bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multilaboratory Assessment of Threshold versus Fold-Change Algorithms for Minimizing Analytical Variability in Multiplexed Pneumococcal IgG Measurements
Authors: Daly Thomas M. , Pickering Jerry W. , Zhang Xiaochun , Prince Harry E. , Hill Harry R. 
Published: May 2014

ABSTRACTPneumococcal vaccination is frequently used to assess a patient's humoral immune function. The comparison of pre- and postvaccination levels of antipneumococcal antibodies is widely held to be the gold standard for documenting a response. However, many of the published criteria for defining an adequate response are based on assays that are no longer widely available. We compared the clinical classification of patient response by multiplex pneumococcal assays currently performed at three large reference laboratories using a variety of published criteria for defining responses in adults. The classification of responders agreed for 79% of the patients when using a threshold-based algorithm compared to 57 to 96% of the patients when using various fold-change-based algorithms. The highest rate of discordance was seen when the most stringent criteria for response were used (4-fold increase postvaccination in 70% of serotypes). The discordant samples tended to show similar patterns of response across all three assays, with small variations in the final number of serotypes converting postvaccination. We conclude that the use of published cut points for documenting response to pneumococcal vaccination can be affected by interlaboratory differences in pneumococcal assays, particularly for algorithms that require large fold changes for a response to be documented. However, the overall patterns of response were similar in virtually all samples, regardless of the assay used.
Interleukin 1 (IL-1)- and IL-23-Mediated Expansion of Filarial Antigen-Specific Th17 and Th22 Cells in Filarial Lymphedema
Authors: Anuradha R. , George P. Jovvian , Chandrasekaran V. , Kumaran P. Paul , Nutman Thomas B. , Babu Subash 
Published: May 2014

ABSTRACTLymphatic filarial disease is known to be associated with elevated Th1 responses and normal or diminished Th2 responses to parasite-specific antigens. The roles of Th17 cells and the recently described Th22 cells have not been examined in detail in either filarial infection itself or in filarial disease (e.g., lymphedema and elephantiasis). To explore the roles of Th17 and Th22 cells and their subsets, we examined the frequencies of these cells in individuals with filarial lymphedema (chronic pathology [CP]), in clinically asymptomatic infected (INF) individuals, and in uninfected (UN) individualsex vivoand in response to parasite and nonparasite antigens. Those with disease (CP) had significantly expanded frequencies of Th17 and Th22 cells, compared with either INF or UN individuals, at baseline (ex vivo) and in response to parasite antigens. This antigen-driven expansion of Th17 and Th22 cells was dependent on interleukin 1 (IL-1), IL-23, and, to lesser extent, transforming growth factor β (TGF-β), as blockade of any of these cytokines resulted in significantly diminished frequencies of Th17 and Th22 cells. Our findings, therefore, suggest that filarial parasite-driven expansion of Th17 and Th22 cells is associated with the pathogenesis of filarial infections and disease.
Comparative Evaluation of 11 Commercialized Rapid Diagnostic Tests for Detecting Trypanosoma cruzi Antibodies in Serum Banks in Areas of Endemicity and Nonendemicity
Authors: Sánchez-Camargo Claudia L. , Albajar-Viñas Pedro , Wilkins Patricia P. , Nieto Javier , Leiby David A. , Paris Luc , Scollo Karenina , Flórez Carolina , Guzmán-Bracho Carmen , Luquetti Alejandro O. , Calvo Nidia , Tadokoro Kenji , Saez-Alquezar Amadeo , Palma Pedro Pablo , Martin Miguel , Flevaud Laurence 
Published: May 2014

