bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucose‐6‐phosphate dehydrogenase deficiency in transfusion medicine: the unknown risks
Authors: Francis R. O. , Jhang J. S. , Pham H. P. , Hod E. A. , Zimring J. C. , Spitalnik S. L.
Published: July 2013

The hallmark of glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is red blood cell (RBC) destruction in response to oxidative stress. Patients requiring RBC transfusions may simultaneously receive oxidative medications or have concurrent infections, both of which can induce haemolysis in G6PD‐deficient RBCs. Although it is not routine practice to screen healthy blood donors for G6PD deficiency, case reports identified transfusion of G6PD‐deficient RBCs as causing haemolysis and other adverse events. In addition, some patient populations may be more at risk for complications associated with transfusions of G6PD‐deficient RBCs because they receive RBCs from donors who are more likely to have G6PD deficiency. This review discusses G6PD deficiency, its importance in transfusion medicine, changes in the RBC antioxidant system (of which G6PD is essential) during refrigerated storage and mechanisms of haemolysis. In addition, as yet unanswered questions that could be addressed by translational and clinical studies are identified and discussed.
Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects
Authors: Remme Carol Ann
Published: July 2013

Abstract  Over the last two decades, an increasing number of SCN5A mutations have been described in patients with long QT syndrome type 3 (LQT3), Brugada syndrome, (progressive) conduction disease, sick sinus syndrome, atrial standstill, atrial fibrillation, dilated cardiomyopathy, and sudden infant death syndrome (SIDS). Combined genetic, electrophysiological and molecular studies have provided insight into the dysfunction and dysregulation of the cardiac sodium channel in the setting of SCN5A mutations identified in patients with these inherited arrhythmia syndromes. However, risk stratification and patient management is hindered by the reduced penetrance and variable disease expressivity in sodium channelopathies. Furthermore, various SCN5A‐related arrhythmia syndromes are known to display mixed phenotypes known as cardiac sodium channel overlap syndromes. Determinants of variable disease expressivity, including genetic background and environmental factors, are suspected but still largely unknown. Moreover, it has become increasingly clear that sodium channel function and regulation is more complicated than previously assumed, and the sodium channel may play additional, as of yet unrecognized, roles in cardiac structure and function. Development of cardiac structural abnormalities secondary to SCN5A mutations has been reported, but the clinical relevance and underlying mechanisms are unclear. Increased insight into these issues would enable a major next step in research related to cardiac sodium channel disease, ultimately enabling improved diagnosis, risk stratification and treatment strategies.
Normal mucus formation requires cAMP‐dependent HCO3− secretion and Ca2+‐mediated mucin exocytosis
Authors: Yang Ning , Garcia Mary Abigail S. , Quinton Paul M.
Published: July 2013

Key points

HCO3− is required for gel‐forming mucins to form normal mucus, but how?

Two apparently separate signalling pathways are activated concurrently to bring mucus formation to completion: a Ca2+‐mediated pathway mainly directs goblet cell exocytosis, and an independent cAMP‐mediated pathway stimulates HCO3− secretion to help discharge exocytosed mucus.

cAMP‐dependent HCO3− secretion fails, disrupting the normal formation and discharge of mucins in cystic fibrosis (CF) leading to pathologically viscous and tenacious mucus in affected organs.

This work advances our understanding of the role of cAMP (CFTR)‐dependent HCO3− secretion in forming normal mucus and underscores a new importance of addressing the defect in HCO3− secretion as a critical new therapeutic target in CF.

Abstract  Evidence from the pathology in cystic fibrosis (CF) and recent results in vitro indicate that HCO3− is required for gel‐forming mucins to form the mucus that protects epithelial surfaces. Mucus formation and release is a complex process that begins with an initial intracellular phase of synthesis, packaging and apical granule exocytosis that is followed by an extracellular phase of mucin swelling, transport and discharge into a lumen. Exactly where HCO3− becomes crucial in these processes is unknown, but we observed that in the presence of HCO3−, stimulating dissected segments of native mouse intestine with 5‐hydroxytryptamine (5–HT) and prostaglandin E2 (PGE2) induced goblet cell exocytosis followed by normal mucin discharge in wild‐type (WT) intestines. CF intestines that inherently lack cystic fibrosis transmembrane conductance regulator (CFTR)‐dependent HCO3− secretion also demonstrated apparently normal goblet cell exocytosis, but in contrast, this was not followed by similar mucin discharge. Moreover, we found that even in the presence of HCO3−, when WT intestines were stimulated only with a Ca2+‐mediated agonist (carbachol), exocytosis was followed by poor discharge as with CF intestines. However, when the Ca2+‐mediated agonist was combined with a cAMP‐mediated agonist (isoproterenol (isoprenaline) or vasoactive intestinal peptide) in the presence of HCO3− both normal exocytosis and normal discharge was observed. These results indicate that normal mucus formation requires concurrent activation of a Ca2+‐mediated exocytosis of mucin granules and an independent cAMP‐mediated, CFTR‐dependent, HCO3− secretion that appears to mainly enhance the extracellular phases of mucus excretion.
Formalizing and Exploring the Transferability of Inclusive Design Rules
Authors: Sangelkar Shraddha , McAdams Daniel A.
Published: July 2013

