstitial cells of Cajal (ICC), as pacemaker cells of the gut, contribute to rhythmic peristalsis and muscle excitability through initiation of slow-wave activity, which subsequently actively propagates into the musculature. An E-4031-sensitive K+ current makes a critical contribution to membrane potential in ICC. This study provides novel features of this current in ICC in physiological solutions and seeks to identify the channel isoform. In situ hybridization and Kit immunohistochemistry were combined to assess ether-a-go-go-related gene (ERG) mRNA expression in ICC in mouse jejunum, while the translated message was assessed by immunofluorescence colocalization of ERG and Kit proteins. E-4031-sensitive currents in cultured ICC were studied by the whole cell patch-clamp method, with physiological K+ concentration in the bath and the pipette. In situ hybridization combined with Kit immunohistochemistry detected m-erg1 and m-erg3, but not m-erg2, mRNA in ICC. ERG3 protein was colocalized with Kit-immunoreactive ICC in jejunum sections, but ERG1 protein was visualized only in the smooth muscle cells. At physiological K+ concentration, the E-4031-sensitive outward current in ICC was different from its counterpart in cardiac and gut smooth muscle cells. In particular, inactivation upon depolarization and recovery from inactivation by hyperpolarization were modest in ICC. In summary, the E-4031-sensitive currents influence the kinetics of the pacemaker activity in ICC and contribute to maintenance of the resting membrane potential in smooth muscle cells, which together constitute a marked effect on tissue excitability. Whereas this current is mediated by ERG1 in smooth muscle, it is primarily mediated by ERG3 in ICC.
Ultrafast sodium channel block by dietary fish oil prevents dofetilide-induced ventricular arrhythmias in rabbit hearts
Authors: Dujardin K. S. , Dumotier B. , David M. , Guizy M. , Valenzuela C. , Hondeghem L. M.
Published: August 2008

Several epidemiologic and clinical studies show that following myocardial infarction, dietary supplements of ω-3 polyunsaturated fatty acids (ω3FA) reduce sudden death. Animal data show that ω3FA have antiarrhythmic properties, but their mechanisms of action require further elucidation. The effects of ω3FA supplementation were studied in female rabbits to analyze whether their antiarrhythmic effects are due to a reduction of triangulation, reverse use-dependence, instability, and dispersion (TRIaD) of the cardiac action potential (TRIaD as a measure of proarrhythmic effects). In Langendorff-perfused hearts challenged by a selective rapidly activating delayed rectifier potassium current inhibitor that has been shown to exhibit proarrhythmic effects (dofetilide; 1 to 100 nM), ω3FA pretreatment (30 days; n = 6) prolonged the plateau phase of the monophasic action potential; did not slow the terminal fast repolarization; reduced the dofetilide-induced prolongation of the action potential duration; reduced dofetilide-induced triangulation; and reduced dofetilide-induced reverse use-dependence, instability of repolarization, and dispersion. Dofetilide reduced excitability in ω3FA-pretreated hearts but not in control hearts. Whereas torsades de pointes (TdP) were observed in five out of six in control hearts, none were observed in ω3FA-pretreated hearts. Docosahexaenoic acid (DHA) inhibited the sodium current with ultrafast kinetics. Dietary ω3FA supplementation markedly reduced dofetilide-induced TRIaD and abolished dofetilide-induced TdP. Ultrafast sodium channel block by DHA may account for the antiarrhythmic protection of the dietary supplements of ω3FA against dofetilide-induced proarrhythmia observed in this animal model.
Impaired Dendritic Cell Function in Aging Leads to Defective Antitumor Immunity
Authors: Grolleau-Julius Annabelle , Harning Erin K. , Abernathy Lisa M. , Yung Raymond L.
Published: August 2008