ABSTRACT

Chagas disease is one of the main public health issues in Latin America. Increasingly during the past few decades,
Trypanosoma cruzi
infection has been detected in North America, Europe, and the Western Pacific, mainly as a result of population movement. The limited availability of rapid serological diagnostic tests hinders rapid diagnosis and early treatment in areas of endemicity and nonendemicity. In collaboration with 11 national reference laboratories (NRLs) from different geographical areas, we evaluated the performances of commercialized serological rapid diagnostic tests (RDT) for
T. cruzi
infection. Eleven commercialized
T. cruzi
infection RDTs were evaluated on a total of 474 samples extensively tested with at least three different techniques for Chagas disease, maintained at controlled low temperatures, and stored in the serum banks of the 11 NRLs. We measured the sensitivity, specificity, and concordance of each RDT and provided an additional questionnaire to evaluate its ease of use. The selected RDTs in this study were performed under controlled laboratory conditions. Out of the 11 RDTs, we found 8 of them to be useful, with the cassette format favored over the strip. We did not observe significant differences in RDT performances in the different regions. Overall, the performance results were lower than those disclosed by the manufacturers. The results of this evaluation validate the possibility of using RDTs to diagnose Chagas disease, thereby decreasing the time to treatment at a primary health care facility for patients who are willing to be treated. Further studies should be conducted in the laboratory and in the field to confirm these data, expressly to evaluate reproducibility in resource-limited settings, or using whole blood in clinical settings in areas of endemicity and nonendemicity.
The Capnocytophaga canimorsus Isolate That Caused Sepsis in an Immunosufficient Man Was Transmitted by the Large Pine Weevil Hylobius abietis
Authors: Tuuminen Tamara , Viiri Heli , Vuorinen Sakari 
Published: May 2014

ABSTRACTThe first vector-borneCapnocytophaga canimorsussepsis case is presented. An immunocompetent male who denied any contact with canines and who worked in a sawmill was bitten on his neck by a large pine weevil (Hylobius abietisL.; Coleoptera: Curculionidae). Bacteriological diagnosis was confirmed by 16S rRNA gene sequence analysis.
RIOK3 Is an Adaptor Protein Required for IRF3-Mediated Antiviral Type I Interferon Production
Authors: Feng Jun , De Jesus Paul D. , Su Victoria , Han Stephanie , Gong Danyang , Wu Nicholas C. , Tian Yuan , Li Xudong , Wu Ting-Ting , Chanda Sumit K. , Sun Ren 
Published: May 2014

ABSTRACT
Detection of cytosolic nucleic acids by pattern recognition receptors leads to the induction of type I interferons (IFNs) and elicits the innate immune response. We report here the identification of RIOK3 as a novel adaptor protein that is essential for the cytosolic nucleic acid-induced type I IFN production and for the antiviral response to gammaherpesvirus through two independent kinome-wide RNA interference screens. RIOK3 knockdown blocks both cytosolic double-stranded B-form DNA and double-stranded RNA-induced IRF3 activation and IFN-β production. In contrast, the overexpression of RIOK3 activates IRF3 and induces IFN-β. RIOK3 functions downstream of TBK1 and upstream of IRF3 activation. Furthermore, RIOK3 physically interacts with both IRF3 and TBK1 and is necessary for the interaction between TBK1 and IRF3. In addition, global transcriptome analysis shows that the expression of many gene involved antiviral responses is dependent on RIOK3. Thus, knockdown of RIOK3 inhibits cellular antiviral responses against both DNA and RNA viruses (herpesvirus and influenza A virus). Our data suggest that RIOK3 plays a critical role in the antiviral type I IFN pathway by bridging TBK1 and IRF3.

IMPORTANCE
The innate immune response, such as the production of type I interferons, acts as the first line of defense, limiting infectious pathogens directly and shaping the adaptive immune response. In this study, we identified RIOK3 as a novel regulator of the antiviral type I interferon pathway. Specifically, we found that RIOK3 physically interacts with TBK1 and IRF3 and bridges the functions between TBK1 and IRF3 in the activation of type I interferon pathway. The identification of a cellular kinase that plays a role the type I interferon pathway adds another level of complexity in the regulation of innate immunity and will have implications for developing novel strategies to combat viral infection.
Antibody-Mediated Enhancement of Parvovirus B19 Uptake into Endothelial Cells Mediated by a Receptor for Complement Factor C1q
Authors: von Kietzell Kristina , Pozzuto Tanja , Heilbronn Regine , Grössl Tobias , Fechner Henry , Weger Stefan 
Published: May 2014

