bluuebunny/crossref_metadata_2025 huggingface dataset:
Low‐Chlorinated Non‐Dioxin‐like Polychlorinated Biphenyls Present in Blood and Breast Milk Induce Higher Levels of Reactive Oxygen Species in Neutrophil Granulocytes than High‐Chlorinated Congeners
Authors: Berntsen Hanne Friis , Fonnum Frode , Walaas Sven Ivar , Bogen Inger Lise
Published: May 2016

Despite their ban several decades ago, polychlorinated biphenyls (PCBs) still pose a health threat to human beings due to their persistent and accumulative nature and continued presence in the environment. Non‐dioxin‐like (NDL)‐PCBs have earlier been found to have effects on the immune system, including human neutrophil granulocytes. The aim of this study was to investigate the differences between ortho‐chlorinated NDL‐PCBs with a low or high degree of chlorination in their capability to induce the production of reactive oxygen species (ROS) in human neutrophil granulocytes in vitro. We used some of the congeners occurring at the highest levels in blood, breast milk and food: PCB 52 representing the low‐chlorinated congeners and PCB 180 the high‐chlorinated congeners. In addition, the extensively studied PCB 153 was included as a reference compound. ROS production was assessed with the luminol‐amplified chemiluminescence and DCF fluorescence assays. The involvement of intracellular signalling mechanisms was investigated using different pharmacological substances. At high concentrations (10–20 μM), PCB 52 induced more ROS than PCB 153 and PCB 180. The role of extracellular signal‐regulated kinase (ERK) 1/2 and/or ERK 5 signalling in PCB‐induced ROS production was implicated through the reduction in ROS in the presence of the specific inhibitor U0126, whereas reduced ROS production after the use of SB203580 and SP600125 indicated the involvement of the p38 mitogen‐activated protein kinase (MAPK) and c‐Jun amino‐terminal kinase (JNK) pathways, respectively. In addition, the calcineurin inhibitor FK‐506, the intracellular calcium chelator BAPTA‐AM and the antioxidant vitamin E reduced the levels of ROS. The intracellular signalling mechanisms involved in ROS production in human neutrophil granulocytes appeared to be similar for PCB 52, PCB 153 and PCB 180. Based on the results from the present and previous studies, we conclude that for abundant ortho‐chlorinated PCBs found in the blood, low‐chlorinated congeners induce higher production of ROS in neutrophil granulocytes than high‐chlorinated congeners. This could be relevant during acute exposure scenarios when high concentrations of PCBs are present.
Delivery of Type 2 diabetes care in low‐ and middle‐income countries: lessons from Lima, Peru
Authors: Cardenas M. K. , Miranda J. J. , Beran D.
Published: May 2016

Aims

The health system's response is crucial to addressing the increasing burden of diabetes, particularly that affecting low‐ and middle‐income countries. This study aims to assess the facilitators and barriers that help or hinder access to care for people with diabetes in Peru.

Methods

We used a survey tool to design and collect qualitative and quantitative data from primary and secondary sources of information at different levels of the health system. We performed 111 interviews in Lima, the capital city of Peru, with patients with diabetes, healthcare providers and healthcare officials. We applied the six building blocks framework proposed by the World Health Organization in our analysis.

Results

We found low political commitment, as well as several barriers that directly affect access to medicines, regular laboratory check‐ups and follow‐up appointments for diabetes, especially at the primary healthcare level. Three major system‐level barriers were identified: (1) the availability of information at different healthcare system levels that affects several processes in the healthcare provision; (2) insufficient financial resources; and (3) insufficient human resources trained in diabetes management.

