bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Early Dengue Virus Infection in Mice as Modulated by Aedes aegypti Probing
Authors: McCracken M. K. , Christofferson R. C. , Chisenhall D. M. , Mores C. N.
Published: November 2013

Dengue virus (DENV), the etiologic agent of dengue fever, is transmitted during probing of human skin by infected-mosquito bite. The expectorated viral inoculum also contains an assortment of mosquito salivary proteins that have been shown to modulate host hemostasis and innate immune responses. To examine the potential role of mosquito probing in DENV establishment within the vertebrate host, we inoculated mice intradermally with DENV serotype 2 strain 1232 at sites where
Aedes aegypti
had or had not probed immediately prior. We assayed these sites 3 h postinoculation with transcript arrays for the Toll-like receptor (TLR), RIG-I-like receptor, and NOD-like receptor signaling pathways of the innate immune system. We then chose TLR7, transcription factor p65 (RelA), gamma interferon (IFN-γ), and IFN-γ-inducible protein 10 (IP-10) from the arrays for further investigation and assayed these transcripts at 10 min, 3 h, and 6 h postinoculation. The transcripts for TLR7, RelA, IFN-γ, and IP-10 were significantly downregulated between 2- and 3-fold in the group subjected to mosquito probing relative to the virus-only inoculation group at 3 h postinoculation. A reduction in these transcripts could indicate reduced DENV recognition and antigen presentation and diminished inhibition of viral replication and spread. Further, mosquito probing resulted in viremia titers significantly higher than those in mice that did not receive probing.
A. aegypti
probing has a significant effect on the innate immune response to DENV infection and generates an early immune environment more permissive to the establishment of infection.
Adenovirus Death Protein (ADP) Is Required for Lytic Infection of Human Lymphocytes
Authors: Murali V. K. , Ornelles D. A. , Gooding L. R. , Wilms H. T. , Huang W. , Tollefson A. E. , Wold W. S. M. , Garnett-Benson C.
Published: November 2013

The adenovirus death protein (ADP) is expressed at late times during a lytic infection of species C adenoviruses. ADP promotes the release of progeny virus by accelerating the lysis and death of the host cell. Since some human lymphocytes survive while maintaining a persistent infection with species C adenovirus, we compared ADP expression in these cells with ADP expression in lymphocytes that proceed with a lytic infection. Levels of ADP were low in KE37 and BJAB cells, which support a persistent infection. In contrast, levels of ADP mRNA and protein were higher in Jurkat cells, which proceed with a lytic infection. Epithelial cells infected with an ADP-overexpressing virus died more quickly than epithelial cells infected with an ADP-deleted virus. However, KE37, and BJAB cells remained viable after infection with the ADP-overexpressing virus. Although the levels of ADP mRNA increased in KE37 and BJAB cells infected with the ADP-overexpressing virus, the fraction of cells with detectable ADP was unchanged, suggesting that the control of ADP expression differs between epithelial and lymphocytic cells. When infected with an ADP-deleted adenovirus, Jurkat cells survived and maintained viral DNA for greater than 1 month. These findings are consistent with the notion that the level of ADP expression determines whether lymphocytic cells proceed with a lytic or a persistent adenovirus infection.
Mapping of Betapapillomavirus Human Papillomavirus 5 Transcription and Characterization of Viral-Genome Replication Function
Authors: Sankovski Eve , Männik Andres , Geimanen Jelizaveta , Ustav Ene , Ustav Mart
Published: November 2013

Betapapillomavirus replication and transcription have not been studied in detail because of a lack of suitable cellular systems supporting human papillomavirus (HPV) genome replication. We have recently shown that the human osteosarcoma cell line U2OS provides a useful environment for the genome replication of many different HPVs, including the betapapillomaviruses HPV5 and HPV8. Using mutational analysis and complementation assay, we demonstrated herein that the viral early proteins E1 and E2 are viral transfactors that are necessary and sufficient for HPV5 genome replication. We also identified four HPV5 early promoter regions with transcription start sites (TSSs) at nucleotides (nt) 184/191, 460, 840, and 1254, respectively, and the HPV late promoter with a TSS at nt 7640. In addition, we mapped the HPV5 early polyadenylation cleavage sites via 3′ rapid amplification of cDNA ends (3′RACE) to nt 4457 and 4475. In total, 14 different viral mRNA species, originating from the HPV5 genome, were mapped in U2OS cells during transient and stable replication. The main splicing donor and acceptor sites identified herein are consistent with the data previously obtained in HPV5-positive skin lesions. In addition, we identified novel E8 open reading frame (ORF)-containing transcripts (E8^E1C and E8^E2C) expressed from the HPV5 genome. Similar to several other papillomaviruses, the product of the E8^E2C mRNA acts as a repressor of viral genome replication.
Intracellular Dynamics of HIV Infection
Authors: Petravic Janka , Ellenberg Paula , Chan Ming-Liang , Paukovics Geza , Smyth Redmond P. , Mak Johnson , Davenport Miles P.
Published: November 2013