ABSTRACTDespite its strong host tropism for erythroid progenitor cells, human parvovirus B19 (B19V) can also infect a variety of additional cell types. Acute and chronic inflammatory cardiomyopathies have been associated with a high prevalence of B19V DNA in endothelial cells of the myocardium. To elucidate the mechanisms of B19V uptake into endothelium, we first analyzed the surface expression of the well-characterized primary B19V receptor P antigen and the putative coreceptors α5β1integrins and Ku80 antigen on primary and permanent endothelial cells. The receptor expression pattern and also the primary attachment levels were similar to those in the UT7/Epo-S1 cell line regarded as functional for B19V entry, but internalization of the virus was strongly reduced. As an alternative B19V uptake mechanism in endothelial cells, we demonstrated antibody-dependent enhancement (ADE), with up to a 4,000-fold increase in B19V uptake in the presence of B19V-specific human antibodies. ADE was mediated almost exclusively at the level of virus internalization, with efficient B19V translocation to the nucleus. In contrast to monocytes, where ADE of B19V has been described previously, enhancement does not rely on interaction of the virus-antibody complexes with Fc receptors (FcRs), but rather, involves an alternative mechanism mediated by the heat-sensitive complement factor C1q and its receptor, CD93. Our results suggest that ADE represents the predominant mechanism of endothelial B19V infection, and it is tempting to speculate that it may play a role in the pathogenicity of cardiac B19V infection.IMPORTANCEBoth efficient entry and productive infection of human parvovirus B19 (B19V) seem to be limited to erythroid progenitor cells. However,in vivo, the viral DNA can also be detected in additional cell types, such as endothelial cells of the myocardium, where its presence has been associated with acute and chronic inflammatory cardiomyopathies. In this study, we demonstrated that uptake of B19V into endothelial cells most probably does not rely on the classical receptor-mediated route via the primary B19V receptor P antigen and coreceptors, such as α5β1integrins, but rather on antibody-dependent mechanisms. Since the strong antibody-dependent enhancement (ADE) of B19V entry requires the CD93 surface protein, it very likely involves bridging of the B19V-antibody complexes to this receptor by the complement factor C1q, leading to enhanced endocytosis of the virus.
Cytosolic PrP Can Participate in Prion-Mediated Toxicity
Authors: Thackray Alana M. , Zhang Chang , Arndt Tina , Bujdoso Raymond 
Published: May 2014

ABSTRACT

Prion diseases are characterized by a conformational change in the normal host protein PrPC. While the majority of mature PrPC is tethered to the plasma membrane by a glycosylphosphatidylinositol anchor, topological variants of this protein can arise during its biosynthesis. Here we have generated
Drosophila
transgenic for cytosolic ovine PrP in order to investigate its toxic potential in flies in the absence or presence of exogenous ovine prions. While cytosolic ovine PrP expressed in
Drosophila
was predominantly detergent insoluble and showed resistance to low concentrations of proteinase K, it was not overtly detrimental to the flies. However,
Drosophila
transgenic for cytosolic PrP expression exposed to classical or atypical scrapie prion inocula showed a faster decrease in locomotor activity than similar flies exposed to scrapie-free material. The susceptibility to classical scrapie inocula could be assessed in
Drosophila
transgenic for panneuronal expression of cytosolic PrP, whereas susceptibility to atypical scrapie required ubiquitous PrP expression. Significantly, the toxic phenotype induced by ovine scrapie in cytosolic PrP transgenic
Drosophila
was transmissible to recipient PrP transgenic flies. These data show that while cytosolic PrP expression does not adversely affect
Drosophila
, this topological PrP variant can participate in the generation of transmissible scrapie-induced toxicity. These observations also show that PrP transgenic
Drosophila
are susceptible to classical and atypical scrapie prion strains and highlight the utility of this invertebrate host as a model of mammalian prion disease.