Inclusive products intend to equally serve people with and without a disability. This paper focuses on creating guidelines that are applicable during the early stages of designing inclusive products. Actionfunction diagrams are used to formally compare existing inclusive products to their typical counterparts to study the design similarities and differences in the context of accessibility. A data mining technique, association rule learning, generates rules through comparison of inclusive and typical product data. In prior work, generation of function-based association rules for inclusive design has been performed on a smaller scale using this method; this research seeks to extend and formalize the same method, by studying a larger set of inclusive products. Trends in the generation of rules are analyzed indicating that a finite set of rules should be applicable to an arbitrarily large set of products. Further, the rules are analyzed in detail to evaluate their potential for transferability and reuse from one product to another. Of particular interest is the transferability of the rules across apparently disparate product domains such as garden tools and residential furniture. The conceptual and physical similarity of the rules is discussed in the context of creating inclusive product families based on a platform of inclusive elements.
Conservative Surrogate Model Using Weighted Kriging Variance for Sampling-Based RBDO
Authors: Zhao Liang , Choi K. K. , Lee Ikjin , Gorsich David
Published: July 2013

In sampling-based reliability-based design optimization (RBDO) of large-scale engineering applications, the Monte Carlo simulation (MCS) is often used for the probability of failure calculation and probabilistic sensitivity analysis using the prediction from the surrogate model for the performance function evaluations. When the number of samples used to construct the surrogate model is not enough, the prediction from the surrogate model becomes inaccurate and thus the Monte Carlo simulation results as well. Therefore, to count in the prediction error from the surrogate model and assure the obtained optimum design from sampling-based RBDO satisfies the probabilistic constraints, a conservative surrogate model, which is not overly conservative, needs to be developed. In this paper, a conservative surrogate model is constructed using the weighted Kriging variance where the weight is determined by the relative change in the corrected Akaike Information Criterion (AICc) of the dynamic Kriging model. The proposed conservative surrogate model performs better than the traditional Kriging prediction interval approach because it reduces fluctuation in the Kriging prediction bound and it performs better than the constant safety margin approach because it adaptively accounts large uncertainty of the surrogate model in the region where samples are sparse. Numerical examples show that using the proposed conservative surrogate model for sampling-based RBDO is necessary to have confidence that the optimum design satisfies the probabilistic constraints when the number of samples is limited, while it does not lead to overly conservative designs like the constant safety margin approach.
Roughness evolution during the atomic layer deposition of metal oxides
Authors: Premkumar Peter Antony , Delabie Annelies , Rodriguez Leonard N. J. , Moussa Alain , Adelmann Christoph
Published: July 2013

The evolution of the surface roughness during the atomic-layer deposition (ALD) of Al2O3, NiO, and HfO2 was studied by atomic-force microscopy and nonspecular x-ray reflectance. The results indicate that the crystallinity of the films played a crucial role in the roughness evolution during ALD. While the ALD of amorphous oxide films showed replication of the initial starting surface with no roughness build-up, the ALD of polycrystalline oxide films led to a strong anomalous dependence of the roughness on the film thickness. This behavior is explained within a model taking into account spatial variations of the adsorption site density.
A Population of Fast Radio Bursts at Cosmological Distances
Authors: Thornton D. , Stappers B. , Bailes M. , Barsdell B. , Bates S. , Bhat N. D. R. , Burgay M. , Burke-Spolaor S. , Champion D. J. , Coster P. , D'Amico N. , Jameson A. , Johnston S. , Keith M. , Kramer M. , Levin L. , Milia S. , Ng C. , Possenti A. , van Straten W.
Published: July 2013

Mysterious Radio Bursts

It has been uncertain whether single, short, and bright bursts of radio emission that have been observed are celestial or terrestrial in origin.

Thornton
et al.

(p.
53
; see the Perspective by

Cordes

) report the detection of four nonrepeating radio transient events with millisecond duration in data from the 64-meter Parkes radio telescope in Australia. The properties of these radio bursts indicate that they had their origin outside our galaxy, but it is not possible to tell what caused them. Because the intergalactic medium affects the characteristics of the bursts, it will be possible to use them to study its properties.
Making Macrophages Eat Cancer
Authors: Kershaw Michael H. , Smyth Mark J.
Published: July 2013

Antibody-based therapies to treat cancer may get a boost from an adjuvant that prevents cancer cells from escaping engulfment by macrophages.

[Also see Report by

Weiskopf
et al.

]
A Kinetic Test Characterizes Kinase Intramolecular and Intermolecular Autophosphorylation Mechanisms
Authors: Dodson Charlotte A. , Yeoh Sharon , Haq Tamanna , Bayliss Richard
Published: July 2013

Mathematical analysis of enzyme kinetics reveals different modes of kinase autophosphorylation.
Bacterial Peritonitis Due to Acinetobacter baumannii Sequence Type 25 with Plasmid-Borne New Delhi Metallo-β-Lactamase in Honduras
Authors: Waterman Paige E. , McGann Patrick , Snesrud Erik , Clifford Robert J. , Kwak Yoon I. , Munoz-Urbizo Ivón P. , Tabora-Castellanos Juana , Milillo Michael , Preston Lan , Aviles Ricardo , Sutter Deena E. , Lesho Emil P.
Published: July 2013

