bluuebunny/crossref_metadata_2025 huggingface dataset:
Radon and Asbestos: A Study of Agenda Setting and Causal Stories
Authors: Scheberle Denise
Published: September 2005

Employing Kingdon's model of agenda setting (1984) and Stone's notion of causal stories (1989), this article examines how public concerns about radon and asbestos reached the congressional agenda. Several conclusions about agenda setting and causal stories are offered: First, scientific consensus about health risks was a necessary, but not sufficient, condition for radon and asbestos to achieve agenda status. Second, media involvement and the presence of policy entrepreneurs were critical factors in the agenda setting process. Third, differing incentives within the policy stream (for radon) and the political stream (for asbestos) affected the speed by which agenda setting occurred, as well as the shaping of formal policy.
Toward a Research and Training Capacity in Disability Policy
Authors: DeJong Gerben
Published: September 2005

This paper describes the research and training infrastructure that is needed if disability policy is to flourish as a viable field of inquiry. Due to its interdisciplinary character, no one discipline or academic field has adopted disability policy as its own, and as a result, has not developed the infrastructure needed to give disability policy the visibility and focus it deserves. This paper explores the reasons for the field's underdevelopment and proposes several developmental steps essential to its future success, Inparticular, the paper proposes (a) an academic home for disability policy, (b) the development of curriculum, (c) graduate and post‐doctoral research opportunities, (d) recruitment of students with disabilities, and (e) the establishment of policy research centers. The paper notes achievements already in place, such as a policy journal and the development of professional organizations. Finally, the paper notes the important role of both private and public funding.
The Future of Disability Policy as a Field of Research
Authors: Fox Daniel M.
Published: September 2005

Although the opportunities for research in disability policy are increasing, they remain considerably fewer than in adjacent areas, notably in policy for health, social services, and education. This article explores the new salience of research on disability policy, describes why its importance is likely to increase, and then explores some issues that reveal the under development of the field.
Crossover of Ba(Ti,Y)O3Solid Solutions to Ba3Ti2YO8.5–BaTiO3Composites and their Dielectric Properties
Authors: Zhi Jing , Yu Zhi , Ang Chen
Published: September 2005

Ceramic samples with the nominal composition (1−x) BaTiO3+xBa3Ti2YO8.5(x=0−0.535) were prepared by the mixed oxide method. X‐ray diffraction (XRD) analysis shows that the materials are of single phase with a cubic symmetry asx≤0.16. The compositions of the solid solutions (x≤0.16) can be expressed equivalently as Ba(Ti1−yYy)O3−δ(y≤0.122,y=x/(1+2x)). Forx>0.16, the materials are diphasic composites consisting of Ba(Ti1−yYy)O3(y=0.122) and Ba3Ti2YO8.5. The microstructure observation by scanning electron microscopy supports the XRD result. The dielectric behavior and phase transitions of the solid solutions (x≤0.16) vary with different Y concentrations. The dielectric constant of the composites (x>0.16) follows approximately the Lichteneker relation in a wide temperature range.
Fabrication of Open‐Cell, Microcellular Silicon Carbide Ceramics by Carbothermal Reduction
Authors: Kim Young‐Wook , Kim Shin‐Han , Song In‐Hyuck , Kim Hai‐Doo , Park Chul B.
Published: September 2005

A novel processing route for developing open‐cell, microcellular SiC ceramics has been developed. The strategy adopted for making microcellular SiC ceramics involved the following: (i) fabricating a formed body from a mixture of polysiloxane, phenol resin (used as a carbon source), polymer microbeads (used as sacrificial templates), and Al2O3–Y2O3 (an optional sintering additive); (ii) cross‐linking the polysiloxane in the formed body; (iii) transforming the polysiloxane and phenol resin by pyrolysis into silicon oxycarbide and C, respectively; and (iv) synthesizing SiC by carbothermal reduction. By controlling the microbead and additive contents, it was possible to adjust the porosity so that it ranged from 60% to 95%.
Executive functioning in depressed patients with suicidal ideation
Authors: Marzuk P. M. , Hartwell N. , Leon A. C. , Portera L.
Published: September 2005

Objective:  Suicidal thinking has been associated with cognitive rigidity, however, not all depressed patients contemplate suicide. Therefore, we hypothesized that compared with depressed subjects without suicidal ideation, depressed individuals with suicidal ideation would display poorer performance on measures of executive functioning that involve mental flexibility.

Method:  In‐patients with a current major depressive episode who had no current suicidal ideation (n = 28) were compared with those who had current suicidal ideation (n = 25) on measures of executive functioning and two neurocognitive tests that predominantly assess non‐frontal regions.

Results:  Compared with non‐suicidal depressed patients, depressed suicidal patients performed significantly worse on several measures of executive functioning after controlling for age, IQ, severity of depression and prior suicide attempts. The two groups performed similarly on tests that predominantly assess non‐frontal regions.

Conclusion:  Depressed individuals contemplating suicide have cognitive rigidity, which does not appear to be a global brain dysfunction. Suicidal mental states may result from dysfunctional executive decision‐making that is associated with the frontal lobe.
Mental and physical complaints in thyroid disorders in the general population
Authors: Grabe H. J. , Völzke H. , Lüdemann J. , Wolff B. , Schwahn C. , John U. , Meng W. , Freyberger H. J.
Published: September 2005

Objective: To test the hypothesis that untreated overt and subclinical thyroid disorders and autoimmune thyroiditis (AIT) are associated with mental and physical complaints in the general population.