IMPORTANCE
During prion diseases, the host protein PrPC converts into an abnormal conformer, PrPSc, a process coupled to the generation of transmissible prions and neurotoxicity. While PrPC is principally a glycosylphosphatidylinositol-anchored membrane protein, the role of topological variants, such as cytosolic PrP, in prion-mediated toxicity and prion formation is undefined. Here we generated
Drosophila
transgenic for cytosolic PrP expression in order to investigate its toxic potential in the absence or presence of exogenous prions. Cytosolic ovine PrP expressed in
Drosophila
was not overtly detrimental to the flies. However, cytosolic PrP transgenic
Drosophila
exposed to ovine scrapie showed a toxic phenotype absent from similar flies exposed to scrapie-free material. Significantly, the scrapie-induced toxic phenotype in cytosolic transgenic
Drosophila
was transmissible to recipient PrP transgenic flies. These data show that cytosolic PrP can participate in the generation of transmissible prion-induced toxicity and highlight the utility of
Drosophila
as a model of mammalian prion disease.
Novel Roles of Cytoplasmic ICP0: Proteasome-Independent Functions of the RING Finger Are Required To Block Interferon-Stimulated Gene Production but Not To Promote Viral Replication
Authors: Taylor Kathryne E. , Chew Marianne V. , Ashkar Ali A. , Mossman Karen L. 
Published: May 2014

ABSTRACT
The immediate-early protein ICP0 from herpes simplex virus 1 (HSV-1) plays pleiotropic roles in promoting viral lytic replication and reactivation from latency. Most of the known actions of ICP0 occur in the nucleus and are thought to involve the E3 ubiquitin ligase activity of its RING finger domain, which targets proteins for degradation via the proteasome. Although ICP0 translocates to the cytoplasm as the infection progresses, little is known about its activities in this location. Here, we show that cytoplasmic ICP0 has two distinct functions. In primary cell cultures and in an intravaginal mouse model, cytoplasmic ICP0 promotes viral replication in the absence of an intact RING finger domain. Additionally, ICP0 blocks the activation of interferon regulatory factor 3 (IRF3), a key transcription factor of the innate antiviral response, in a mechanism that requires the RING finger domain but not the proteasome. To our knowledge, this is the first observation of a proteasome-independent function of the RING finger domain of ICP0. Collectively, these results underscore the importance of cytoplasm-localized ICP0 and the diverse nature of its activities.

IMPORTANCE
Despite ICP0 being a well-studied viral protein, the significance of its cytoplasmic localization has been largely overlooked. This is, in part, because common experimental manipulations result in the restriction of ICP0 to the nucleus. By overcoming this constraint, we both further characterize the ability of cytoplasmic ICP0 to inhibit antiviral signaling and show that ICP0 at this site has unexpected activities in promoting viral replication. This demonstrates the importance of considering location when analyzing protein function and adds a new perspective to our understanding of this multifaceted protein.
Replication of Many Human Viruses Is Refractory to Inhibition by Endogenous Cellular MicroRNAs
Authors: Bogerd Hal P. , Skalsky Rebecca L. , Kennedy Edward M. , Furuse Yuki , Whisnant Adam W. , Flores Omar , Schultz Kimberly L. W. , Putnam Nicole , Barrows Nicholas J. , Sherry Barbara , Scholle Frank , Garcia-Blanco Mariano A. , Griffin Diane E. , Cullen Bryan R. 
Published: May 2014

ABSTRACT
The issue of whether viruses are subject to restriction by endogenous microRNAs (miRNAs) and/or by virus-induced small interfering RNAs (siRNAs) in infected human somatic cells has been controversial. Here, we address this question in two ways. First, using deep sequencing, we demonstrate that infection of human cells by the RNA virus dengue virus (DENV) or West Nile virus (WNV) does not result in the production of any virus-derived siRNAs or viral miRNAs. Second, to more globally assess the potential of small regulatory RNAs to inhibit virus replication, we used gene editing to derive human cell lines that lack a functional Dicer enzyme and that therefore are unable to produce miRNAs or siRNAs. Infection of these cells with a wide range of viruses, including DENV, WNV, yellow fever virus, Sindbis virus, Venezuelan equine encephalitis virus, measles virus, influenza A virus, reovirus, vesicular stomatitis virus, human immunodeficiency virus type 1, or herpes simplex virus 1 (HSV-1), failed to reveal any enhancement in the replication of any of these viruses, although HSV-1, which encodes at least eight Dicer-dependent viral miRNAs, did replicate somewhat more slowly in the absence of Dicer. We conclude that most, and perhaps all, human viruses have evolved to be resistant to inhibition by endogenous human miRNAs during productive replication and that dependence on a cellular miRNA, as seen with hepatitis C virus, is rare. How viruses have evolved to avoid inhibition by endogenous cellular miRNAs, which are generally highly conserved during metazoan evolution, remains to be determined.