Early studies of HIV infection dynamics suggested that virus-producing HIV-infected cells had an average half-life of approximately 1 day. However, whether this average behavior is reflective of the dynamics of individual infected cells is unclear. Here, we use HIV-enhanced green fluorescent protein (EGFP) constructs and flow cytometry sorting to explore the dynamics of cell infection, viral protein production, and cell death
in vitro
. By following the numbers of productively infected cells expressing EGFP over time, we show that infected cell death slows down over time. Although infected cell death
in vivo
could be very different, our results suggest that the constant decay of cell numbers observed
in vivo
during antiretroviral treatment could reflect a balance of cell death and delayed viral protein production. We observe no correlation between viral protein production and death rate of productively infected cells, showing that viral protein production is not likely to be the sole determinant of the death of HIV-infected cells. Finally, we show that all observed features can be reproduced by a simple model in which infected cells have broad distributions of productive life spans, times to start viral protein production, and viral protein production rates. This broad spectrum of the level and timing of viral protein production provides new insights into the behavior and characteristics of HIV-infected cells.
Autographa californicaNucleopolyhedrovirus Ac76: a Dimeric Type II Integral Membrane Protein That Contains an Inner Nuclear Membrane-Sorting Motif
Authors: Wei Denghui , Wang Yan , Zhang Xiaomei , Hu Zhaoyang , Yuan Meijin , Yang Kai
Published: November 2013

Our previous study showed that the
Autographa californica
Nucleopolyhedrovirus
(AcMNPV)
ac76
gene is essential for both budded virion (BV) and occlusion-derived virion (ODV) development. More importantly, deletion of
ac76
affects intranuclear microvesicle formation. However, the exact role by which
ac76
affects virion morphogenesis remains unknown. In this report, we characterized the expression, distribution, and topology of Ac76 to further understand the functional role of Ac76 in virion morphogenesis. Ac76 contains an α-helical transmembrane domain, and phase separation showed that it was an integral membrane protein. In AcMNPV-infected cells, Ac76 was detected as a stable dimer that was resistant to SDS and thermal denaturation, and only a trace amount of monomer was detected. A coimmunoprecipitation assay demonstrated the dimerization of Ac76 by high-affinity self-association. Western blot analyses of purified virions and their nucleocapsid and envelope fractions showed that Ac76 was associated with the envelope fractions of both BVs and ODVs. Immunoelectron microscopy revealed that Ac76 was localized to the plasma membrane, endoplasmic reticulum (ER), nuclear membrane, intranuclear microvesicles, and ODV envelope. Amino acids 15 to 48 of Ac76 were identified as an atypical inner nuclear membrane-sorting motif because it was sufficient to target fusion proteins to the ER and nuclear membrane in the absence of viral infection and to the intranuclear microvesicles and ODV envelope during infection. Topology analysis of Ac76 by selective permeabilization showed that Ac76 was a type II integral membrane protein with an N terminus exposed to the cytosol and a C terminus hidden in the ER lumen.
Inhibition of NF-κB-Mediated Inflammation in Severe Acute Respiratory Syndrome Coronavirus-Infected Mice Increases Survival
Authors: DeDiego Marta L. , Nieto-Torres Jose L. , Regla-Nava Jose A. , Jimenez-Guardeño Jose M. , Fernandez-Delgado Raul , Fett Craig , Castaño-Rodriguez Carlos , Perlman Stanley , Enjuanes Luis
Published: November 2013

Severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiological agent of a respiratory disease that has a 10% mortality rate. We previously showed that SARS-CoV lacking the E gene (SARS-CoV-ΔE) is attenuated in several animal model systems. Here, we show that absence of the E protein resulted in reduced expression of proinflammatory cytokines, decreased numbers of neutrophils in lung infiltrates, diminished lung pathology, and increased mouse survival, suggesting that lung inflammation contributed to SARS-CoV virulence. Further, infection with SARS-CoV-ΔE resulted in decreased activation of NF-κB compared to levels for the wild-type virus. Most important, treatment with drugs that inhibited NF-κB activation led to a reduction in inflammation and lung pathology in both SARS-CoV-infected cultured cells and mice and significantly increased mouse survival after SARS-CoV infection. These data indicated that activation of the NF-κB signaling pathway represents a major contribution to the inflammation induced after SARS-CoV infection and that NF-κB inhibitors are promising antivirals in infections caused by SARS-CoV and potentially other pathogenic human coronaviruses.
Adenovirus Detection by the cGAS/STING/TBK1 DNA Sensing Cascade
Authors: Lam Eric , Stein Saskia , Falck-Pedersen Erik
Published: November 2013

Adenovirus (Ad) infection triggers a cell-specific antiviral response following exposure of viral DNA to the intracellular compartment. A variety of DNA sensors (DAI, AIM2, DDx41, RNA polymerase [Pol] III, and IFI16 [p204]) have been identified in recent years; however, the DNA sensor involved in detection of adenovirus has not been established. Cyclic GMP-AMP synthase (cGAS), a DNA sensor that produces a cyclic guanine-adenine dinucleotide (cGAMP) inducer of STING, has been examined to determine its role in generating an antiadenoviral response. Short hairpin RNA (shRNA) lentiviral vectors targeting TBK1, STING, and cGAS were established in murine MS1 endothelial and RAW 264.7 macrophage cell lines. Knockdown of TBK1, STING, and cGAS results in a dramatic reduction in the activation of the primary antiviral response marker phosphorylated interferon (IFN) response factor 3 (IRF3) following exposure to adenovirus. Furthermore, activation of secondary type I IFN signaling targets (
ptyr
STAT1 and
ptyr
STAT2 [
ptyr
STAT1/2]) was also compromised. Consistent with compromised activation of primary and secondary response markers, transcriptional activation of IRF3-responsive genes (beta IFN [IFN-β], ISG15, ISG54) and secondary response transcripts were diminished in cells knocked down in cGAS, STING, or TBK1. These data establish cGAS as the dominant cytosolic DNA sensor responsible for detection of internalized adenovirus leading to induction of the type I interferon antiviral cascade.
Role of Palatine Tonsils as a Prion Entry Site in Classical and Atypical Experimental Sheep Scrapie
Authors: Cancedda Maria G. , Di Guardo Giovanni , Chiocchetti Roberto , Demontis Francesca , Marruchella Giuseppe , Sorteni Caterina , Maestrale Caterina , Lai Alfio , Ligios Ciriaco
Published: November 2013