Method: A total of 3790 participants from the Study of Health in Pomerania (SHIP) with no known thyroid disorders were analyzed concerning their thyroid function (TSH, FT3, FT4), autoantibodies (TPO‐Ab), their thyroid structure and size and their mental and physical complaints (Zerssen Complaint Scale).

Results: Overt hyperthyroidism (prevalence: 0.4%) was associated with a significantly lower total complaint‐score than euthyroid subjects. Subjects with overt hypothyroidism (0.5%), subclinical hypothyroidism (0.7%), or subclinical hyperthyroidism (1.6%) were not different from controls in their total complaints. Females with AIT showed higher scores of tachycardia and anxiety independent from their thyroid function.

Conclusion: In non‐patient samples, hyperthyroidism is associated with positive effects on self‐rated mental and physical health. AIT may be associated with negative effects on health also in euthyroid subjects.
Quantification of the risk of poststroke depression: the Italian multicenter observational study DESTRO
Authors: Paolucci S. , Gandolfo C. , Provinciali L. , Torta R. , Sommacal S. ,   (on behalf of DESTRO Study Group), Toso V.
Published: September 2005

Objective:  The Italian multicenter observational study depression in stroke (DESTRO) aimed to identify risk factors for poststroke depression (PSD) and quantify the likelihood of it arising in various categories of patients.

Method:  Mood evaluation was performed in 1064 consecutive stroke patients by means of Beck Depression Inventory and Visual Analog Mood Scale. Depressive symptoms were classified using the DSM‐IV and revised WHO criteria for depression in the course of a neurological disorder.

Results:  Poststroke depression was seen in 36% of the survivors, with dysthymia by far the predominant form (80.7%). Female sex, disability, previous cerebrovascular or depressive episodes were significantly associated with an increased risk of depression. Combinations of these factors raised the risk of PSD exponentially, from 24.3 to 89.1%. The site of the stroke did not come into the uni‐ or multivariate analysis.

Conclusion.:  At admission, it is possible to predict the likelihood of PSD and quantify the relative risk.
Neuropsychiatric symptoms in patients with multiple sclerosis
Authors: Figved N. , Klevan G. , Myhr K. M. , Glad S. , Nyland H. , Larsen J. P. , Harboe E. , Omdal R. , Aarsland D.
Published: September 2005

Objective:  To explore the range of psychiatric symptoms in patients with multiple sclerosis (MS) and their association with neurological disability.

Method:  Patients diagnosed with MS during 1998–2000 in Rogaland and Hordaland counties, western Norway, were included. Psychiatric symptoms were assessed by the Neuropsychiatric Inventory (NPI). Patients with systemic lupus erythematosus (SLE) served as controls.

Results:  Eighty‐six of 93 eligible MS patients were included, and 80% showed at least one psychiatric symptom. The most frequent symptoms were depression (59%), sleep disturbance (48%), irritability/emotional lability (42%), and apathy (31%). Depression was associated with higher disability score. MS patients showed significantly higher NPI irritability score (P = 0.002), appetite disturbance score (P < 0.001), and apathy score (P = 0.01) than SLE patients.

Conclusion:  Neuropsychiatric symptoms occur frequently in patients with MS. Irritability and apathy are independent of disability and chronic disease and represent unique disease manifestations.
Analysis of bone–implant interaction phenomena by using a numerical approach
Authors: Natali Arturo N. , Pavan Piero G. , Ruggero Andrea L.
Published: September 2005

Objectives: The purpose of the present work is to investigate the interaction phenomena occurring between endosseus dental implants and peri‐implant bone tissue.

Material and methods: Detailed finite element models are adopted in order to analyze the actual behavior of bone–implant system depending on implant and anatomical site configuration and loading conditions. Different types of titanium dental implants are considered. Implant finite element models are obtained through a reverse engineering procedure and adopting specific software for the reconstruction of geometrical configuration. Anatomical sites are modeled starting from computerized tomography data, according to specific image processing procedures.

Results: Occlusal static forces are applied to the implants and their effects on the bone–implant interface region are evaluated. The influence of several parameters, such as morphometry of anatomical site or loading condition, on the biomechanical response of bone–implant system is considered.

Conclusions: The evaluation of the biomechanical response of implant–bone compound necessarily requires the adoption of accurate numerical models, accounting for the complex geometry of threaded implants, as well as of the anatomy of the patients to be able to provide for reliable results pertaining to stress/strain path on peri‐implant bone tissue.
Permucosal implants combined with iliac crest onlay grafts used in extreme atrophy of the mandible: long‐term results of a prospective study
Authors: Verhoeven Jan Willem , Cune Marco Stephan , Ruijter Jan
Published: September 2005

Abstract: Thirteen patients received an onlay bone‐graft augmentation to their severely atrophic mandible in combination with simultaneous implant insertion. This treatment modality was studied in a long‐term prospective clinical and radiographic study. A reproducible measurement method, consisting of oblique lateral cephalometric radiographs, in combination with an image analysis system, was used to accurately assess the graft resorption rate. On average, 51% (95% confidence interval 42–61%) of the grafted bone height remained after 10–11 years. Resorption of the graft occurred mainly during the first years and showed a marked degree of individual variance. In the following years, the resorption rate followed a predictable pattern in most of our patients. Ventral and dorsal sites exhibited a similar degree of resorption. Peri‐implantitis occurred in nine patients. Ten muco‐gingival surgical interventions were necessary in four of these nine patients. No implants were lost and 12 patients indicated that they were satisfied. It is concluded that the described surgical technique should be used on stringent indication only, and alternative techniques are discussed.
Sequential compound exocytosis of large dense‐core vesicles in PC12 cells studied with TEPIQ (two‐photon extracellular polar‐tracer imaging‐based quantification) analysis
Authors: Kishimoto Takuya , Liu Ting‐Ting , Hatakeyama Hiroyasu , Nemoto Tomomi , Takahashi Noriko , Kasai Haruo
Published: September 2005