A carbapenem-resistant
Acinetobacter baumannii
strain was isolated from the peritoneal fluid of a patient with complicated intra-abdominal infection and evaluated at the Multidrug-resistant Organism Repository and Surveillance Network by whole-genome sequencing and real-time PCR. The isolate was sequence type 25 and susceptible to colistin and minocycline, with low MICs of tigecycline.
bla
NDM-1
was located on a plasmid with >99% homology to pNDM-BJ02. The isolate carried numerous other antibiotic resistance genes, including the 16S methylase gene,
armA
.
Discovery of Novel Small-Molecule HIV-1 Replication Inhibitors That Stabilize Capsid Complexes
Authors: Lamorte Louie , Titolo Steve , Lemke Christopher T. , Goudreau Nathalie , Mercier Jean-François , Wardrop Elizabeth , Shah Vaibhav B. , von Schwedler Uta K. , Langelier Charles , Banik Soma S. R. , Aiken Christopher , Sundquist Wesley I. , Mason Stephen W.
Published: July 2013

The identification of novel antiretroviral agents is required to provide alternative treatment options for HIV-1-infected patients. The screening of a phenotypic cell-based viral replication assay led to the identification of a novel class of 4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (pyrrolopyrazolone) HIV-1 inhibitors, exemplified by two compounds: BI-1 and BI-2. These compounds inhibited early postentry stages of viral replication at a step(s) following reverse transcription but prior to 2 long terminal repeat (2-LTR) circle formation, suggesting that they may block nuclear targeting of the preintegration complex. Selection of viruses resistant to BI-2 revealed that substitutions at residues A105 and T107 within the capsid (CA) amino-terminal domain (CA
NTD
) conferred high-level resistance to both compounds, implicating CA as the antiviral target. Direct binding of BI-1 and/or BI-2 to CA
NTD
was demonstrated using isothermal titration calorimetry and nuclear magnetic resonance (NMR) chemical shift titration analyses. A high-resolution crystal structure of the BI-1:CA
NTD
complex revealed that the inhibitor bound within a recently identified inhibitor binding pocket (CA
NTD
site 2) between CA helices 4, 5, and 7, on the surface of the CA
NTD
, that also corresponds to the binding site for the host factor CPSF-6. The functional consequences of BI-1 and BI-2 binding differ from previously characterized inhibitors that bind the same site since the BI compounds did not inhibit reverse transcription but stabilized preassembled CA complexes. Hence, this new class of antiviral compounds binds CA and may inhibit viral replication by stabilizing the viral capsid.
Immunochromatographic Detection of the Group B Streptococcus Antigen from Enrichment Cultures
Authors: Matsui Hidehito , Kimura Juri , Higashide Masato , Takeuchi Yoshio , Okue Kuniyuki , Cui Longzhu , Nakae Taiji , Sunakawa Keisuke , Hanaki Hideaki
Published: July 2013

Group B
Streptococcus
(GBS;
Streptococcus agalactiae
) is a leading cause of serious neonatal infections. The Centers for Disease Control and Prevention recommends GBS screening for all pregnant women during the 35th to 37th weeks of gestation. Although GBS screening has been performed mainly by the culture-based method, it takes several days to obtain a reliable result. In this study, we developed a rapid immunochromatographic test (ICT) for the detection of GBS-specific surface immunogenic protein in 15 min using an overnight enrichment culture. The ICT was prepared using two anti-Sip monoclonal antibodies. This ICT was able to detect recombinant Sip levels of 0.5 ng/ml, or about 10
6
CFU/ml of GBS cells, in tests with 9 GBS strains of different serotypes. The cross-reactivity test using 26 species of microorganism showed no detectable false-positive result. Reactivity of the ICT with 229 GBS strains showed one false-negative result that was attributable to the production of truncated Sip. Among 260 enrichment cultures of vaginal swabs, 17 produced red to orange pigments in Granada medium, and they were all GBS and Sip positive. Among 219 pigment-negative cultures, 12 were GBS positive and 10 were Sip positive. Two Sip-negative cultures contained GBS cells below the limit of detection by the ICT. Among 207 GBS-negative cultures, only one was Sip positive, which was attributable to GBS cell debris. Thus, the sensitivity and specificity of the ICT appeared to be 93.1% and 99.6%, respectively. The newly developed ICT is readily applicable to clinical use in the detection of GBS.
Severity of Allergic Airway Disease Due to House Dust Mite Allergen Is Not Increased after Clinical Recovery of Lung Infection with Chlamydia pneumoniae in Mice
Authors: Dutow Pavel , Lingner Sandra , Laudeley Robert , Glage Silke , Hoymann Heinz-Gerd , Dittrich Anna-Maria , Fehlhaber Beate , Müller Meike , Braun Armin , Klos Andreas
Published: July 2013

Chlamydia pneumoniae
is associated with chronic inflammatory lung diseases like bronchial asthma and chronic obstructive pulmonary disease. The existence of a causal link between allergic airway disease and
C. pneumoniae
is controversial. A mouse model was used to address the question of whether preceding
C. pneumoniae
lung infection and recovery modifies the outcome of experimental allergic asthma after subsequent sensitization with house dust mite (HDM) allergen. After intranasal infection, BALB/c mice suffered from pneumonia characterized by an increased clinical score, reduction of body weight, histopathology, and a bacterial load in the lungs. After 4 weeks, when infection had almost resolved clinically, HDM allergen sensitization was performed for another 4 weeks. Subsequently, mice were subjected to a methacholine hyperresponsiveness test and sacrificed for further analyses. As expected, after 8 weeks,
C. pneumoniae
-specific antibodies were detectable only in infected mice and the titer was significantly higher in the
C. pneumoniae
/HDM allergen-treated group than in the
C. pneumoniae
/NaCl group. Intriguingly, airway hyperresponsiveness and eosinophilia in bronchoalveolar lavage fluid were significantly lower in the
C. pneumoniae
/HDM allergen-treated group than in the mock/HDM allergen-treated group. We did observe a relationship between experimental asthma and chlamydial infection. Our results demonstrate an influence of sensitization to HDM allergen on the development of a humoral antibacterial response. However, our model demonstrates no increase in the severity of experimental asthma to HDM allergen as a physiological allergen after clinically resolved severe chlamydial lung infection. Our results rather suggest that allergic airway disease and concomitant cellular changes in mice are decreased following
C. pneumoniae
lung infection in this setting.
Evaluation of a New Commercially Available Immunoglobulin M Capture Enzyme-Linked Immunosorbent Assay for Diagnosis of Dengue Virus Infection
Authors: Namekar Madhuri , Ellis Esther M. , O'Connell Maile , Elm Joe , Gurary Alexandra , Park Sarah Y. , Imrie Allison , Nerurkar Vivek R.
Published: July 2013