Atypical and classical scrapie-infected sheep brain tissue was monolaterally injected into the tonsils of lambs to investigate their role as a prion entry point. We first detected classical PrP
Sc
within the inoculated tonsil and in the ipsilateral retropharyngeal lymph node at 3 months postinoculation (p.i.). At 7 months p.i., PrP
Sc
colonized other lymphoid tissues bilaterally, including ileal Peyer's patches. The earliest PrP
Sc
deposition within the brain was ipsilaterally observed at 9 months p.i. in the substantia reticularis of the medulla oblongata. At 12 months p.i., PrP
Sc
deposition was present bilaterally in the nucleus parasympathicus nervi vagi, as well as in the intermediolateral cell column of the thoracolumbar spinal cord. No PrP
Sc
was detected in the lambs inoculated with atypical scrapie. These findings suggest that neuroinvasion may naturally occur from the tonsil after a widespread prion replication within the lymphoid tissues during classical scrapie only, thus mimicking the pathogenesis after oral ingestion.
The Human Alpha Defensin HD5 Neutralizes JC Polyomavirus Infection by Reducing Endoplasmic Reticulum Traffic and Stabilizing the Viral Capsid
Authors: Zins Stephen R. , Nelson Christian D. S. , Maginnis Melissa S. , Banerjee Rahul , O'Hara Bethany A. , Atwood Walter J.
Published: November 2013

Progressive multifocal leukoencephalopathy (PML) is a fatal disease with limited treatment options, both clinically and in the research pipeline. Potential therapies would target and neutralize its etiologic agent, JC polyomavirus (JCPyV). The innate immune response to JCPyV infection has not been studied, and little is known about the initial host response to polyomavirus infection. This study examined the ability of a human alpha defensin, HD5, to neutralize JCPyV infection in human fetal glial cells. We show that HD5, by binding to the virion, blocks infection. The JCPyV-HD5 complexes bind to and enter host cells but are reduced in their ability to reach the endoplasmic reticulum (ER), where virions are normally uncoated. Furthermore, HD5 binding to the virion stabilizes the capsid and prevents genome release. Our results show that HD5 neutralizes JCPyV infection at an early postentry step in the viral life cycle by stabilizing the viral capsid and disrupting JCPyV trafficking. This study provides a naturally occurring platform for developing antivirals to treat PML and also expands on the known capabilities of human defensins.
Signaling Pathways in Murine Dendritic Cells That Regulate the Response to Vesicular Stomatitis Virus Vectors That Express Flagellin
Authors: Smedberg Jason R. , Westcott Marlena M. , Ahmed Maryam , Lyles Douglas S.
Published: November 2013

Vesicular stomatitis virus (VSV) vectors that express heterologous antigens have shown promise as vaccines in preclinical studies. The efficacy of VSV-based vaccines can be improved by engineering vectors that enhance innate immune responses. We previously generated a VSV vaccine vector that incorporates two enhancing strategies: an M protein mutation (M51R) that prevents the virus from suppressing host antiviral responses and a gene encoding bacterial flagellin (M51R-F vector). The rationale was that intracellular expression of flagellin would activate innate immune pathways in addition to those activated by virus alone. This was tested with dendritic cells (DCs) from mice containing deletions in key signaling molecules. Infection of DC with either M51R or M51R-F vector induced the production of interleukin-12 (IL-12) and IL-6 and increased surface expression of T cell costimulatory molecules. These responses were dramatically reduced in DCs from IPS-1
−/−
mice. Infection with M51R-F vector also induced the production of IL-1β. In addition, in approximately half of the DCs, M51R-F vector induced pyroptosis, a proinflammatory-type of cell death. These responses to flagellin were ablated in DCs from NLRC4
−/−
mice but not Toll-like receptor 5-deficient (TLR5
−/−
) mice, indicating that they resulted from inflammasome activation. These results demonstrate that flagellin induces additional innate immune mechanisms over those induced by VSV alone.
A Lethal Disease Model for Hantavirus Pulmonary Syndrome in Immunosuppressed Syrian Hamsters Infected with Sin Nombre Virus
Authors: Brocato Rebecca L. , Hammerbeck Christopher D. , Bell Todd M. , Wells Jay B. , Queen Laurie A. , Hooper Jay W.
Published: November 2013