We investigated exocytosis of PC12 cells using two‐photon excitation imaging and extracellular polar tracers (TEP imaging) at the basal region of PC12 cells adjacent to the glass cover slip. TEPIQ (two‐photon extracellular polar‐tracer imaging‐based quantification) analysis revealed that most exocytosis was mediated by large dense‐core vesicles (LVs) with a mean diameter of 220 nm, and that exocytosis of LVs occurred slowly with a mean latency of ∼7 s even though exocytosis was induced with large increases in cytosolic Ca2+ concentration by uncaging of a caged‐Ca2+ compound. We also found that 97% of exocytic LVs remained poised at the plasma membrane, 72% maintained their fusion pores in an open conformation for more than 30 s, and 76% triggered sequential compound exocytosis of vesicles that were located deeper in the cytosol. Sequential compound exocytosis by PC12 cells was confirmed by electron microscopic investigation with photoconversion of diaminobenzidine by FM1‐43 (a polar membrane tracer). Our data suggest that pre‐stimulus docking of LVs to the plasma membrane does not necessarily hasten the fusion reaction, while docking and resulting stability of exocytic LVs facilitates sequential compound exocytosis, and thereby allowing mobilization of deep vesicles.
Transient Thermomechanical Simulation of Laser Hammering in Optoelectronic Package Manufacturing
Authors: Ting Ben , Manno Vincent P.
Published: September 2005

Laser hammering (LH) is a process used in the manufacturing of butterfly optoelectronic packages to correct laser-to-fiber misalignment that occurs when the semiconductor lasers are welded in place. High-power, precisely positioned pulsed lasers are used in LH to induce deformation of the fiber support housing to, in turn, induce realignment. A thermomechanical modeling study of LH is reported in this paper, which focuses on the degree to which a steady-state model can predict the asymptotic state of a transient response subjected to a periodic laser excitation. A baseline, two-dimensional fiber mounting/ferrule geometry is employed in a finite element analysis simulation case study. Various laser wave forms are applied to focus spot location sizes of 50 and 200μm over a range of applied heat fluxes (10-1000W∕mm2). Effects of laser energy deposition location, as well as the use of multiple lasers, are also studied. The results show that the steady-state solution is in good agreement with the asymptotic transient response for horizontal fiber displacement and fiber temperature. The laser focus spot surface temperature predictions are also found to be in reasonable agreement. However, the vertical fiber displacement tends to be overpredicted by the steady-state solution, sometimes by as much as an order of magnitude. The causes, both physical and computational, of this disagreement are discussed.
Modeling of Interfacial Delamination in Plastic IC Packages Under Hygrothermal Loading
Authors: Tay Andrew A. O.
Published: September 2005

Ever since the discovery of the “popcorn” failure of plastic-encapsulated integrated-circuit (IC) packages in the 1980s, much effort has been devoted to understanding the failure mechanism and modeling it. It has been established that such failures are due to the combined effects of thermal stresses and hygrostresses that arise during solder reflow of plastic IC packages. In recent years interfacial fracture mechanics has been applied successfully to the analysis of delamination or crack propagation along interfaces in plastic IC packages. This paper presents some fundamental aspects of interfacial fracture mechanics and describes some of the numerical techniques available for calculating the strain energy release rate and mode mixity at the tips of cracks at interfaces in plastic-encapsulated IC packages. A method of calculating the combined effects of thermal stress and hygrostress on the energy release rate is also described. Some case studies are presented that illustrate how the techniques are applied to predicting delaminaton in IC packages. Some experimental verification of predictive methodology is also presented.
Viscoelastic Characterization of Low-Dielectric Constant SiLK Films Using Nanoindentation in Combination With Finite Element Modeling
Authors: den Toonder J. M. J. , Ramone Y. , van Dijken A. R. , Beijer J. G. J. , Zhang G. Q.
Published: September 2005

SiLK is a polymer material developed for use as a thin-film dielectric in the interconnect structure of high-density integrated circuits. Among others, its thermomechanical properties play a dominant role for the integrity and reliability of the interconnect during processing, testing, and use. Being a polymer, SiLK may show viscoelastic (time-dependent) behavior. In this paper, we use nanoindentation techniques in combination with analytical and finite element modeling (FEM) to determine the viscoelastic properties of a thin SiLK film on a silicon substrate. Indentation-creep experiments show that this SiLK film indeed responds in a viscoelastic way. This may be caused by the non fully cross-linked test samples prepared using nonstandard processing. Using the FEM simulation, we find that the behavior of this thin SiLK film can be described with a linear viscoelastic model up to the characteristic stress and strain levels of approximately 200MPa and 3%, respectively. For higher stress and strain levels, the response becomes nonlinear. The results are validated with independent indentation load-unload measurements.
Multiscale Mechanics in Microelectronics: A Paradigm in Miniaturization
Authors: Geers M. G. D. , Kouznetsova V. , Brekelmans W. A. M.
Published: September 2005