Conclusion

Despite an initial political commitment by the Peruvian government to improve the delivery of diabetes care, there exist several key limitations that affect access to adequate diabetes care, especially at the primary healthcare level. In a context in which various low‐ and middle‐income countries are aiming to achieve universal health coverage, this study provides lessons for the implementation of strategies related to diabetes care delivery.
Sexy again: the renaissance of neutrophils in psoriasis
Authors: Schön Michael P. , Broekaert Sigrid M. C. , Erpenbeck Luise
Published: May 2016

Notwithstanding their prominent presence in psoriatic skin, the functional role of neutrophilic granulocytes still remains somewhat enigmatic. Sparked by exciting scientific discoveries regarding neutrophil functions within the last years, the interest in these short‐lived cells of the innate immune system has been boosted recently. While it had been known for some time that neutrophils produce and respond to a number of inflammatory mediators, recent research has linked neutrophils with the pathogenic functions of IL‐17, possibly in conjunction with the formation of NETs (neutrophil extracellular traps). Antipsoriatic therapies exert their effects, at least in part, through interference with neutrophils. Neutrophils also appear to connect psoriasis with comorbid diseases. However, directly tampering with neutrophil functions is not trivial as evinced by the failure of therapeutic approaches targeting redundantly regulated cellular communication networks. It has also become apparent that neutrophils link important pathogenic functions of the innate and the adaptive immune system and that they are intricately involved in regulatory networks underlying the pathophysiology of psoriasis. In order to advocate intensified research into the role of this interesting cell population, we here highlight some features of neutrophils and put them into perspective with our current view of the pathophysiology of psoriasis.
Varying proliferative and clonogenic potential in NRAS‐mutated congenital melanocytic nevi according to size
Authors: Guégan Sarah , Kadlub Natacha , Picard Arnaud , Rouillé Thomas , Charbel Christelle , Coulomb‐L'Hermine Aurore , How‐Kit Alexandre , Fraitag Sylvie , Aractingi Selim , Fontaine Romain H.
Published: May 2016

Congenital melanocytic nevi (CMN) are benign proliferations that may be associated with various consequences depending on their size. They are characterized by a specific molecular signature, namely a postzygotic somatic NRAS or BRAF mutation. We have recently reported that large CMN (lCMN), which are classically associated with an increased melanoma risk, harbour cell subpopulations with specific clonogenic and tumorigenic potential. We wished to ascertain whether cells displaying similar properties persisted postnatally in medium CMN (mCMN). Eighteen medium M1, nine large and one giant NRAS‐mutated CMN were prospectively included in the study. Subpopulations of mCMN cells expressed stem cell/progenitor lineage markers such as Sox10, nestin and Oct4, as was the case in lCMN. Nevertheless, conversely to lCMN, mCMN cells with clonogenic properties were rarer. In vitro, approximatively one in 1500 cells isolated from fresh mCMN formed colonies that could be passaged. In vivo, mCMN seemed to harbour cells with less proliferative potential than the larger lesions as lCMN biopsies displayed a threefold expansion compared to mCMN when xenografted in Rag2−/− mice. Thus, our data revealed variations in clonogenicity and tumorigenic properties in NRAS‐mutated CMN according to size.
Preclinical and human surrogate models of itch
Authors: Hoeck Emil A. , Marker Jens B. , Gazerani Parisa , H. Andersen Hjalte , Arendt‐Nielsen Lars
Published: May 2016

Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine‐resistant itch, are limited. Relevant preclinical and human surrogate models of non‐histaminergic itch are needed to accelerate the development of novel antipruritics and diagnostic tools. Advances in basic itch research have facilitated the development of diverse models of itch and associated dysaesthesiae. While experimental itch in humans is induced over a short period of time and usually assessed psychophysically, the study of itch reactions in animals allows for both short‐term and long‐term studies but relies heavily on behavioural assessments. This review provides a background and a presentation of the established models of itch currently applied in animals and humans with emphasis on translatability.
Results of human factors testing in a novel Hemodialysis system designed for ease of patient use
Authors: Wilcox Stephen B. , Carver Michelle , Yau May , Sneeringer Peter , Prichard Sarah , Alvarez Luis , Chertow Glenn M.
Published: May 2016

Introduction Home hemodialysis has not been widely adopted despite superior outcomes relative to conventional in‐center hemodialysis. Patients receiving home hemodialysis experience high rates of technique failure owing to machine complexity, training burden, and the inability to master treatments independently.