We evaluated the FDA-cleared InBios dengue virus (DENV) IgM capture enzyme-linked immunosorbent assay (ELISA) for qualitative detection of anti-DENV IgM antibodies from 79 serum samples obtained from dengue virus-infected patients or suspected dengue cases. The agreement, sensitivity, and specificity of the InBios assay compared to the gold standard in-house DENV IgM capture ELISA were 94, 92, and 94%, respectively. We conclude that the InBios DENV IgM capture ELISA can be effectively used for rapid diagnosis of acute or recent DENV infection.
Emerging 8-Methoxyfluoroquinolone Resistance among Methicillin-Susceptible Staphylococcus epidermidis Isolates Recovered from Patients with Endophthalmitis
Authors: Bispo Paulo J. M. , Alfonso Eduardo C. , Flynn Harry W. , Miller Darlene
Published: July 2013

Fluoroquinolones remain the most commonly used antimicrobials for the prevention and management of bacterial endophthalmitis. Coagulase-negative staphylococci are the most frequently recovered pathogens. Increasing resistance among this group has paralleled the presence of methicillin resistance. From 2005 to 2010, we recovered 38 methicillin-susceptible
Staphylococcus epidermidis
(MSSE) isolates from endophthalmitis patients at our institute, including 15 (39.5%) isolates resistant to gatifloxacin and moxifloxacin, members of the C-8-methoxyfluoroquinolones family. Mutations in the quinolone resistance-determining regions (QRDR) of
gyrA
and
parC
were determined and correlated with fluoroquinolone MICs based on Etests of these 15 MSSE isolates. High-level resistance (MIC, >32 μg/ml) to gatifloxacin and moxifloxacin was documented for 46.7% of the MSSE isolates, and low-level resistance (MIC, 2 to 4 μg/ml) was determined for 53.3%. The MICs for ciprofloxacin, levofloxacin, and ofloxacin were >32 μg/ml for all isolates. The amino acid substitution Ser84Phe in
gyrA
was found among all isolates. A second mutation in
gyrA
(Glu88Lys) resulted in high-level resistance to moxifloxacin and gatifloxacin. Almost all (92.8%) isolates presented double point mutations in the
parC
gene at codons 80 and 84 with different combinations. Eighty-seven percent of the patients had prior exposure to topical 8-methoxyfluoroquinolones. Prior exposure to the 8-methoxyfluoroquinolones may contribute to the selection of MSSE strains containing multiple mutations in the QRDRs of
gyrA
and
parC
that results in low- and high-level resistance to these agents.
Molecular Diagnosis of Polycystic Echinococcosis Due to Echinococcus vogeli in a Paraguayan Immigrant in Argentina
Authors: Grenouillet F. , Frider B. , Alvarez Rodriguez J. , Amante M. , Pestalardo M. L. , Cazorla A. , Bresson-Hadni S. , Millon L.
Published: July 2013

Polycystic echinococcosis due to
Echinococcus vogeli
is a rare parasitic infection that occurs in rural areas of Central and South America. Only molecular identification performed on formalin-fixed paraffin-embedded liver tissue samples gave an unequivocal diagnosis of this disease in a Paraguayan immigrant in Argentina.
Comparison of the FilmArray RP, Verigene RV+, and Prodesse ProFLU+/FAST+ Multiplex Platforms for Detection of Influenza Viruses in Clinical Samples from the 2011-2012 Influenza Season in Belgium
Authors: Van Wesenbeeck Liesbeth , Meeuws Hanne , Van Immerseel Andrea , Ispas Gabriela , Schmidt Kristiane , Houspie Lieselot , Van Ranst Marc , Stuyver Lieven
Published: July 2013

Respiratory tract infections (RTIs) are caused by a plethora of viral and bacterial pathogens. In particular, lower RTIs are a leading cause of hospitalization and mortality. Timely detection of the infecting respiratory pathogens is crucial to optimize treatment and care. In this study, three U.S. Food and Drug Administration-approved molecular multiplex platforms (Prodesse ProFLU+/FAST+, FilmArray RP, and Verigene RV+) were evaluated for influenza virus detection in 171 clinical samples collected during the Belgian 2011-2012 influenza season. Sampling was done using mid-turbinate flocked swabs, and the collected samples were stored in universal transport medium. The amount of viral RNA present in the swab samples ranged between 3.07 and 8.82 log
10
copies/ml. Sixty samples were concordant influenza A virus positive, and 8 samples were found to be concordant influenza B virus positive. Other respiratory viruses that were detected included human rhinovirus/enterovirus, respiratory syncytial virus, parainfluenza virus type 1, human metapneumovirus, and coronavirus NL63. Twenty-five samples yielded discordant results across the various assays which required further characterization by sequencing. The FilmArray RP and Prodesse ProFLU+/FAST+ assays were convenient to perform with regard to sensitivity, ease of use, and low percentages of invalid results. Although the limit of sensitivity is of utmost importance, many other factors should be taken into account in selecting the most convenient molecular diagnostic assay for the detection of respiratory pathogens in clinical samples.
Evolutionarily Conserved Epitopes on Human Immunodeficiency Virus Type 1 (HIV-1) and Feline Immunodeficiency Virus Reverse Transcriptases Detected by HIV-1-Infected Subjects
Authors: Sanou Missa P. , Roff Shannon R. , Mennella Antony , Sleasman John W. , Rathore Mobeen H. , Yamamoto Janet K. , Levy Jay A.
Published: July 2013