This paper reviews the inherent change in the observed mechanical behavior of electronic components, structures, and multimaterials as a result of the ongoing miniaturization. In general, the size of microstructures is no longer negligible with respect to the component size in micro and submicron applications. Additionally, surface layers start to play a more prominent role in the mechanical response. Microstructural effects, macroscopically triggered gradient effects, and surface effects jointly appear and constitute the various size effects that can be observed. Classical continuum mechanics theories fail to describe these phenomena, and higher-order multiscale theories are required to arrive at an appropriate prediction of the mechanical behavior of miniaturized structures.
An Experimental Study of Transient Heat Transfer From Discrete Heat Sources in Water Cooled Vertical Rectangular Channel
Authors: Bhowmik H. , Tou K. W.
Published: September 2005

Experiments are performed to study the single-phase transient forced convection heat transfer on an array of 4×1 flush-mounted discrete heat sources in a vertical rectangular channel during the pump-on transient operation. Water is the coolant media and the flow covers the wide range of laminar flow regime with Reynolds number, based on heat source length, from 800 to 2625. The applied uniform heat flux ranges from 1 to 7W∕cm2. For flush-mounted heaters the heat transfer characteristics are studied and correlations are presented for four chips as well as for overall data in the transient regime. The experimental results indicate that the heat transfer coefficient is affected strongly by the number of chips and the Reynolds number. Finally the general impacts of heat source protrusions (B=1, 2 mm) on heat transfer behavior of four chips are investigated by comparing the results obtained from flush-mounted (B=0) heaters.
A Multidisciplinary Design and Optimization Methodology for Ball Grid Array Packages Using Artificial Neural Networks
Authors: Hadim Hamid , Suwa Tohru
Published: September 2005

A systematic multidisciplinary electronics packaging design and optimization methodology, which takes into account the complexity of multiple design trade-offs, operated in conjunction with the artificial neural networks (ANNs) technique is presented. To demonstrate its capability, this method is applied to a plastic ball grid array package design. Multidisciplinary criteria including thermal, structural, electromagnetic leakage, and cost are optimized simultaneously using key design parameters as variables. A simplified routability criterion is also considered as a constraint. ANNs are used for thermal and structural performance predictions which resulted in large reduction in computational time. The present methodology is able to provide the designers a tool for systematic evaluation of the design trade-offs which are represented in the objective function. This methodology can be applied to any electronic product design at any packaging level from the system level to the chip level.
Achieving Stability of Lipopolysaccharide-Induced NF-κB Activation
Authors: Covert Markus W. , Leung Thomas H. , Gaston Jahlionais E. , Baltimore David
Published: September 2005

The activation dynamics of the transcription factor NF-κB exhibit damped oscillatory behavior when cells are stimulated by tumor necrosis factor–α (TNFα) but stable behavior when stimulated by lipopolysaccharide (LPS). LPS binding to Toll-like receptor 4 (TLR4) causes activation of NF-κB that requires two downstream pathways, each of which when isolated exhibits damped oscillatory behavior. Computational modeling of the two TLR4-dependent signaling pathways suggests that one pathway requires a time delay to establish early anti-phase activation of NF-κB by the two pathways. The MyD88-independent pathway required Inferon regulatory factor 3–dependent expression of TNFα to activate NF-κB, and the time required for TNFα synthesis established the delay.
Influence of the Atlantic Subpolar Gyre on the Thermohaline Circulation
Authors: Hátún Hjálmar , Sandø Anne Britt , Drange Helge , Hansen Bogi , Valdimarsson Heðinn
Published: September 2005

During the past decade, record-high salinities have been observed in the Atlantic Inflow to the Nordic Seas and the Arctic Ocean, which feeds the North Atlantic thermohaline circulation (THC). This may counteract the observed long-term increase in freshwater supply to the area and tend to stabilize the North Atlantic THC. Here we show that the salinity of the Atlantic Inflow is tightly linked to the dynamics of the North Atlantic subpolar gyre circulation. Therefore, when assessing the future of the North Atlantic THC, it is essential that the dynamics of the subpolar gyre and its influence on the salinity are taken into account.
Cpx Signal Transduction Is Influenced by a Conserved N-Terminal Domain in the Novel Inhibitor CpxP and the Periplasmic Protease DegP
Authors: Buelow Daelynn R. , Raivio Tracy L.
Published: September 2005

In
Escherichia coli
, envelope stress can be overcome by three different envelope stress responses: the σ
E
stress response and the Bae and Cpx two-component systems. The Cpx envelope stress response is controlled by the sensor kinase CpxA, the response regulator CpxR, and the novel periplasmic protein CpxP. CpxP mediates feedback inhibition of the Cpx pathway through a hypothetical interaction with the sensing domain of CpxA. No informative homologues of CpxP are known, and thus it is unclear how CpxP exerts this inhibition. Here, we identified six
cpxP
loss-of-function mutations using a CpxP-β-lactamase (CpxP′-′Bla) translational fusion construct. These loss-of-function mutations identified a highly conserved, predicted α-helix in the N-terminal domain of CpxP that affects both the function and the stability of the protein. In the course of this study, we also found that CpxP′-′Bla stability is differentially controlled by the periplasmic protease DegP in response to inducing cues and that mutation of
degP
diminishes Cpx pathway activity. We propose that the N-terminal α-helix is an important functional domain for inhibition of the Cpx pathway and that CpxP is subject to DegP-dependent proteolysis.
Tn5386, a Novel Tn916-Like Mobile Element inEnterococcus faeciumD344R That Interacts with Tn916To Yield a Large Genomic Deletion
Authors: Rice Louis B. , Carias Lenore L. , Marshall Steven , Rudin Susan D. , Hutton-Thomas Rebecca
Published: September 2005