Sin Nombre virus (SNV) is a rodent-borne hantavirus that causes hantavirus pulmonary syndrome (HPS) predominantly in North America. SNV infection of immunocompetent hamsters results in an asymptomatic infection; the only lethal disease model for a pathogenic hantavirus is Andes virus (ANDV) infection of Syrian hamsters. Efforts to create a lethal SNV disease model in hamsters by repeatedly passaging virus through the hamster have demonstrated increased dissemination of the virus but no signs of disease. In this study, we demonstrate that immunosuppression of hamsters through the administration of a combination of dexamethasone and cyclophosphamide, followed by infection with SNV, results in a vascular leak syndrome that accurately mimics both HPS disease in humans and ANDV infection of hamsters. Immunosuppressed hamsters infected with SNV have a mean number of days to death of 13 and display clinical signs associated with HPS, including pulmonary edema. Viral antigen was widely detectable throughout the pulmonary endothelium. Histologic analysis of lung sections showed marked inflammation and edema within the alveolar septa of SNV-infected hamsters, results which are similar to what is exhibited by hamsters infected with ANDV. Importantly, SNV-specific neutralizing polyclonal antibody administered 5 days after SNV infection conferred significant protection against disease. This experiment not only demonstrated that the disease was caused by SNV, it also demonstrated the utility of this animal model for testing candidate medical countermeasures. This is the first report of lethal disease caused by SNV in an adult small-animal model.
Promyelocytic Leukemia Protein Is a Cell-Intrinsic Factor Inhibiting Parvovirus DNA Replication
Authors: Mitchell Angela M. , Hirsch Matthew L. , Li Chengwen , Samulski R. Jude
Published: November 2013

Tripartite motif proteins are important viral restriction factors and affect processes ranging from uncoating to transcription to immune signaling. Specifically, the promyelocytic leukemia protein (TRIM19; also called PML) is a viral restriction factor inhibiting processes from uncoating to transcription to cell survival. Here we investigated PML's effect on adeno-associated virus (AAV), a parvovirus used for gene delivery. Although dependovirus (AAV) and autonomous parvovirus (minute virus of mice) replication centers can colocalize with PML, PML's functional effect on parvoviruses is unknown. Using PML knockout mice, we determined that PML knockout enhances recombinant AAV2 (rAAV2) transduction at a range of vector doses in both male and female mice. In fact, male and female PML knockout mice exhibited up to 56-fold and 28-fold increases in transduction, respectively. PML inhibited several rAAV serotypes, suggesting a conserved mechanism, and organ specificity correlated with PML expression. Mechanistically, PML inhibited rAAV second-strand DNA synthesis, precluding inhibition of self-complementary rAAV, and did not affect the prior steps in transduction. Furthermore, we confirmed the effect of human PML on rAAV transduction through small interfering RNA (siRNA)-mediated knockdown in HuH7 cells and determined that the highest level of inhibition was due to effects of PML isoform II (PMLII). Overexpression of PMLII resulted in inhibition of second-strand synthesis, vector production, and genome replication. Moreover, wild-type AAV2 production and infectivity were also inhibited by PMLII, demonstrating a PML interaction with wild-type AAV. These data have important implications for AAV-mediated gene therapy. Additionally, PMLII inhibition of AAV second-strand synthesis and replication, which are processes necessary for all parvoviruses, suggests implications for replication of other parvoviruses.
Death Receptor-Mediated Apoptotic Signaling Is Activated in the Brain following Infection with West Nile Virus in the Absence of a Peripheral Immune Response
Authors: Clarke Penny , Leser J. Smith , Quick Eamon D. , Dionne Kalen R. , Beckham J. David , Tyler Kenneth L.
Published: November 2013

Apoptosis is an important mechanism of West Nile virus (WNV) pathogenesis within the central nervous system (CNS). The signaling pathways that result in WNV-induced apoptotic neuronal death within the CNS have not been established. In this study, we identified death receptor (DR)-induced apoptosis as a pathway that may be important in WNV pathogenesis, based on the pattern of differential gene expression in WNV-infected, compared to uninfected, brains. Reverse transcription-PCR (RT-PCR) and Western blotting confirmed that genes involved in DR-induced apoptotic signaling are upregulated in the brain following WNV infection. Activity of the DR-associated initiator caspase, caspase 8, was also increased in the brains of WNV-infected mice and occurred in association with cleavage of Bid and activation of caspase 9. These results demonstrate that DR-induced apoptotic signaling is activated in the brain following WNV infection and suggest that the caspase 8-dependent cleavage of Bid promotes intrinsic apoptotic signaling within the brains of infected animals. Utilization of a novel
ex vivo
brain slice culture (BSC) model of WNV encephalitis revealed that inhibition of caspase 8 decreases virus-induced activation of caspase 3 and tissue injury. The BSC model allows us to examine WNV-induced pathogenesis in the absence of a peripheral immune response. Thus, our results indicate that WNV-induced neuronal injury in the brain is mediated by DR-induced apoptosis signaling and can occur in the absence of infiltrating immune cells. However, astrocytes and microglia were activated in WNV-infected BSC, suggesting that local immune responses influence WNV pathogenesis.
On Dermatomes, Meridians and Points: Results of a Quasiexperimental Study
Authors: Sánchez-Araujo Max , Luckert-Barela Ana J , Sánchez Nathalia , Torres Juan , Conde Jesus Eloy
Published: November 2013

Background

Traditional Chinese medicine (TCM) meridians and points run vertically, reflecting their function in the Zhang-Fu system (meridian pattern). However, the trunk's spinal nerves show a traverse orientation, or a ‘horizontal pattern’.

Objective

The aim of the present work was to evaluate, via a cognitive quasiexperiment, whether the clinical indications of the points on the trunk are associated with their meridian function or with their innervation and visceral–somatic connection.