Methods We conducted human factors testing on 15 health care professionals (HCPs) and 15 patients upon release of the defined training program on the Tablo™ Hemodialysis System. Each participant completed one training and one testing session conducted in a simulated clinical environment. Training sessions lasted <3 hours for HCPs and <4 hours for patients, with an hour break between sessions for knowledge decay. During the testing session, we recorded participant behavior and data according to standard performance and safety‐based criteria.

Findings Of 15 HCPs, 10 were registered nurses and five patient care technicians, with a broad range of dialysis work experience and no limitations other than visual correction. Of 15 patients (average age 48 years), 13 reported no limitations and two reported modest limitations—partial deafness and blindness in one eye, respectively. The average error rate was 4.4 per session for HCPs and 2.9 per session for patients out of a total possible 1,710 opportunities for errors. Despite having received minimal training, neither HCPs nor patients committed safety‐related errors that required mitigation; rather, we noted only minor errors and operational difficulties.

Discussion The Tablo™ Hemodialysis System is easy to use, and may help to enable self‐care and home hemodialysis in settings heretofore associated with high rates of technique failure.
Mandatory Vaccination: An Unqualified Defence
Authors: Pierik Roland
Published: May 2016

The 2015 Disneyland outbreak of measles in the US unequivocally brought to light what had been brewing below the surface for a while: a slow but steady decline in vaccination rates resulting in a rising number of outbreaks. This can be traced back to an increasing public questioning of vaccines by an emerging anti‐vaccination movement. This article argues that, in the face of diminishing vaccination rates, childhood vaccinations should not be seen as part of the domain of parental choice but, instead, as a non‐negotiable legal obligation. The first part of the article formulates and defends two arguments in favour of unqualified mandatory childhood vaccination laws. First, government should not permit parents to put their children at avoidable risk of death and suffering; second, government should guard the common good of herd immunity to protect vulnerable persons. The second part rejects legal and pragmatic objections against such mandatory vaccination laws.
Holocene range collapse of giant muntjacs and pseudo‐endemism in the Annamite large mammal fauna
Authors: Turvey Samuel T. , Hansford James , Brace Selina , Mullin Victoria , Gu Shengxiao , Sun Guoping
Published: May 2016

Aim

To clarify the post‐glacial biogeography of the Annamite and eastern Chinese ungulate faunas, and determine whether current understanding of Asian mammalian biogeography is biased by pseudo‐extinctions and pseudo‐endemism associated with a historical extinction filter.

Location

Modern‐day specimens of giant muntjac (Muntiacus vuquangensis) from the Annamite Mountains of Laos and Vietnam were compared with zooarchaeological specimens of extinct giant muntjac (M. gigas) from eastern China, and with a reference sample of northern red muntjac (M. vaginalis) from China, Southeast Asia and South Asia.

Methods

We analysed a data set of antler measurements using Multivariate analyses of variance (MANOVAs), principal component analyses (PCAs) and scaling relationships, to quantify morphometric variation between extinct and living giant muntjacs in relation to variation shown by a different sympatric large‐bodied muntjac species. We also attempted ancient biomolecule analysis of Holocene samples from China.

Results

Although the combined giant muntjac sample can be differentiated from the reference red muntjac sample in all of our multivariate morphometric analyses, no significant differences are shown between extinct and living giant muntjacs using any analyses, matching the pattern seen when comparing conspecific red muntjac samples from across the same geographical region.