We describe Tn5386, a novel ca.-29-kb Tn916-like mobile element discovered to occur in ampicillin-resistant, Tn916-containingEnterococcus faeciumD344R. PCR amplification experiments after overnight growth with or without tetracycline revealed “joint” regions of circularized Tn5386composed of 6-bp sequences linking different transposon termini. In one case (no tetracycline), the termini were consistent with those derived by target site analysis of the integrated element. In the other case, the termini were virtually identical in distance from the integrase binding regions, as seen with Tn916. These data are consistent with a model in which one PCR product results from the action of Tn5386integrase, whereas the other results from the action of the Tn916integrase on Tn5386. Spontaneous conversion of D344R to an ampicillin-susceptible phenotype (D344SRF) was associated with a 178-kb deletion extending from the left end of Tn5386to the left end of Tn916. Examination of the Tn5386junction after the large deletion event suggests that the deletion resulted from an interaction between the nonintegrase ends of Tn5386and Tn916. The terminus of Tn5386identified in this reaction suggested that it may have resulted from the activity of the Tn916integrase (IntTn916). The “joint” of the circular element resulting from this excision was amplifiable from D344R, the sequence of which revealed a heteroduplex consistent with IntTn916-mediated excision. In contrast, Tn5386joints amplified from ampicillin-susceptible D344SRF revealed ends consistent with Tn5386integrase activity, reflecting the absence of Tn916from this strain. Tn5386represents a new member of the Tn916transposon family. Our data suggest that excision of Tn5386can be catalyzed by the Tn916integrase and that large genomic deletions may result from the interaction between these heterologous elements.
Inactivation of Protein Translocation by Cold-Sensitive Mutations in the
yajC
-
secDF
Operon
Authors: Nouwen Nico , Driessen Arnold J. M.
Published: September 2005

Most mutations in the
yajC
-
secDF
operon identified via genetic screens confer a cold-sensitive growth phenotype. Here we report that two of these mutations confer this cold-sensitive phenotype by inactivating the SecDF-YajC complex in protein translocation.
LEPTON FLAVOR VIOLATING SIGNALS OF THE NEUTRAL SCALARS FROM TOPCOLOR SCENARIO AT HADRON COLLIDERS
Authors: YUE CHONG-XING , YU DONG-QI , ZONG ZHENGJUN
Published: September 2005

In the context of topcolor-assisted techicolor (TC2) models, we study the lepton flavor violating (LFV) signals of the neutral scalars (the top-pion and the top-Higgs boson) at hadron colliders via considering their contribution to the processes [Formula: see text] (l = μ or e). We find that the LFV signals of these new particles cannot be detected at the Tevatron with [Formula: see text], while might be observable in the future LHC with [Formula: see text].
ENTANGLED MARKOV CHAINS GENERATED BY SYMMETRIC CHANNELS
Authors: MIYADERA TAKAYUKI
Published: September 2005

A notion of entangled Markov chain was introduced by Accardi and Fidaleo in the context of quantum random walk. They proved that, in the finite-dimensional case, the corresponding states have vanishing entropy density, but they did not prove that they are entangled. In this note this entropy result is extended to the infinite-dimensional case under the assumption of finite speed of hopping. Then the entanglement problem is discussed for spin-1/2, entangled Markov chains generated by a binary symmetric channel with hopping probability 1-q. The von Neumann entropy of these states, restricted on a sublattice is explicitly calculated and shown to be independent of the size of the sublattice. This is a new, purely quantum, phenomenon.

Finally the entanglement property between the sublattices [Formula: see text] and [Formula: see text] is investigated using the PPT criterium. It turns out that, for q≠ 0, 1, ½ the states are non-separable, thus truly entangled, while for q = 0, 1, ½, they are separable.
VACCINE-DERIVED POLIOVIRUSES AND THE ENDGAME STRATEGY FOR GLOBAL POLIO ERADICATION
Authors: Kew Olen M. , Sutter Roland W. , de Gourville Esther M. , Dowdle Walter R. , Pallansch Mark A.
Published: September 2005

As the global eradication of wild poliovirus nears, the World Health Organization (WHO) is addressing challenges unprecedented in public health. The live, attenuated oral poliovirus vaccine (OPV), used for more than four decades to interrupt poliovirus transmission, and the vaccine of choice for developing countries, is genetically unstable. Reversion of the small number of substitutions conferring the attenuated phenotype frequently occurs during OPV replication in humans and is the underlying cause of the rare cases of vaccine-associated paralytic poliomyelitis (VAPP) in OPV recipients and their close contacts. Whereas VAPP has long been recognized, two other adverse events have been identified more recently: (a) long-term excretion of highly evolved vaccine-derived polioviruses (VDPVs) in persons with primary immunodeficiencies, and (b) polio outbreaks associated with circulating VDPVs in areas with low rates of OPV coverage. Developing a posteradication strategy to minimize the risks of VDPV emergence and spread has become an urgent WHO priority.
THE ORIGINS OF NEW PANDEMIC VIRUSES: The Acquisition of New Host Ranges by Canine Parvovirus and Influenza A Viruses
Authors: Parrish Colin R. , Kawaoka Yoshihiro
Published: September 2005