Methods

The points in each dermatome of the trunk were considered crosswise, regardless of their meridians. The clinical indications for each point were differentiated into two mutually exclusive categories: (a) vertical distribution effect (VDE) or ‘meridian pattern’, when indications were quite different regarding the indications for the other points on the dermatome; and (b) transverse distribution effects (TDE) or ‘horizontal pattern’, represented by mainly local or segmental indications except for Shu-Mu points. After observing that the proportions between both categories often exceeded 60% in pilot samples, 60% was adopted as the reference value.

Results

A total of 22 dermatomes accommodated 148 points with 809 indications, of which 189 indications (23.4%) exhibited VDE features, whereas 620 (76.6%) exhibited TDE features.

Conclusions

A TDE/VDE ratio of 3 : 1 implies that the clinical indications for the points of any dermatome on the torso are similar, regardless of their meridians, and suggests that most of the indications for trunk points involve a ‘horizontal pattern’ due to their neurobiological nature. These findings may help in understanding acupuncture's neurobiology and clarify some confusing results of clinical research, for example, excluding sham acupuncture as an inert intervention for future clinical trials.
Challenges with cost-utility analyses of behavioural interventions among older adults at risk for dementia
Authors: Davis Jennifer C , Bryan Stirling , Marra Carlo A , Hsiung Ging-Yuek R , Liu-Ambrose Teresa
Published: November 2013

Background

Cognitive decline is one of the most prominent healthcare issues of the 21st century. Within the context of combating cognitive decline through behavioural interventions, physical activity is a promising approach. There is a dearth of health economic data in the area of behavioural interventions for dementia prevention. Yet, economic evaluations are essential for providing information to policy makers for resource allocation. It is essential we first address population and intervention-specific methodological challenges prior to building a larger evidence base. We use a cost-utility analysis conducted alongside the exercise for cognition and everyday living (EXCEL) study to illustrate methodological challenges specific to assessing the cost-effectiveness of behavioural interventions aimed at older adults at risk of cognitive decline.

Methods

A cost-utility analysis conducted concurrently with a 6-month, three-arm randomised controlled trial (ie, the EXCEL study) was used as an example to identify and discuss methodological challenges.

Results

Both the aerobic training and resistance training interventions were less costly than twice weekly balance and tone classes. In critically evaluating the economic evaluation of the EXCEL study we identified four category-specific challenges: (1) analysing costs; (2) assessing quality-adjusted life-years; (3) Incomplete data; and (4) ‘Intervention’ activities of the control group.

Conclusions

Resistance training and aerobic training resulted in healthcare cost saving and were equally effective to balance and tone classes after only 6 months of intervention. To ensure this population is treated fairly in terms of claims on resources, we first need to identify areas for methodological improvement.
The effect of a clinical pharmacist-led training programme on intravenous medication errors: a controlled before and after study
Authors: Nguyen Huong-Thao , Pham Hong-Tham , Vo Dang-Khoa , Nguyen Tuan-Dung , van den Heuvel Edwin R , Haaijer-Ruskamp Flora M , Taxis Katja
Published: November 2013

Background

Little is known about interventions to reduce intravenous medication administration errors in hospitals, especially in low- and middle-income countries.

Objective

To assess the effect of a clinical pharmacist-led training programme on clinically relevant errors during intravenous medication preparation and administration in a Vietnamese hospital.

Methods

A controlled before and after study with baseline and follow-up measurements was conducted in an intensive care unit (ICU) and a post-surgical unit (PSU). The intervention comprised lectures, practical ward-based teaching sessions and protocols/guidelines, and was conducted by a clinical pharmacist and a nurse. Data on intravenous medication preparation and administration errors were collected by direct observation 12 h/day for seven consecutive days. Generalised estimating equations (GEE) were used to assess the effect of the intervention on the prevalence of clinically relevant erroneous doses, corrected for confounding factors.

Results

1204 intravenous doses were included, 516 during the baseline period (236 on ICU and 280 on PSU) and 688 during the follow-up period (407 on ICU and 281 on PSU). The prevalence of clinically relevant erroneous doses decreased significantly on the intervention ward (ICU) from 64.0% to 48.9% (p<0.001) but was unchanged on the control ward (PSU) (57.9% vs 64.1%; p=0.132). GEE analysis showed that doses on the intervention ward were 2.60 (1.27–5.31) times less likely to have clinically relevant errors (p=0.013).

Conclusions

The pharmacist-led training programme was effective, but the error rate remained relatively high. Further quality improvement strategies are needed, including changes to the working environment and promotion of a safety culture.
Temporal trends in the associations between age, sex and socioeconomic status after death from motor vehicle collisions in England and Wales: 1960–2009
Authors: Fogarty Andrew W , Liu Clarence
Published: November 2013

Objective

To determine the trend in the associations between socioeconomic status and gender with median age at death in England and Wales, from 1960 to 2009.

Methods

Annual cross-sectional studies of all registered deaths from a motor vehicle collision in England and Wales, 1960–2009.

Results

There were 1647 deaths from a motor vehicle collision in 1960 and 964 deaths in 2009. The number of children aged 14 years or less who died in 1960 was 66 and this figure had reduced to 20 deaths by 2009. Individuals in non-manual occupations were consistently more likely to die above the median age of death than those in manual occupations during 1960–1963 (OR 1.66; 95% CI 1.50 to 1.84) and also during 1990–2000 (OR 1.54; 95% CI 1.44 to1.65). For 1960–1969, women had a higher risk of dying at above the annual median age of death (OR 1.72; 95% CI 1.62 to 1.82); for 2001–2009 the corresponding OR was 1.80 (95% CI 1.68 to 1.94).