Anti-human immunodeficiency virus (HIV) cytotoxic T lymphocyte (CTL)-associated epitopes, evolutionarily conserved on both HIV type 1 (HIV-1) and feline immunodeficiency virus (FIV) reverse transcriptases (RT), were identified using gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and carboxyfluorescein diacetate succinimide ester (CFSE) proliferation assays followed by CTL-associated cytotoxin analysis. The peripheral blood mononuclear cells (PBMC) or T cells from HIV-1-seropositive (HIV+) subjects were stimulated with overlapping RT peptide pools. The PBMC from the HIV+subjects had more robust IFN-γ responses to the HIV-1 peptide pools than to the FIV peptide pools, except for peptide-pool F3. In contrast, much higher and more frequent CD8+T-cell proliferation responses were observed with the FIV peptide pools than with the HIV peptide pools. HIV-1-seronegative subjects had no proliferation or IFN-γ responses to the HIV and FIV peptide pools. A total of 24% (40 of 166) of the IFN-γ responses to HIV pools and 43% (23 of 53) of the CD8+T-cell proliferation responses also correlated to responses to their counterpart FIV pools. Thus, more evolutionarily conserved functional epitopes were identified by T-cell proliferation than by IFN-γ responses. In the HIV+subjects, peptide-pool F3, but not the HIV H3 counterpart, induced the most IFN-γ and proliferation responses. These reactions to peptide-pool F3 were highly reproducible and persisted over the 1 to 2 years of testing. All five individual peptides and epitopes of peptide-pool F3 induced IFN-γ and/or proliferation responses in addition to inducing CTL-associated cytotoxin responses (perforin, granzyme A, granzyme B). The epitopes inducing polyfunctional T-cell activities were highly conserved among human, simian, feline, and ungulate lentiviruses, which indicated that these epitopes are evolutionarily conserved. These results suggest that FIV peptides could be used in an HIV-1 vaccine.
Ifit1 Inhibits Japanese Encephalitis Virus Replication through Binding to 5′ Capped 2′-O Unmethylated RNA
Authors: Kimura Taishi , Katoh Hiroshi , Kayama Hisako , Saiga Hiroyuki , Okuyama Megumi , Okamoto Toru , Umemoto Eiji , Matsuura Yoshiharu , Yamamoto Masahiro , Takeda Kiyoshi
Published: July 2013

The interferon-inducible protein with tetratricopeptide (IFIT) family proteins inhibit replication of some viruses by recognizing several types of RNAs, including 5′-triphosphate RNA and 5′ capped 2′-O unmethylated mRNA. However, it remains unclear how IFITs inhibit replication of some viruses through recognition of RNA. Here, we analyzed the mechanisms by which Ifit1 exerts antiviral responses. Replication of a Japanese encephalitis virus (JEV) 2′-O methyltransferase (MTase) mutant was markedly enhanced in mouse embryonic fibroblasts and macrophages lacking Ifit1. Ifit1 bound 5′-triphosphate RNA but more preferentially associated with 5′ capped 2′-O unmethylated mRNA. Ifit1 inhibited the translation of mRNA and thereby restricted the replication of JEV mutated in 2′-O MTase. Thus, Ifit1 inhibits replication of MTase-defective JEV by inhibiting mRNA translation through direct binding to mRNA 5′ structures.
Single Hemagglutinin Mutations That Alter both Antigenicity and Receptor Binding Avidity Influence Influenza Virus Antigenic Clustering
Authors: Li Yang , Bostick David L. , Sullivan Colleen B. , Myers Jaclyn L. , Griesemer Sara B. , StGeorge Kirsten , Plotkin Joshua B. , Hensley Scott E.
Published: July 2013

The hemagglutination inhibition (HAI) assay is the primary measurement used for identifying antigenically novel influenza virus strains. HAI assays measure the amount of reference sera required to prevent virus binding to red blood cells. Receptor binding avidities of viral strains are not usually taken into account when interpreting these assays. Here, we created antigenic maps of human H3N2 viruses that computationally account for variation in viral receptor binding avidities. These new antigenic maps differ qualitatively from conventional antigenic maps based on HAI measurements alone. We experimentally focused on an antigenic cluster associated with a single N145K hemagglutinin (HA) substitution that occurred between 1992 and 1995. Reverse-genetics experiments demonstrated that the N145K HA mutation increases viral receptor binding avidity. Enzyme-linked immunosorbent assays (ELISA) revealed that the N145K HA mutation does not prevent antibody binding; rather, viruses possessing this mutation escape antisera in HAI assays simply by attaching to cells more efficiently. Unexpectedly, we found an asymmetric antigenic effect of the N145K HA mutation. Once H3N2 viruses acquired K145, an epitope involving amino acid 145 became antigenically dominant. Antisera raised against an H3N2 strain possessing K145 had reduced reactivity to H3N2 strains possessing N145. Thus, individual mutations in HA can influence antigenic groupings of strains by altering receptor binding avidity and by changing the dominance of antibody responses. Our results indicate that it will be important to account for variation in viral receptor binding avidity when performing antigenic analyses in order to identify genuine antigenic differences among influenza virus variants.
Herpes Simplex Virus 1-Encoded Tegument Protein VP16 Abrogates the Production of Beta Interferon (IFN) by Inhibiting NF-κB Activation and Blocking IFN Regulatory Factor 3 To Recruit Its Coactivator CBP
Authors: Xing Junji , Ni Liwen , Wang Shuai , Wang Kezhen , Lin Rongtuan , Zheng Chunfu
Published: July 2013