Main conclusions

We find no support for recognizing extinct and living giant muntjacs as distinct taxa, and post‐glacial populations from China and the Annamites should probably all be referred to M. gigas. The likely conspecificity of giant muntjacs across Eastern and Southeast Asia demonstrates that current‐day Asian mammalian biogeography has been shaped by an extinction filter and challenges the idea that the Annamite region represents a cradle of evolution; instead, it may represent a refuge of diversity for some taxa, preserving remnant pseudo‐endemic populations of species that have been extirpated across other parts of their former ranges.
Molecular identification of iridoviruses infecting various sturgeon species in Europe
Authors: Bigarré L , Lesne M , Lautraite A , Chesneau V , Leroux A , Jamin M , Boitard P M , Toffan A , Prearo M , Labrut S , Daniel P
Published: May 2016

Iridoviridae are known to cause disease in sturgeons in North America. Here, histological and molecular methods were used to screen for this family of virus in sturgeons from various European farms with low‐to‐high morbidity. Some histological samples revealed basophilic cells in the gill and labial epithelia, strongly suggesting the accumulation of iridovirus particles. Newly developed generic PCR tests targeting the major capsid protein (MCP) gene of sturgeon iridoviruses identified in North America, namely the white sturgeon iridovirus and the Namao virus (NV), produced positive signals in most samples from four sturgeon species: Russian (Acipenser gueldenstaedtii), Siberian (A. baerii), Adriatic (A. naccarii) and beluga (Huso huso). The sequences of the PCR products were generally highly similar one another, with nucleotide identities greater than 98%. They were also related to (74–88%), although distinct from, American sturgeon iridoviruses. These European viruses were thus considered variants of a single new virus, provisionally named Acipenser iridovirus‐European (AcIV‐E). Moreover, three samples infected with AcIV‐E showed genetic heterogeneity, with the co‐existence of two sequences differing by five nucleotides. One of our European samples carried a virus distinct from AcIV‐E, but closely related to NV identified in Canada (95%). This study demonstrates the presence of two distinct sturgeon iridoviruses in Europe: a new genotype AcIV‐E and an NV‐related virus.
The LAW index as an accurate indicator of the initiation of antiviral treatment in patients with chronic hepatitis B
Authors: Lee Jae Min , Seo Yeon Seok , Kim Tae Hyung , Ahn Jem Ma , Yim Sun Young , Kim Seung Up , Jung Young Kul , Kim Ji Hoon , An Hyunggin , Yim Hyung Joon , Yeon Jong Eun , Lee Hong Sik , Byun Kwan Soo , Um Soon Ho , Kim Chang Duck , Ryu Ho Sang
Published: May 2016

Background and Aim

Considering that inflammation and fibrosis are major factors for the indication of antiviral treatment, liver stiffness measurements could help identify patients who require antiviral treatment. This study evaluated factors that best identify patients who require antiviral treatment and to develop a new indicator for chronic hepatitis B (CHB).

Methods

Patients with CHB were randomly classified into a training or validation group, and a model for predicting necroinflammatory activity ≥ A3 or fibrosis grade ≥ F2 (A3F2) was established in the training group using binary regression analysis and validated in the validation group. Predictive efficacy was compared using area under the receiver‐operating characteristics curve analysis.

Results

Four‐hundred ninety‐two patients were enrolled. In the training group, female sex, aspartate aminotransferase‐to‐platelet count ratio index (APRI), and liver stiffness were independent predictors of A3F2 on multivariate analysis. These variables were used to construct a novel model, called the LAW (liver stiffness, APRI, woman) index, as follows: 1.5 × liver stiffness value (kPa) + 3.9 × APRI + 3.2 if female. The LAW index was a better predictor of A3F2 than the APRI or liver stiffness measurement in both training group (0.870; 95% confidence interval, 0.822–0.910) and validation group (0.862; 95% confidence interval, 0.813–0.903).