Conclusions

There has been a 41% decrease in annual deaths after motor vehicle collisions in England and Wales over the past 50 years. The number of individuals over the age of 74 years dying in motor vehicle collisions has increased slightly, while the number of children's deaths decreased by 70% over the same time period despite driving becoming more common. Involvement in motor vehicle collisions may contribute to the sex and social class gradients in life expectancy observed in England and Wales.
Creep response of recycled asphalt shingles
Authors: Soleimanbeigi Ali , Edil Tuncer B. , Benson Craig H.
Published: November 2013

Recycled asphalt shingles (RAS) mixed with granular materials or cementitiously stabilized to control their otherwise high compressibility provide a viable lightweight structural fill material in highway embankments or backfill behind retaining structures. In this research, deviator creep response of RAS mixed with bottom ash (BA) or stabilized with self-cementing fly ash (FA) was investigated. Systematic constant stress consolidated-drained triaxial tests were conducted on compacted RAS–BA and RAS–FA mixtures at ranges of confining pressures, deviator stresses, and temperatures expected in the field. Results showed that both compacted RAS–BA and RAS–FA mixtures represent classic creep response similar to soils. Creep rupture was observed at deviator stresses higher than 80% of deviator stress at failure. To prevent creep rupture, mobilized shear strength in the design of side slopes of highway embankments containing RAS should be limited to 80% of deviator stress at failure. Creep rate is affected by confining pressures. At a given stress level, the creep rate decreased and the time to creep rupture increased with increasing confining pressure. Temperature change also affects the creep strain and strain rate of compacted RAS–BA and RAS–FA mixtures. The strain rate of the compacted RAS–BA mixture exponentially increased with temperature. However, thermal pre-loading at summer field temperatures significantly reduced the strain rate of the compacted RAS–BA mixture from 64 × 10−6%/min to 3.6 × 10−6%/min and that of the RAS–FA mixture from 190 × 10−6%/min to 6.9 × 10−6%/min. To minimize creep strain and strain rate of structural fill materials containing RAS, construction is recommended during warm seasons. Creep models were developed to evaluate the time-dependent deformation of embankments constructed with RAS mixed with granular materials or stabilized with self-cementing fly ash.
Stratigraphy and infill history of the glacially eroded Matane River Valley, eastern Quebec, Canada
Authors: Marchand Jean-Philippe , Buffin-Bélanger Thomas , Hétu Bernard , St-Onge Guillaume
Published: November 2013

Terraces in the lower Matane River Valley (eastern Quebec, Canada) were studied to describe the stratigraphic architecture of a glacially eroded valley fill. The Matane River Valley hosted a glacial tongue connected with a regional ice cap during the early opening of a calving bay in the modern St. Lawrence Estuary and was subsequently flooded by the Goldthwait Sea as the Laurentide Ice Sheet margin retreated. Stratigraphic, sedimentological, light detection and ranging (LIDAR), and geochemical analyses as well as radiocarbon measurements allowed the identification of four stratigraphic units deposited during and following deglaciation: glacial outwash (unit I), delta bottomsets (unit II), delta foresets (unit III), and fluvial deposits (unit IV). Stable isotope (13C) and C/N ratio values reveal the relative influence of the two end-members (algae and terrestrial plants) on organic matter sources between the stratigraphic units. Climate, major relative sea level fluctuations, and sediment yield are recognized as the main controls on depositional environments in glacially eroded valleys of the northern shore of the Gaspé Peninsula during the Holocene. This paper presents a model of the evolution of the Matane River Valley, which in many points is similar to existing conceptual fjord-valley fill models.
Species diversity of corticolous myxomycetes in Tianmu Mountain National Nature Reserve, China
Authors: Liu Qi-Sha , Yan Shu-Zhen , Dai Jun-Yong , Chen Shuang-Lin
Published: November 2013

The species diversity of corticolous myxomycetes on 4 vegetation types in the Tianmu Mountain National Natural Reserve, eastern China, was examined from 2011 to 2012. A total of 1440 moist chamber cultures were prepared with bark samples, which yielded several hundred collections representing 42 species in 20 genera. It was found that 79% of cultures produced some evidence (either plasmodia or fruiting bodies) of myxomycetes. Eight species (Comatricha elegans, Cribraria confusa, Licea pusilla, Cribraria microcarpa, Collaria arcyrionema, Licea biforis, Arcyria cinerea, and Clastoderma debaryanum) were abundant (exceeding 3% of all records), but about a third of all species were classified as rare. Species richness (S = 33) and diversity (exp[H′] = 16.60, S/G = 1.74) of corticolous myxomycetes were the most diverse in the deciduous broadleaf forest. The species recorded from coniferous forest showed the lowest species richness (S = 21) but the highest evenness (J′ = 0.91). The cluster analyses were based on the Bray–Curtis similarity matrix, and the results indicated that corticolous myxomycete assemblages were distributed by a seasonal and annual pattern. Canonical correspondence analysis showed that season and pH were key factors in determining species distribution.
The role of anisotropy in holographic modified gravity
Authors: Fayaz V. , Hossienkhani H. , Amirabadi M. , Aghamohammadi A.
Published: November 2013