Host cells activate innate immune signaling pathways to defend against invading pathogens. To survive within an infected host, viruses have evolved intricate strategies to counteract host immune responses. Herpesviruses, including herpes simplex virus type 1 (HSV-1), have large genomes and therefore have the capacity to encode numerous proteins that modulate host innate immune responses. Here we define the contribution of HSV-1 tegument protein VP16 in the inhibition of beta interferon (IFN-β) production. VP16 was demonstrated to significantly inhibit Sendai virus (SeV)-induced IFN-β production, and its transcriptional activation domain was not responsible for this inhibition activity. Additionally, VP16 blocked the activation of the NF-κB promoter induced by SeV or tumor necrosis factor alpha treatment and expression of NF-κB-dependent genes through interaction with p65. Coexpression analysis revealed that VP16 selectively blocked IFN regulatory factor 3 (IRF-3)-mediated but not IRF-7-mediated transactivation. VP16 was able to bind to IRF-3 but not IRF-7
in vivo
, based on coimmunoprecipitation analysis, but it did not affect IRF-3 dimerization, nuclear translocation, or DNA binding activity. Rather, VP16 interacted with the CREB binding protein (CBP) coactivator and efficiently inhibited the formation of the transcriptional complexes IRF-3–CBP in the context of HSV-1 infection. These results illustrate that VP16 is able to block the production of IFN-β by inhibiting NF-κB activation and interfering with IRF-3 to recruit its coactivator CBP, which may be important to the early events leading to HSV-1 infection.
Mortality by education level at late-adult ages in Turin: a survival analysis using frailty models with period and cohort approaches
Authors: Zarulli Virginia , Marinacci Chiara , Costa Giuseppe , Caselli Graziella
Published: July 2013

Objectives

Neglecting the presence of unobserved heterogeneity in survival analysis models has been showed to potentially lead to underestimating the effect of the covariates included in the analysis. This study aimed to investigate the role of unobserved heterogeneity of frailty on the estimation of mortality differentials from age 50 on by education level.

Design

Longitudinal mortality follow-up of the census-based Turin population linked with the city registry office.

Setting

Italian North-Western city of Turin, observation window 1971–2007.

Population

391 170 men and 456 216 women followed from age 50.

Primary outcome measures

Mortality rate ratios obtained from survival analysis regression. Models were estimated with and without the component of unobserved heterogeneity of frailty and controlling for mortality improvement over time from both cohort and period perspectives.

Results

In the majority of cases, the models without frailty estimated a smaller educational gradient than the models with frailty.

Conclusions

The results draw the attention of the potential underestimation of the mortality inequalities by socioeconomic levels in survival analysis models when not controlling for unobserved heterogeneity of frailty.
Frequent callers to and users of emergency medical systems: a systematic review
Authors: Scott Jason , Strickland Annette Patricia , Warner Karen , Dawson Pamela
Published: July 2013

Background

There appears to be a paucity of studies examining the characteristics and impact of frequent users upon emergency medical services (EMS).

Objective

To review current primary research on frequent users of EMS and to identify possible gaps in the literature.

Methods

Ovid, PubMed and CINAHL/Medline were systematically searched for articles that were published in English and either referred to frequent callers to or users of an EMS, or referred to frequent users of other services where admissions were via ambulance. Studies were included regardless of quality.

Findings

Eighteen studies were included. Ten were emergency department based, seven in EMS and one in a psychiatric emergency service. In emergency department studies, frequent users were more likely to arrive via ambulance than infrequent users. In EMS studies, between 0.2% and 23% of patients using EMS were frequent users accounting for 1.4% to 40% of all ambulance use. No two EMS studies used the same definition of a frequent user. No studies focused on characteristics of callers to EMS. Two studies explored interventions for frequent callers to EMS, with mixed results in reducing ambulance use.

Discussion

It is unknown to what extent frequent callers impact upon EMS resources. Research should identify predictors and characteristics of frequent users of EMS, and a consistent definition of a frequent caller to or user of EMS would provide greater comparability. The lack of studies identified in this review suggests that further research is needed in order to inform policy and practice.
THERM: the Resuscitation Management score. A prognostic tool to identify critically ill patients in the emergency department
Authors: Cattermole G N , Liow E C H , Graham C A , Rainer T H
Published: July 2013

Introduction

Prognostic scores are widely used in the emergency department (ED) to stratify risk for critically ill patients. The Prince of Wales ED Score (PEDS) was derived specifically for patients in an ED resuscitation room to predict death or intensive care unit (ICU) admission. We aimed to validate and refine this score, in comparison with other scores including the National Early Warning Score (NEWS).

Methods

This was a single-centre prospective study of adult resuscitation-room patients over 3 months.