Conclusions

The LAW index was able to accurately identify patients with CHB who required antiviral treatment. A LAW index of >10.1 could be a strong indicator for the initiation of antiviral treatment in patients with CHB.
HOW DO PATIENTS EXPERIENCE A KIDNEY BIOPSY?
Authors: Finderup Jeanette , Peschardt Laura , Sander Mette Rubin , Nielsen Mette Ulf
Published: May 2016

Background

Guidelines for care before, during and after a kidney biopsy vary nationally and internationally. A literature search has shown few studies about the care before, during and after a kidney biopsy and we found one study from the patients' perspective.

Objectives

The aim of the study is to gain knowledge about patients' experiences before, during and after a kidney biopsy.

Methods

A qualitative study with a phenomenological and hermeneutic approach using ‘observiews’ of seven patients before, during and after a kidney biopsy. Data were analysed using Malterud's principles of systematic text condensation.

Results

Three themes were found: The patients' basic needs, the patient's needs for information and the patients use humour as a coping strategy.

Conclusion and Application to practice

The patients' experiences were characterised by their need to fulfill self‐care requirements, because they had to lie down for four to six hours after the biopsy procedure. There is a need to find evidence for the time the patient need to be bedbound to avoid bleeding complications. The patients' needs for information were different, which explains why information should be individualised. There is particular need for more information after discharge.
Virtue or Art?: Political Friendship Reconsidered
Authors: Eitel Adam
Published: May 2016

InTalking to Strangers(2004), Danielle Allen argues that democratic citizens will need to acquire new habits for contending with distrust in order to prolong the democratic experiment. Though Allen's solution recalls her reading of theRepublic, it is to Aristotle, not Plato, that she turns for help theorizing those habits. Drawing upon theNicomachean Ethics, she proposes arts or techniques that might substitute for and outpace justice by enabling democratic strangers to treat one another like friends. While I endorse Allen's analysis of the problems posed by rising levels of distrust, I propose a different solution. First, I argue that the habits Allen describes would have to be virtues and not merely techniques in order to effect real political change. Then, second, I identify those habits as “piety” and “gratitude”—virtues which, I contend, are not so muchsubstitutes forassupplements tojustice. My argument thus elaborates Thomas Aquinas's account of justice and its “potential parts” in theSumma Theologiae.
Serotonin‐induced contractile responses of esophageal smooth muscle in the house musk shrew (Suncus murinus)
Authors: Shiina T. , Naitou K. , Nakamori H. , Suzuki Y. , Horii K. , Sano Y. , Shimaoka H. , Shimizu Y.
Published: May 2016

Background

Serotonin (5‐hydroxytryptamine, 5‐HT) is a regulatory factor in motility of the gastrointestinal tract including the esophagus. Although we proposed that vagal cholinergic and mast cell‐derived non‐cholinergic components including serotonin coordinately shorten the esophagus, the precise mechanism of serotonin‐induced contractions in the suncus esophagus is still unclear. Therefore, the aims of this study were to determine characteristics of contractile responses induced by serotonin and to identify 5‐HT receptor subtypes responsible for regulating motility in the suncus esophagus.

Methods

An isolated segment of the suncus esophagus was placed in an organ bath, and longitudinal or circular mechanical responses were recorded using a force transducer.

Key Results

Serotonin evoked contractile responses of the suncus esophagus in the longitudinal direction but not in the circular direction. Tetrodotoxin did not affect the serotonin‐induced contractions. Pretreatment with a non‐selective 5‐HT receptor antagonist or double application of 5‐HT1 and 5‐HT2 receptor antagonists blocked the serotonin‐induced contractions. 5‐HT1 and 5‐HT2 receptor agonists, but not a 5‐HT3 receptor agonist, evoked contractile responses in the suncus esophagus.