In this paper, we study a cosmological implication of holographic dark energy in modified gravity. We employ the holographic model of dark energy to obtain the equation of state for the holographic energy density in a nonisotropic universe. The purpose of this work is to develop a reconstruction scheme for the modified gravity with f(R) action using the holographic energy density. Hence one can generate a phantom-like equation of state from a holographic dark energy model in a nonisotropic universe in the modified gravity cosmology framework.
TOPOLOGICAL PHOTONIC STATES
Authors: HE CHENG , LIN LIANG , SUN XIAO-CHEN , LIU XIAO-PING , LU MING-HUI , CHEN YAN-FENG
Published: November 2013

As exotic phenomena in optics, topological states in photonic crystals have drawn much attention due to their fundamental significance and great potential applications. Because of the broken time-reversal symmetry under the influence of an external magnetic field, the photonic crystals composed of magneto-optical materials will lead to the degeneracy lifting and show particular topological characters of energy bands. The upper and lower bulk bands have nonzero integer topological numbers. The gapless edge states can be realized to connect two bulk states. This topological photonic states originated from the topological property can be analogous to the integer quantum Hall effect in an electronic system. The gapless edge state only possesses a single sign of gradient in the whole Brillouin zone, and thus the group velocity is only in one direction leading to the one-way energy flow, which is robust to disorder and impurity due to the nontrivial topological nature of the corresponding electromagnetic states. Furthermore, this one-way edge state would cross the Brillouin center with nonzero group velocity, where the negative-zero-positive phase velocity can be used to realize some interesting phenomena such as tunneling and backward phase propagation. On the other hand, under the protection of time-reversal symmetry, a pair of gapless edge states can also be constructed by using magnetic–electric coupling meta-materials, exhibiting Fermion-like spin helix topological edge states, which can be regarded as an optical counterpart of topological insulator originating from the spin–orbit coupling. The aim of this article is to have a comprehensive review of recent research literatures published in this emerging field of photonic topological phenomena. Photonic topological states and their related phenomena are presented and analyzed, including the chiral edge states, polarization dependent transportation, unidirectional waveguide and nonreciprocal optical transmission, all of which might lead to novel applications such as one-way splitter, optical isolator and delay line. In addition, the possible prospect and development of related topics are also discussed.
BROKEN SYMMETRY AND TOPOLOGY IN PHOTONIC ANALOG OF GRAPHENE
Authors: OCHIAI TETSUYUKI
Published: November 2013

We review how broken symmetries affect optical properties in photonic analog of graphene, namely, honeycomb-lattice photonic crystals (PhCs). The spatial symmetry of the honeycomb lattice yields Dirac spectra at Brillouin zone corners without fine tuning of physical parameters. In addition, the "Dirac-mass" gap can be introduced by breaking the time-reversal symmetry and/or the space-inversion symmetry. These two symmetries are closely related to the topology of radiation fields in momentum space, and are linked with nontrivial edge states if the system has edges. We show that an effective Hamiltonian for photon obtained with the aid of group theory predicts a modulation of chiral edge states that are hardly implemented in electronic graphene. Numerical simulation of the honeycomb-lattice PhCs of infinitely-long cylinders, confirms the prediction fairly well.
ADAPTIVE WEIGHTED LEAST SQUARES SVM BASED SNOWING MODEL FOR IMAGE DENOISING
Authors: ZHENG SHENG , YANG CHANGCAI , HENDRIKS EMILE A. , WANG XIAOJUN
Published: November 2013

We propose a snowing model to iteratively smoothe the various image noises while preserving the important image structures such as edges and lines. Considering the gray image as a digital terrain model, we develop an adaptive weighted least squares support vector machine (LS-SVM) to iteratively estimate the optimal gray surface underlying the noisy image. The LS-SVM works on Gaussian noise while the weighted LS-SVM works on the outliers and non-Gaussian noise. To improve its performance in preserving the directional signal while suppressing the noise, the dominant orientation information of the gradients is integrated into the weighting scheme. The contribution of each attribute to the final LS-SVM model is adaptively determined in a fitness modulated, elongated, elliptical contour spread along the direction of the local edge structure. The farther away from the hyperplane in kernel space the point is, the less weight it gets, while the point on the direction of the local structure gets more weight. With adaptive weighting scheme, the robust LS-SVM smoothes most strongly along the edges, rather than across them, while it minimizes the effects of outliers, and results in strong preservation of details in the final output. The iteratively adaptive reweighted LS-SVM simulated the snowing process. The investigation on real images contaminated by mixture Gaussian noise has demonstrated that the performance of the present method is stable and reliable under noise distributions varying from Gaussian to impulsive.
AN EXTENSION OF THE Q DIVERSITY METRIC FOR INFORMATION PROCESSING IN MULTIPLE CLASSIFIER SYSTEMS: A FIELD EVALUATION
Authors: SCIARRONE FILIPPO
Published: November 2013