We recently reported that bone marrow–derived dendritic cells (DC) from aged miced are less effective than their young counterparts in inducing the regression of B16-ovalbumin (OVA) melanomas. To examine the underlying mechanisms, we investigated the effect of aging on DC tumor antigen presentation and migration. Although aging does not affect the ability of DCs to present OVA peptide(257–264), DCs from aged mice are less efficient than those from young mice in stimulating OVA-specific T cells in vitro. Phenotypic analysis revealed a selective decrease in DC-specific/intracellular adhesion molecule type-3–grabbing nonintegrin (DC-SIGN) level in aged DCs. Adoptive transfer experiments showed defective in vivo DC trafficking in aging. This correlates with impaired in vitro migration and defective CCR7 signaling in response to CCL21 in aged DCs. Interestingly, vaccination of young mice using old OVA peptide(257–264)–pulsed DCs (OVA PP-DC) resulted in impaired activation of OVA-specific CD8+ T cells in vivo. Effector functions of these T cells, as determined by IFN-γ production and cytotoxic activity, were similar to those obtained from mice vaccinated with young OVA PP-DCs. A decreased influx of intratumor CD8+ T cells was also observed. Importantly, although defective in vivo migration could be restored by increasing the number of old DCs injected, the aging defect in DC tumor surveillance and OVA-specific CD8+ T-cell induction remained. Taken together, our findings suggest that defective T-cell stimulation contributes to the observed impaired DC tumor immunotherapeutic response in aging. [Cancer Res 2008;68(15):6341–9]
Phosphatidylinositol 3-Kinase Inhibition Broadly Sensitizes Glioblastoma Cells to Death Receptor– and Drug-Induced Apoptosis
Authors: Opel Daniela , Westhoff Mike-Andrew , Bender Ariane , Braun Veit , Debatin Klaus-Michael , Fulda Simone
Published: August 2008

The aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway has been reported to correlate with adverse clinical outcome in human glioblastoma in vivo. However, the question of how this survival network can be successfully targeted to restore the sensitivity of glioblastoma to apoptosis induction has not yet been answered. Here, we report that inhibition of PI3K by LY294002 broadly sensitizes wild-type and mutant PTEN glioblastoma cells to both death receptor– and chemotherapy-induced apoptosis, whereas mammalian target of rapamycin (mTOR) inhibition is not sufficient to restore apoptosis sensitivity. LY294002 significantly enhances apoptosis triggered by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), agonistic anti-CD95 antibodies, or several anticancer drugs (i.e., doxorubicin, etoposide, and vincristine) in a highly synergistic manner. In addition, LY294002 cooperates with TRAIL or doxorubicin to suppress colony formation, thus also showing a strong effect on long-term survival. Similarly, genetic knockdown of PI3K subunits p110α and/or p110β by RNA interference (RNAi) primes glioblastoma cells for TRAIL- or doxorubicin-mediated apoptosis. In contrast to PI3K inhibition, pharmacologic or genetic blockade of mTOR by RAD001 (everolimus), rapamycin, or RNAi fails to enhance TRAIL- or doxorubicin-induced apoptosis. Analysis of apoptosis pathways reveals that PI3K inhibition acts in concert with TRAIL or doxorubicin to trigger mitochondrial membrane permeabilization, caspase activation, and caspase-dependent apoptosis, which are abolished by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. Most importantly, PI3K inhibition by LY294002 sensitizes primary cultured glioblastoma cells obtained from surgical specimens to TRAIL- or chemotherapy-induced cell death. By showing that PI3K inhibition broadly primes glioblastoma cells for apoptosis, our findings provide the rationale for using PI3K inhibitors in combination regimens to enhance TRAIL- or chemotherapy-induced apoptosis in glioblastoma. [Cancer Res 2008;68(15):6271–80]
Inhibition of Metastatic Outgrowth from Single Dormant Tumor Cells by Targeting the Cytoskeleton
Authors: Barkan Dalit , Kleinman Hynda , Simmons Justin L. , Asmussen Holly , Kamaraju Anil K. , Hoenorhoff Mark J. , Liu Zi-yao , Costes Sylvain V. , Cho Edward H. , Lockett Stephen , Khanna Chand , Chambers Ann F. , Green Jeffrey E.
Published: August 2008

Metastatic breast cancer may emerge from latent tumor cells that remain dormant at disseminated sites for many years. Identifying mechanisms regulating the switch from dormancy to proliferative metastatic growth has been elusive due to the lack of experimental models of tumor cell dormancy. We characterized the in vitro growth characteristics of cells that exhibit either dormant (D2.0R, MCF-7, and K7M2AS1.46) or proliferative (D2A1, MDA-MB-231, and K7M2) metastatic behavior in vivo. Although these cells proliferate readily in two-dimensional culture, we show that when grown in three-dimensional matrix, distinct growth properties of the cells were revealed that correlate to their dormant or proliferative behavior at metastatic sites in vivo. In three-dimensional culture, cells with dormant behavior in vivo remained cell cycle arrested with elevated nuclear expression of p16 and p27. The transition from quiescence to proliferation of D2A1 cells was dependent on fibronectin production and signaling through integrin β1, leading to cytoskeletal reorganization with filamentous actin (F-actin) stress fiber formation. We show that phosphorylation of myosin light chain (MLC) by MLC kinase (MLCK) through integrin β1 is required for actin stress fiber formation and proliferative growth. Inhibition of integrin β1 or MLCK prevents transition from a quiescent to proliferative state in vitro. Inhibition of MLCK significantly reduces metastatic outgrowth in vivo. These studies show that the switch from dormancy to metastatic growth may be regulated, in part, through epigenetic signaling from the microenvironment, leading to changes in the cytoskeletal architecture of dormant cells. Targeting this process may provide therapeutic strategies for inhibition of the dormant-to-proliferative metastatic switch. [Cancer Res 2008;68(15):6241–50]
The Arf/p53 Pathway in Cancer and Aging
Authors: Matheu Ander , Maraver Antonio , Serrano Manuel
Published: August 2008