Transfer of viruses between hosts to create a new self-sustaining epidemic is rare; however, those new viruses can cause severe outbreaks. Examples of such viruses include three pandemic human influenza A viruses and canine parvovirus in dogs. In each case one virus made the original transfer and spread worldwide, and then further adaptation resulted in the emergence of variants worldwide. For the influenza viruses several changes were required for growth and spread between humans, and the emergence of human H2N2 and H3N2 strains in 1957 and 1968 involved the acquisition of three or two new genomic segments, respectively. Adaptation to humans involved several viral genes including the hemagglutinin, the neuraminidase, and the replication proteins. The canine adaptation of the parvoviruses involved capsid protein changes altering the recognition of the host transferrin receptors, allowing canine transferrin receptor binding and its use as a receptor for cell infection.
REGULATION OF BACTERIAL GENE EXPRESSION BY RIBOSWITCHES
Authors: Winkler Wade C. , Breaker Ronald R.
Published: September 2005

Riboswitches are structured domains that usually reside in the noncoding regions of mRNAs, where they bind metabolites and control gene expression. Like their protein counterparts, these RNA gene control elements form highly specific binding pockets for the target metabolite and undergo allosteric changes in structure. Numerous classes of riboswitches are present in bacteria and they comprise a common and robust metabolite-sensing system.
TRANSLATIONAL REGULATION OFGCN4AND THE GENERAL AMINO ACID CONTROL OF YEAST
Authors: Hinnebusch Alan G.
Published: September 2005

Cells reprogram gene expression in response to environmental changes by mobilizing transcriptional activators. The activator protein Gcn4 of the yeast Saccharomyces cerevisiae is regulated by an intricate translational control mechanism, which is the primary focus of this review, and also by the modulation of its stability in response to nutrient availability. Translation of GCN4 mRNA is derepressed in amino acid-deprived cells, leading to transcriptional induction of nearly all genes encoding amino acid biosynthetic enzymes. The trans-acting proteins that control GCN4 translation have general functions in the initiation of protein synthesis, or regulate the activities of initiation factors, so that the molecular events that induce GCN4 translation also reduce the rate of general protein synthesis. This dual regulatory response enables cells to limit their consumption of amino acids while diverting resources into amino acid biosynthesis in nutrient-poor environments. Remarkably, mammalian cells use the same strategy to downregulate protein synthesis while inducing transcriptional activators of stress-response genes under various stressful conditions, including amino acid starvation.
Effects of tyrosine phosphorylation of cortactin on podosome formation in A7r5 vascular smooth muscle cells
Authors: Zhou Shutang , Webb Bradley A. , Eves Robert , Mak Alan S.
Published: September 2005

Cortactin, a predominant substrate of Src family kinases, plays an important role in Arp2/3-dependent actin polymerization in lamellipodia and membrane ruffles and was recently shown to be enriched in podosomes induced by either c-Src or phorbol ester. However, the mechanisms by which cortactin regulates podosome formation have not been determined. In this study, we showed that cortactin is required for podosome formation, using siRNA knockdown of cortactin expression in smooth muscle A7r5 cells. Treatment with phorbol ester or expression of constitutively active c-Src induced genesis of cortactin-containing podosomes as well as increase in phosphorylation of cortactin at Y421 and Y466, the Src phosphorylation sites on cortactin. The Src kinase inhibitor SU-6656 significantly inhibited formation of podosomes induced by phorbol ester and phosphorylation of cortactin, whereas PKCα inhibitor did not affect podosome formation in c-Src-transfected cells. Unexpectedly, expression of cortactin mutants containing Y421F, Y421D, Y466F, or Y466D mutated sites did not affect podosome formation or cortactin translocation to podosomes, although endogenous tyrosine-phosphorylated cortactin at Y421 and Y466 was present in podosomes. Our data indicate that 1) PKCα acts upstream of Src in phosphorylation of cortactin and podosome formation in smooth muscle cells; 2) expression of cortactin is essential for genesis of podosomes; 3) phosphorylation at Y421 and Y466 is not required for translocation of cortactin to podosomes, although phosphorylation at these sites appears to be enriched in podosomes; and 4) tyrosine phosphorylation of cortactin may be involved in regulation of stability and turnover of podosomes, rather than targeting this protein to the site of podosome formation.
EnteropathogenicEscherichia coliinhibits butyrate uptake in Caco-2 cells by altering the apical membrane MCT1 level
Authors: Borthakur Alip , Gill Ravinder K. , Hodges Kim , Ramaswamy Krishnamurthy , Hecht Gail , Dudeja Pradeep K.
Published: September 2005