Comparison of scores was made using receiver operating characteristic analysis. Physiological and blood test variables were compared according to the composite primary outcome: admission to ICU or death within 7 days of attendance. Multivariate logistic regression was used to derive a new prediction score, which was validated in comparison with NEWS using the historic dataset from which PEDS had been derived.

Results

234 patients were included; 37 were admitted to ICU or died within 7 days. PEDS performed adequately but was not superior to other scores. A simple pragmatic score, The Resuscitation Management score (THERM) was derived which outperformed NEWS in derivation and validation sets.

Conclusions

PEDS is at least as good as other scores, including NEWS. However, it is unwieldy and relies on results not immediately accessible in the ED. THERM is a new score, derived and validated in an ED setting, using variables readily available, and simple to calculate and stratify. THERM outperforms NEWS and could be used in preference in critically ill ED patients.
Finite-time H∞ filtering for discrete-time Markovian jump systems with partly unknown transition probabilities
Authors: Cheng Jun , Zhu Hong , Zhong Shouming , Zhang Yuping , Li Guihua
Published: July 2013

This paper addresses the problems of finite-time stochastic stability and stabilization for linear Markovian jump systems subject to partial information on the transition probabilities. By introducing bounded finite time and stochastic character, sufficient conditions that can ensure bounded finite time and H∞ finite-time bounded filtering are derived. Finally, an example is given to illustrate the efficiency of the proposed method.
The effect of bicarbonate on menadione-induced redox cycling and cytotoxicity: potential involvement of the carbonate radical
Authors: Aljuhani Naif , Michail Karim , Karapetyan Zubeida , Siraki Arno G.
Published: July 2013

We have investigated the effect of NaHCO3on menadione redox cycling and cytotoxicity. A cell-free system utilized menadione and ascorbic acid to catalyze a redox cycle, and we utilized murine hepatoma (Hepa 1c1c7) cells for in vitro experiments. Experiments were performed using low (2 mmol/L) and physiological (25 mmol/L) levels of NaHCO3in buffer equilibrated to physiological pH. Using oximetry, ascorbic acid oxidation, and ascorbyl radical detection, we found that menadione redox cycling was enhanced by NaHCO3. Furthermore, Hepa 1c1c7 cells treated with menadione demonstrated cytotoxicity that was significantly increased with physiological concentrations of NaHCO3in the media, compared with low levels of NaHCO3. Interestingly, the inhibition of superoxide dismutase (SOD) with 2 different metal chelators was associated with a protective effect against menadione cytotoxicity. Using isolated protein, we found a significant increase in protein carbonyls with menadione–ascorbate–SOD with physiological NaHCO3levels; low NaHCO3or SOD-free reactions produced lower levels of protein carbonyls. In conclusion, these findings suggest that the hydrogen peroxide generated by menadione redox cycling together with NaHCO3–CO2are potential substrates for SOD peroxidase activity that can lead to carbonate-radical-enhanced cytotoxicity. These findings demonstrate the importance of NaHCO3in menadione redox cycling and cytotoxicity.
Cardioprotection against myocardial reperfusion injury: successes, failures, and perspectives
Authors: Duicu Oana M. , Angoulvant Denis , Muntean Danina M.
Published: July 2013

The past few decades have witnessed an enormous number of research strategies aimed at protecting the heart against myocardial ischemia–reperfusion injury. Several randomized clinical trials are nowadays in progress testing whether promising therapeutic strategies aimed at preventing lethal reperfusion injury can be translated from bench to bedside. Many of these interventions, either pharmacological or mechanical, are targeting mitochondria as the final effectors of cardioprotection. Despite encouraging pre-clinical studies and small proof of concept clinical trials, there are still several limitations that may jeopardize the efficacy of cardioprotective strategies. These limitations include clinical setting, patient profile, drug administration, and methods for evaluating treatment efficacy. Identifying potential mechanistic and methodological pitfalls in the field may improve future translational research.
IMPROVING ROBUSTNESS OF COUPLED NETWORKS AGAINST CASCADING FAILURES
Authors: WANG JIANWEI , JIANG CHEN , QIAN JIANFEI
Published: July 2013

Many real-world networks interact with other networks by only several links, for example, transportation networks and aviation networks among cities, internet router network among the different regions, power supply network among cities and so on. Understanding how to protect these coupled networks and improve their robustness against cascading failures is very important. By protecting the edges between coupled networks, we investigate its efficiency on improving the robustness of coupled networks against cascading failures. Fixing the total protective cost of coupled networks, we find that adjusting the capacities of the edges among coupled networks can better improve the robustness of coupled networks against cascading failures and observe that the more uniform the distribution of the edge load, the more effective the protection strategy. In addition, by immunizing the edges among coupled networks, we compare two protecting methods and find that the immunization strategy can better protect coupled networks. Our results are useful not only for how to protect coupled networks from the local perspective, but also for significantly improving the robustness of a single network by protecting some key edges.
CHARMONIUM PRODUCTION IN Pb–Pb COLLISIONS AT ALICE: FROM SUPPRESSION TO REGENERATION?
Authors: SCOMPARIN ENRICO
Published: July 2013