Arf and p53 are regarded among the most relevant tumor suppressors based on their ubiquitous and frequent inactivation in human cancer. The Arf/p53 pathway protects cells against several types of damage and this is the basis of its tumor suppressor activity. Interestingly, aging is a process associated with the accumulation of damage derived from chronic stresses of small magnitude. In agreement with its damage protection role, it has been recently described that the Arf/p53 pathway not only protects mammalian organisms from cancer but also from aging. However, there is also evidence that p53, under certain circumstances, such as when constitutively active, can induce aging. We discuss here the current evidence linking the Arf/p53 pathway to the process of aging and present a unified model. [Cancer Res 2008;68(15):6031–4]
Oct-3/4 Expression Reflects Tumor Progression and Regulates Motility of Bladder Cancer Cells
Authors: Chang Chao-Ching , Shieh Gia-Shing , Wu Pensee , Lin Chia-Cheng , Shiau Ai-Li , Wu Chao-Liang
Published: August 2008

Cancer and embryonic stem cells exhibit similar behavior, including immortal, undifferentiated, and invasive activities. Here, we show that in clinical samples bladder tumors with intense expression of stem cell marker Oct-3/4 (also known as POU5F1) are associated with further disease progression, greater metastasis, and shorter cancer-related survival compared with those with moderate and low expressions. Expression of Oct-3/4 is detected in human bladder transitional cell carcinoma samples and cell lines. Overexpression of Oct-3/4 enhances, whereas knockdown of Oct-3/4 expression by RNA interference reduces, migration and invasion of bladder cancer cells. Oct-3/4 can up-regulate fibroblast growth factor-4 and matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-13 production, which may contribute to tumor metastasis. Finally, we show that Ad5WS4, an E1B-55 kD–deleted adenovirus driven by the Oct-3/4 promoter, exerts potent antitumor activity against bladder cancer in a syngeneic murine tumor model. Therefore, our results implicate that Oct-3/4 may be useful as a novel tumor biological and prognostic marker and probably as a potential therapeutic target for bladder cancer. [Cancer Res 2008;68(15):6281–91]
Genomic Profiling of MicroRNA and Messenger RNA Reveals Deregulated MicroRNA Expression in Prostate Cancer
Authors: Ambs Stefan , Prueitt Robyn L. , Yi Ming , Hudson Robert S. , Howe Tiffany M. , Petrocca Fabio , Wallace Tiffany A. , Liu Chang-Gong , Volinia Stefano , Calin George A. , Yfantis Harris G. , Stephens Robert M. , Croce Carlo M.
Published: August 2008

MicroRNAs are small noncoding RNAs that regulate the expression of protein-coding genes. To evaluate the involvement of microRNAs in prostate cancer, we determined genome-wide expression of microRNAs and mRNAs in 60 primary prostate tumors and 16 nontumor prostate tissues. The mRNA analysis revealed that key components of microRNA processing and several microRNA host genes, e.g., MCM7 and C9orf5, were significantly up-regulated in prostate tumors. Consistent with these findings, tumors expressed the miR-106b-25 cluster, which maps to intron 13 of MCM7, and miR-32, which maps to intron 14 of C9orf5, at significantly higher levels than nontumor prostate. The expression levels of other microRNAs, including a number of miR-106b-25 cluster homologues, were also altered in prostate tumors. Additional differences in microRNA abundance were found between organ-confined tumors and those with extraprostatic disease extension. Lastly, we found evidence that some microRNAs are androgen-regulated and that tumor microRNAs influence transcript abundance of protein-coding target genes in the cancerous prostate. In cell culture, E2F1 and p21/WAF1 were identified as targets of miR-106b, Bim of miR-32, and exportin-6 and protein tyrosine kinase 9 of miR-1. In summary, microRNA expression becomes altered with the development and progression of prostate cancer. Some of these microRNAs regulate the expression of cancer-related genes in prostate cancer cells. [Cancer Res 2008;68(15):6162–70]
Reciprocal Relationship betweenO6-Methylguanine-DNA Methyltransferase P140K Expression Level and Chemoprotection of Hematopoietic Stem Cells
Authors: Milsom Michael D. , Jerabek-Willemsen Moran , Harris Chad E. , Schambach Axel , Broun Emily , Bailey Jeff , Jansen Michael , Schleimer David , Nattamai Kalpana , Wilhelm Jamie , Watson Amanda , Geiger Hartmut , Margison Geoffrey P. , Moritz Thomas , Baum Christopher , Thomale Jürgen , Williams David A.
Published: August 2008