IMPORTANCE
Eukaryotic cells express a wide range of small regulatory RNAs, including miRNAs, that have the potential to inhibit the expression of mRNAs that show sequence complementarity. Indeed, previous work has suggested that endogenous miRNAs have the potential to inhibit viral gene expression and replication. Here, we demonstrate that the replication of a wide range of pathogenic viruses is not enhanced in human cells engineered to be unable to produce miRNAs, indicating that viruses have evolved to be resistant to inhibition by miRNAs. This result is important, as it implies that manipulation of miRNA levels is not likely to prove useful in inhibiting virus replication. It also focuses attention on the question of how viruses have evolved to resist inhibition by miRNAs and whether virus mutants that have lost this resistance might prove useful, for example, in the development of attenuated virus vaccines.
Rules and Exceptions: Sialic Acid Variants and Their Role in Determining Viral Tropism
Authors: Stehle Thilo , Khan Zaigham M. 
Published: May 2014

ABSTRACT

Sialic acids decorate the surfaces of most mammalian cells and are used by many viruses as attachment receptors. In contrast to other mammals, humans cannot synthesize a version of sialic acid known as
N
-glycolyl neuraminic acid. This difference is exploited by some viruses to establish tropism. Here we compare recently determined structures of closely related animal and human polyomaviruses and examine their strategies for engaging specific sialic acid variants.
Pore-pressure cycling experiments on Mx80 Bentonite
Authors: Graham C. C. , Harrington J. F. , Cuss R. J. , Sellin P. 
Published: May 2014

Abstract

The Swedish concept for geological disposal of radioactive waste involves the use of bentonite as part of an engineered barrier system. A primary function of the bentonite is its ability to swell when hydrated by its surroundings. One particular uncertainty is the impact on this function, resulting from deviations in pore-water pressure,
p

w

, from expected
in situ
hydrostatic conditions. We present results from a series of laboratory experiments designed to investigate the form of the relationship between swelling pressure and
p

w

, for compacted Mx80 bentonite, from low to elevated applied water pressure conditions. The experiments were conducted using constant volume cells, designed to allow the total stresses acting on the surrounding vessel to be monitored (at five locations) during clay swelling. The results demonstrate that swelling pressure reduces non-linearly with increasing
p

w

, becoming less sensitive to changes at elevated pressures. After cyclic loading a marked hysteresis was also observed, with swelling pressure remaining elevated after a subsequent reduction in applied water pressure. Such behaviour may impact the mechanical and transport properties of the bentonite and its resulting performance. However, such hysteric behaviour was not always observed. Further testing is required to better understand the causes of this phenomenon and the controls on such behaviour.
Full-scale 3D modelling of a nuclear waste repository in the Callovo-Oxfordian clay. Part 1: thermo-hydraulic two-phase transport of water and hydrogen
Authors: Brommundt J. , Kaempfer Th. U. , Enssle C. P. , Mayer G. , Wendling J. 
Published: May 2014

Abstract
The development of deep geological repositories for nuclear waste requires a sound system understanding, to which performance analyses by means of numerical flow and transport simulations form an important contribution. In this context, we present modelling studies of the thermo-hydraulic two-phase transport of water and hydrogen in the planned French repository in this paper, part 1. Part 2 of this paper uses the same modelling concept extended to include radionuclide transport. The numerical TOUGH2-MP-model encompasses the host rock from cap to bed rock, including the repository in full 3D. We compare two repository layouts and assess their robustness through sensitivity simulations with varied key parameters and hydrogen generation regimes, and a coupling of hydrogen generation to water availability. The results show that a continuous gas phase functions as balancing system between connected waste areas. Its extension and continuity depend on the permeability and diffusion parameters, and the amount and temporal regime of hydrogen production. Naturally, the available storage volumes have an impact as well. The layout with larger storage volume behaves more benevolenty towards parameter variations. Overall, both layouts perform satisfactorily. Our methodology enables detailed studies of the global system behaviour and helps to compare different repository layouts.