Heavy quarkonium states are considered as one of the key observables for the study of the phase transition from a system made of hadrons towards a Quark–Gluon Plasma (QGP). In the last 25 years, experiments at CERN and Brookhaven have studied collisions of heavy ions looking for a suppression of charmonia/bottomonia, considered as a signature of the phase transition. After an introduction to the main concepts behind these studies and a short review of the SPS and RHIC results, I will describe the results obtained in Pb – Pb collisions by the ALICE experiment at the LHC. The ALICE findings will be critically compared to those of lower energy experiments, to CMS results, and to model calculations. The large cross-sections for heavy-quark production at LHC energies are expected to induce a novel production mechanism for charmonia in heavy-ion collisions, related to a recombination of [Formula: see text] pairs along the history of the collision and/or at hadronization. The occurrence of such a process at the LHC will be discussed. Finally, prospects for future measurements will be shortly addressed.
ADAPTIVE FUNCTION Q-S SYNCHRONIZATION OF DIFFERENT CHAOTIC (HYPER-CHAOTIC) SYSTEMS
Authors: ZHAO JIAKUN , WU YING , WANG YUYING
Published: July 2013

This paper presents the general method for the adaptive function Q-S synchronization of different chaotic (hyper-chaotic) systems. Based upon the Lyapunov stability theory, the dynamical evolution can be achieved by the Q-S synchronization with a desired scaling function between the different chaotic (hyper-chaotic) systems. This approach is successfully applied to two examples: Chen hyper-chaotic system drives the Lorenz hyper-chaotic system; Lorenz system drives Lü hyper-chaotic system. Numerical simulations are used to validate and demonstrate the effectiveness of the proposed scheme.
A SPACE–TIME CE/SE METHOD FOR SOLVING HYPERBOLIC HEAT CONDUCTION MODEL
Authors: QAMAR SHAMSUL , ASHRAF WAQAS
Published: July 2013

This paper is concerned with the numerical approximation of one and two-dimensional models describing heat conduction in solids at low temperature. The system contains a conservation equation for the energy density and balance equations for the heat fluxes along each characteristic direction. A conservation element and solution element method (CE/E) is proposed for solving the given model. The method has already shown its efficiency and accuracy for solving a wide range of engineering problems. This technique is considerably different in both logic and design from the well-established finite volume schemes. The scheme treats space and time in a unified manner where conserved variables and their gradients are considered as independent unknowns. To illustrate the performance of the CE/SE method, several one and two-dimensional numerical case studies are carried out. The results of kinetic flux vector splitting (KFVS) scheme and central scheme are also presented for the comparison and further validation of our numerical results. The computations of this paper demonstrates that CE/SE method is effective in handling such problems.
DNA ORIGAMI SITE-SPECIFIC ARRANGEMENT OF GOLD NANOPARTICLES
Authors: GEORGE AMOAKO , YE RIAN , ZHUANG LIZHOU , YANG XIAOHONG , SHEN ZHIYONG , ZHOU MING
Published: July 2013

Controlling matter at the nanoscale holds a lot of promise in nanotechnology. The DNA origami is promising if used as a template to design and arrange matter at the nanoscale. We have used the DNA origami approach to engineer staple strands at selected sites for attachment of gold nanoparticles. The covalent attachment of thiol-modified DNA oligomers was used to functionalize gold nanoparticles. These oligomers then hybridize with complementary strands extended on selected staple strands on the DNA origami surface with nanometer precision. Gold nanoparticles of 5 nm diameter were arranged across a DNA origami tube to form a C -shape which has potential use in electronics and plasmonics. Agarose gel electrophoresis, AFM, UV-Vis spectroscopy and TEM were used to characterize the structure.
DETERMINISTIC SEISMIC HAZARD ANALYSIS OF ANDAMAN AND NICOBAR ISLANDS
Authors: KATARIA N. P. , SHRIKHANDE M. , DAS J. D.
Published: July 2013

An important component of hazard mitigation is to estimate the future hazard for design calculations. In the present study, a deterministic seismic hazard assessment of Andaman and Nicobar region is carried out, which is one of the most seismically active regions of India. The study area is divided into seven seismogenic source zones based on seismicity and tectonic setting. For ground motion estimation at Andaman and Nicobar, for each seismogenic zone different attenuation relationship is used as per tectonic setting of that seismogenic zone. In order to generate the site specific design spectrum, final results are calculated in the form of peak ground acceleration (PGA) and 5%-damped pseudo-spectral acceleration (PSA) for 0.2 s and 1 s. Calculated results are compared with some earlier works for the studied area and the probable reasons for variations are discussed.
Constraints on Antarctic Ice Sheet configuration during and following the Last Glacial Maximum and its episodic contribution to sea-level rise
Authors: Anderson John B. , Kirshner Alexandra E. , Simms Alexander R.
Published: July 2013

Marine geological studies provide a record of diachronous expansion and retreat of the Antarctic Peninsula Ice Sheet, West Antarctic Ice Sheet and East Antarctic Ice Sheet during the past
c.
30 000 cal yr BP. Retreat of these ice sheets and Antarctica’s contribution to sea-level rise was largely complete by the early Holocene. Estimates of ice sheet thickness, based on maximum grounding depths, range from 640 to 1640 m on the inner continental shelf. Grounding depths on the outer continental shelf equate to minimum thicknesses of 410–950 m. Geomorphic features indicate that retreat from the continental shelf was mostly step-wise around the continent, a result of the different factors that control ice sheet behaviour and the degree to which these factors vary regionally. Thus, the nature of post-LGM (Last Glacial Maximum) sea-level rise was episodic and believed to have been punctuated by rapid pulses triggered by individual ice stream collapse. Most of these pulses would have been of sub-metre magnitudes and below the resolution of existing sea-level curves, but they would have had significant impact on coastal evolution, especially along low-gradient coasts.