Retroviral-mediated delivery of the P140K mutant O6-methylguanine-DNA methyltransferase (MGMTP140K) into hematopoietic stem cells (HSC) has been proposed as a means to protect against dose-limiting myelosuppressive toxicity ensuing from chemotherapy combining O6-alkylating agents (e.g., temozolomide) with pseudosubstrate inhibitors (such as O6-benzylguanine) of endogenous MGMT. Because detoxification of O6-alkylguanine adducts by MGMT is stoichiometric, it has been suggested that higher levels of MGMT will afford better protection to gene-modified HSC. However, accomplishing this goal would potentially be in conflict with current efforts in the gene therapy field, which aim to incorporate weaker enhancer elements to avoid insertional mutagenesis. Using a panel of self-inactivating gamma-retroviral vectors that express a range of MGMTP140K activity, we show that MGMTP140K expression by weaker cellular promoter/enhancers is sufficient for in vivo protection/selection following treatment with O6-benzylguanine/temozolomide. Conversely, the highest level of MGMTP140K activity did not promote efficient in vivo protection despite mediating detoxification of O6-alkylguanine adducts. Moreover, very high expression of MGMTP140K was associated with a competitive repopulation defect in HSC. Mechanistically, we show a defect in cellular proliferation associated with elevated expression of MGMTP140K, but not wild-type MGMT. This proliferation defect correlated with increased localization of MGMTP140K to the nucleus/chromatin. These data show that very high expression of MGMTP140K has a deleterious effect on cellular proliferation, engraftment, and chemoprotection. These studies have direct translational relevance to ongoing clinical gene therapy studies using MGMTP140K, whereas the novel mechanistic findings are relevant to the basic understanding of DNA repair by MGMT. [Cancer Res 2008;68(15):6171–80]
Long-term Dietary Cadmium Intake and Postmenopausal Endometrial Cancer Incidence: A Population-Based Prospective Cohort Study
Authors: Åkesson Agneta , Julin Bettina , Wolk Alicja
Published: August 2008

Environmental pollutants mimicking the effects of estrogen are suggested to contribute to the high incidence of hormone-related cancers, but supporting data are sparse. A potent estrogen-like activity of the pollutant cadmium, mediated via the estrogen receptor-α, has been shown in vivo. We prospectively examined the association between cadmium exposure and incidence of postmenopausal endometrial cancer. The Swedish Mammography Cohort is a population-based prospective cohort of 30,210 postmenopausal women free of cancer diagnose at baseline (1987) and who completed a food frequency questionnaire at baseline and in 1997. We estimated the dietary cadmium intake based on the questionnaire data and the cadmium content in all foods. During 16.0 years (484,274 person-years) of follow-up between the baseline and mid-2006, we ascertained 378 incident cases of endometrioid adenocarcinoma. The average estimated dietary cadmium intake was 15 μg/day (80% from cereals and vegetables). Cadmium intake was statistically significantly associated with increased risk of endometrial cancer in all women; the multivariate relative risk (RR) was 1.39 [95% confidence interval (CI), 1.04–1.86; Ptrend = 0.019], comparing highest tertile versus lowest. Among never-smoking women with body mass index (BMI) of <27 kg/m2, the RR was 1.86 (95% CI, 1.13–3.08; Ptrend = 0.009). We observed a 2.9-fold increased risk (95% CI, 1.05–7.79) associated with long-term cadmium intake consistently above the median at both baseline 1987 and in 1997 in never-smoking women with low bioavailable estrogen (BMI of <27 kg/m2 and nonusers of postmenopausal hormones). Our results support the hypothesis that cadmium may exert estrogenic effects and thereby increase the risk of hormone-related cancers. [Cancer Res 2008;68(15):6435–41]