Enteropathogenic Escherichia coli (EPEC), a food-borne human pathogen, is responsible for infantile diarrhea, especially in developing countries. The pathophysiology of EPEC-induced diarrhea, however, is not completely understood. Our recent studies showed modulation of Na+/H+and Cl−/HCO3−exchange activities in Caco-2 cells in response to EPEC infection. We hypothesized that intestinal short-chain fatty acid absorption mediated by monocarboxylate transporter 1 (MCT1) might also be altered by EPEC infection. The aim of the current studies was to examine the effect of EPEC infection on butyrate uptake. Caco-2 cells were infected with wild-type EPEC, various mutant strains, or nonpathogenic E. coli HS4, and [14C]butyrate uptake was determined. EPEC, but not nonpathogenic E. coli, significantly decreased butyrate uptake. Infection of cells with strains harboring mutations in escN, which encodes a putative ATPase for the EPEC type III secretion system (TTSS), or in the espA, espB, or espD genes encoding structural components of the TTSS, had no effect on butyrate uptake, indicating the TTSS dependence. On the other hand, strains with mutations in the effector protein genes espF, espG, espH, and map inhibited butyrate uptake, similar to the wild-type EPEC. Surface expression of MCT1 decreased considerably after EPEC but not after nonpathogenic E. coli infection. In conclusion, our studies demonstrate inhibition of MCT1-mediated butyrate uptake in Caco-2 cells in response to EPEC infection. This inhibition was dependent on a functional TTSS and the structural proteins EspA, -B, and -D of the translocation apparatus.
Peroxynitrite reduces the endothelium-derived hyperpolarizing factor component of coronary flow-mediated dilation in PECAM-1-knockout mice
Authors: Liu Yanping , Bubolz Aaron H. , Shi Yang , Newman Peter J. , Newman Debra K. , Gutterman David D.
Published: September 2005

Platelet endothelial cell adhesion molecule 1 (PECAM-1) is capable of transducing signals in endothelial cells exposed to shear; however, the biological consequences of this signal transduction are unknown. Because shear stress elicits flow-mediated dilation (FMD), we examined whether steady-state FMD in mouse coronary arteries (MCAs) is affected in the PECAM-1 knockout (KO) mouse. MCAs were isolated from wild-type (WT) or KO mice and prepared for videomicroscopy, histofluorescence, Western blotting, and immunohistochemistry. FMD was examined in the absence and presence of Nω-nitro-l-arginine methyl ester (l-NAME) and l-NAME+indomethacin (INDO). FMD was reduced in KO relative to WT MCAs, but the l-NAME-inhibitable portion of FMD was similar between the two. The INDO-sensitive component of FMD was diminished in KO MCAs. In contrast, the residual component of dilation, presumably because of endothelium-derived hyperpolarizing factor (EDHF), was abolished in KO MCAs. Histofluorescence showed relatively more superoxide (O2−·; oxy-ethidium fluorescence) and peroxide production (dihydrochlorofluorescene fluoresecence) in KO MCAs at rest. Flow augmented O2−· and peroxide production in WT MCAs but had little effect on KO MCAs. Enhanced nitric oxide generation was observed in arteries from KO mice, accompanied with increased eNOS S1177 phosphorylation. In vessels from KO mice, treatment with ebselen decreased peroxynitrite (ONOO−) formation and improved the reduced FMD, largely due to restoration of the presumed EDHF component. These results suggest that PECAM-1 is necessary for normal FMD in the mouse coronary circulation. In the absence of this adhesion and signaling molecule, ONOO− production is increased concomitant with a reduction in both the EDHF and INDO-sensitive components of FMD.
Carotid sinus nerve is involved in cardiorespiratory responses to intracarotid injection of capsaicin in the rat
Authors: Wang Rurong , Xu Fadi , Zhuang Jianguo , Zhang Cancan
Published: September 2005

The carotid sinus nerve (CSN), important in cardiorespiratory modulation, mainly contains C fibers (CSCFs). Previous studies have demonstrated that selective stimulation of bronchopulmonary C fibers (PCFs) via right atrial injection of capsaicin (Cap; ∼0.25 μg) results in an apnea (∼3 s) associated with hypotension and bradycardia. The present study was undertaken to determine the effects of activating CSCFs on cardiorespiratory activities. Intracarotid injection of Cap was performed before and after bilateral transection of the CSN in anesthetized and spontaneously breathing rats. Our results showed that 1) low doses of Cap (up to 2 ng) produced an increase in minute ventilation by elevating both tidal volume and respiratory frequency with the threshold dosage at 1.0 ng ( P < 0.05); 2) high doses (4–64 ng) generated an apnea (prolongation of expiratory duration by ∼8-fold) and hypertension ( P < 0.05); 3) bilateral transection of the CSN reduced excitatory and inhibitory respiratory responses by 30 and 81%, respectively, and increased the hypertension by 88% ( P < 0.05); and 4) the same doses of Cap delivered into the right atrium to stimulate PCFs failed to evoke detectable cardiorespiratory responses. Our results suggest that compared with PCFs, CSCFs are more sensitive to Cap stimulation and that activation of these fibers significantly modulates cardiorespiratory activity in anesthetized rats.
Inhibitory Sharpening of Receptive Fields Contributes to Whisker Map Plasticity in Rat Somatosensory Cortex
Authors: Foeller Elisabeth , Celikel Tansu , Feldman Daniel E.
Published: September 2005