Nowadays, in pattern recognition and classification, does not exist a dominant classifier for all data distributions. Also, data distribution of the task at hand is usually unknown, i.e. there is no algorithm achieving the best accuracy for all situations. An answer and a challenge to this problem is to build ensembles of classifiers working together, i.e. Multiple Classifier Systems, instead of building and running different classifiers separately: Multiple Classifier Systems can show better performance than a single classifier, provided a careful choice of the individual classifiers composing it. Furthermore, diversity among single classifiers, measured by some diversity metrics, is known to be a necessary condition to improve the ensemble performance. In this paper we extend the use of one of the most used diversity metrics, that is the Q diversity metric, from an oracle output to a soft output for the choice of the best classifier ensemble. We introduce the Qt diversity metric, i.e. an extension of the Q metric to multi-label and multi-ranking Multiple Classifier Systems. A field evaluation of this metric is presented in a text categorization case study, using as a test set the standard document corpus Reuters 21578 ModApte 10. Our results strengthen the use of the extended metric in multi-label and multi-ranking Multiple Classifier Systems.
A UNIVARIATE PHASE SPECTRUM MODEL FOR SIMULATION OF NONSTATIONARY EARTHQUAKE GROUND MOTIONS
Authors: PENG YONGBO , LI JIE
Published: November 2013

A family of simulation methods for nonstationary earthquake ground motions is proposed. It employs a univariate model of phase spectrum built up on a time argument associated with the concept of starting-time of phase evolution of frequency components. This phase model allows a feasible phase spectrum just using few variables of the starting-time in numerical implementation. In order to reduce the computational effort of the starting-time, a wave-group propagation formulation is also introduced. Two observed ground motions at the type-II site, i.e. Northridge and Chi-Chi waves, are investigated for illustrative purposes. Inspired from the proposed method, a numerical technique for the spatial variation of ground motions is also developed, and the investigation of coherency function between the example ground motions observed at different stations is carried out. Numerical results prove the validity and applicability of the simulation scheme. This methodology provides a new perspective towards the representation of nonstationary stochastic ground motions.
Portable robot for autonomous venipuncture using 3D near infrared image guidance
Authors: Chen Alvin , Nikitczuk Kevin , Nikitczuk Jason , Maguire Tim , Yarmush Martin
Published: November 2013

Venipuncture is pivotal to a wide range of clinical interventions and is consequently the leading cause of medical injury in the U.S. Complications associated with venipuncture are exacerbated in difficult settings, where the rate of success depends heavily on the patient's physiology and the practitioner's experience. In this paper, we describe a device that improves the accuracy and safety of the procedure by autonomously establishing a peripheral line for blood draws and IV's. The device combines a near-infrared imaging system, computer vision software, and a robotically driven needle within a portable shell. The device operates by imaging and mapping in real-time the 3D spatial coordinates of subcutaneous veins in order to direct the needle into a designated vein. We demonstrate proof of concept by assessing imaging performance in humans and cannulation accuracy on an advanced phlebotomy training model.
Evidence of K+ channel function in epithelial cell migration, proliferation, and repair
Authors: Girault Alban , Brochiero Emmanuelle
Published: November 2013

Efficient repair of epithelial tissue, which is frequently exposed to insults, is necessary to maintain its functional integrity. It is therefore necessary to better understand the biological and molecular determinants of tissue regeneration and to develop new strategies to promote epithelial repair. Interestingly, a growing body of evidence indicates that many members of the large and widely expressed family of K+ channels are involved in regulation of cell migration and proliferation, key processes of epithelial repair. First, we briefly summarize the complex mechanisms, including cell migration, proliferation, and differentiation, engaged after epithelial injury. We then present evidence implicating K+ channels in the regulation of these key repair processes. We also describe the mechanisms whereby K+ channels may control epithelial repair processes. In particular, changes in membrane potential, K+ concentration, cell volume, intracellular Ca2+, and signaling pathways following modulation of K+ channel activity, as well as physical interaction of K+ channels with the cytoskeleton or integrins are presented. Finally, we discuss the challenges to efficient, specific, and safe targeting of K+ channels for therapeutic applications to improve epithelial repair in vivo.
MicroRNA-194 (miR-194) regulates ROMK channel activity by targeting intersectin 1
Authors: Lin Dao-Hong , Yue Peng , Zhang Chengbiao , Wang Wen-Hui
Published: November 2013

The aim of the study is to explore the role of miR-194 in mediating the effect of high-K (HK) intake on ROMK channel. Northern blot analysis showed that miR-194 was expressed in kidney and that HK intake increased while low-K intake decreased the expression of miR-194. Real-time PCR analysis further demonstrated that HK intake increased the miR-194 expression in the cortical collecting duct. HK intake decreased the expression of intersectin 1 (ITSN1) which enhanced With-No-Lysine Kinase (WNK)-induced endocytosis of ROMK. Expression of miR-194 mimic decreased luciferase reporter gene activity in HEK293 T cells transfected with ITSN-1–3′UTR containing the complementary seed sequence for miR-194. In contrast, transfection of miR-194 inhibitor increased the luciferase activity. This effect was absent in the cells transfected with mutated 3′UTR of ITSN1 in which the complimentary seed sequence was deleted. Moreover, the inhibition of miR-194 expression increased the protein level of endogenous ITSN1 in HEK293T cells. Expression of miR-194 mimic also decreased the translation of exogenous ITSN1 in the cells transfected with the ITSN1 containing 3′UTR but not with 3′UTR-free ITSN1. Expression of pre-miR-194 increased K currents and ROMK expression in the plasma membrane in ROMK-transfected cells. Coexpression of ITSN1 reversed the stimulatory effect of miR-194 on ROMK channels. This effect was reversed by coexpression of ITSN1. We conclude that miR-194 regulates ROMK channel activity by modulating ITSN1 expression thereby enhancing ITSN1/WNK-dependent endocytosis. It is possible that miR-194 is involved in mediating the effect of a HK intake on ROMK channel activity.