The role of inhibition in sensory cortical map plasticity is not well understood. Here we tested whether inhibition contributes to expression of receptive field plasticity in developing rat somatosensory (S1) cortex. In normal rats, microiontophoresis of gabazine (SR 95531), a competitive γ-aminobutyric acid (GABA)-A receptor antagonist, preferentially disinhibited surround whisker responses relative to principal whisker responses, indicating that GABAA inhibition normally acts to sharpen whisker tuning. Plasticity was induced by transiently depriving adolescent rats of all but one whisker; this causes layer 2/3 (L2/3) receptive fields to shift away from the deprived principal whisker and toward the spared surround whisker. In units with shifted receptive fields, gabazine preferentially disinhibited responses to the deprived principal whisker, unlike in controls, suggesting that GABAA inhibition was acting to preferentially suppress these responses relative to spared whisker responses. This effect was not observed for L2/3 units that did not express receptive field plasticity or in layer 4, where receptive field plasticity did not occur. Thus GABAA inhibition promoted expression of sensory map plasticity by helping to sharpen receptive fields around the spared input.
Gene Expression Profiling of Microsatellite Unstable and Microsatellite Stable Endometrial Cancers Indicates Distinct Pathways of Aberrant Signaling
Authors: Risinger John I. , Maxwell G. Larry , Chandramouli Gadisetti V.R. , Aprelikova Olga , Litzi Tracy , Umar Asad , Berchuck Andrew , Barrett J. Carl
Published: September 2005

Microsatellite instability (MSI) is a molecular phenotype present in ∼25% of endometrial cancers. We examined the global gene expression profiles of early-stage endometrioid endometrial cancers with and without the MSI phenotype to test the hypothesis that MSI phenotype may determine a unique molecular signature among otherwise similar cancers. Unsupervised principal component analysis of the expression data from these cases indicated two distinct groupings of cancers based on MSI phenotype. A relatively small number of array features (392) at high statistical value (P < 0.001) were identified that drive the instability signature in these cancers; 109 of these transcripts differed by at least 2-fold. These data identify distinct gene expression profiles for MSI and microsatellite stable (MSS) cancers, which suggest that cancers with MSI develop in part by different mechanisms from their similar stable counterparts. In particular, we found evidence that two members of the secreted frizzled related protein family (SFRP1 and SFRP4) were more frequently down-regulated in MSI cancers as compared with MSS cancers. Down-regulation was accompanied by promoter hypermethylation for SFRP1. SFRP1 was hypermethylated in 8 of 12 MSI cancers whereas only 3 of 16 MSS cancers were methylated. The WNT target fibroblast growth factor 18 was found to be up-regulated in MSI cancers. These data classify histologically similar endometrioid endometrial cancers into two distinct groupings with implications affecting therapy and prevention.
Escape from Therapy-Induced Accelerated Cellular Senescence in p53-Null Lung Cancer Cells and in Human Lung Cancers
Authors: Roberson Rachel S. , Kussick Steven J. , Vallieres Eric , Chen Szu-Yu J. , Wu Daniel Y.
Published: September 2005

Accelerated cellular senescence (ACS) has been described for tumor cells treated with chemotherapy and radiation. Following exposure to genotoxins, tumor cells undergo terminal growth arrest and adopt morphologic and marker features suggestive of cellular senescence. ACS is elicited by a variety of chemotherapeutic agents in the p53-null, p16-deficient human non–small cell H1299 carcinoma cells. After 10 to 21 days, infrequent ACS cells (1 in 106) can bypass replicative arrest and reenter cell cycle. These cells express senescence markers and resemble the parental cells in their transcription profile. We show that these escaped H1299 cells overexpress the cyclin-dependent kinase Cdc2/Cdk1. The escape from ACS can be disrupted by Cdc2/Cdk1 kinase inhibitors or by knockdown of Cdc2/Cdk1 with small interfering RNA and can be promoted by expression of exogenous Cdc2/Cdk1. We also present evidence that ACS occurs in vivo in human lung cancer following induction chemotherapy. Viable tumors following chemotherapy also overexpress Cdc2/Cdk1. We propose that ACS is a mechanism of in vivo tumor response and that mechanisms aberrantly up-regulate Cdc2/Cdk1 promotes escape from the senescence pathway may be involved in a subset of tumors and likely accounts for tumor recurrence/progression.
A Novel Polypyrimidine Antitumor Agent FdUMP[10] Induces Thymineless Death with Topoisomerase I-DNA Complexes
Authors: Liao Zhi-Yong , Sordet Olivier , Zhang Hong-Liang , Kohlhagen Glenda , Antony Smitha , Gmeiner William H. , Pommier Yves
Published: September 2005

FdUMP[10], a 10mer of 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP), the thymidylate synthase inhibitory metabolite of 5-fluorouracil (FU), is most closely correlated with the DNA topoisomerase I (Top1) inhibitor camptothecin in the National Cancer Institute COMPARE analysis, but not with FU. FdUMP[10] exhibits more potent antiproliferative activity than FdUMP or 5-fluoro-2′-deoxyuridine (FdU) and is markedly more active than FU. Camptothecin-resistant P388/CPT45 cells lacking Top1 are cross-resistant to FdUMP[10] as well as to FdUMP, FdU, and the thymidylate synthase inhibitor raltitrexed (Tomudex). FdUMP[10] induces DNA single-strand breaks and cellular Top1-DNA complexes. Such complexes are also observed in response to FdUMP, FdU, raltitrexed, and FU. The FdUMP[10]-induced Top1-DNA complexes are not inhibited by the caspase inhibitor z-VAD-fmk and form independently of apoptotic DNA fragmentation, indicating that they do not correspond to apoptotic Top1-DNA complexes. In biochemical assay, Top1 is directly trapped at uracil and FdU misincorporation sites. We propose that FdUMP[10] damages DNA by trapping Top1 at uracil and FdU misincorporation sites resulting from thymidylate synthase inhibition and thymine depletion.