Conclusion & Inferences

The findings suggest that serotonin induces contractile responses of the longitudinal smooth muscle in the muscularis mucosae of the suncus esophagus that are mediated via 5‐HT1 and 5‐HT2 receptors on muscle cells. The serotonin‐induced contractions might contribute to esophageal peristalsis and emetic response.
Effect of salivary agglutination on oral streptococcal clearance by human polymorphonuclear neutrophil granulocytes
Authors: Itzek A. , Chen Z. , Merritt J. , Kreth J.
Published: May 2016

Salivary agglutination is an important host defense mechanism to aggregate oral commensal bacteria as well as invading pathogens. Saliva flow and subsequent swallowing more easily clear aggregated bacteria compared with single cells. Phagocytic clearance of bacteria through polymorphonuclear neutrophil granulocytes also seems to increase to a certain extent with the size of bacterial aggregates. To determine a connection between salivary agglutination and the host innate immune response by phagocytosis, an in vitro agglutination assay was developed reproducing the average size of salivary bacterial aggregates. Using the oral commensal Streptococcus gordonii as a model organism, the effect of salivary agglutination on phagocytic clearance through polymorphonuclear neutrophil granulocytes was investigated. Here we describe how salivary aggregates of S. gordonii are readily cleared through phagocytosis, whereas single bacterial cells showed a significant delay in being phagocytosed and killed. Furthermore, before phagocytosis the polymorphonuclear neutrophil granulocytes were able to induce a specific de‐aggregation, which was dependent on serine protease activity. The data presented suggest that salivary agglutination of bacterial cells leads to an ideal size for recognition by polymorphonuclear neutrophil granulocytes. As a first line of defense, these phagocytic cells are able to recognize the aggregates and de‐aggregate them via serine proteases to a more manageable size for efficient phagocytosis and subsequent killing in the phagolysosome. This observed mechanism not only prevents the rapid spreading of oral bacterial cells while entering the bloodstream but would also avoid degranulation of involved polymorphonuclear neutrophil granulocytes, so preventing collateral damage to nearby tissue.
Internet Gaming Disorder as a formative construct: Implications for conceptualization and measurement
Authors: van Rooij Antonius J , Van Looy Jan , Billieux Joël
Published: May 2016

Some people have serious problems controlling their Internet and video game use. The DSM‐5 now includes a proposal for ‘Internet Gaming Disorder’ (IGD) as a condition in need of further study. Various studies aim to validate the proposed diagnostic criteria for IGD and multiple new scales have been introduced that cover the suggested criteria. Using a structured approach, we demonstrate that IGD might be better interpreted as a formative construct, as opposed to the current practice of conceptualizing it as a reflective construct. Incorrectly approaching a formative construct as a reflective one causes serious problems in scale development, including: (i) incorrect reliance on item‐to‐total scale correlation to exclude items and incorrectly relying on indices of inter‐item reliability that do not fit the measurement model (e.g., Cronbach's α); (ii) incorrect interpretation of composite or mean scores that assume all items are equal in contributing value to a sum score; and (iii) biased estimation of model parameters in statistical models. We show that these issues are impacting current validation efforts through two recent examples. A reinterpretation of IGD as a formative construct has broad consequences for current validation efforts and provides opportunities to reanalyze existing data. We discuss three broad implications for current research: (i) composite latent constructs should be defined and used in models; (ii) item exclusion and selection should not rely on item‐to‐total scale correlations; and (iii) existing definitions of IGD should be enriched further.
Contextualizing individual differences in error monitoring: Links with impulsivity, negative affect, and conscientiousness
Authors: Hill Kaylin E. , Samuel Douglas B. , Foti Dan
Published: May 2016

The error‐related negativity (ERN) is a neural measure of error processing that has been implicated as a neurobehavioral trait and has transdiagnostic links with psychopathology. Few studies, however, have contextualized this traitlike component with regard to dimensions of personality that, as intermediate constructs, may aid in contextualizing links with psychopathology. Accordingly, the aim of this study was to examine the interrelationships between error monitoring and dimensions of personality within a large adult sample (N = 208). Building on previous research, we found that the ERN relates to a combination of negative affect, impulsivity, and conscientiousness. At low levels of conscientiousness, negative urgency (i.e., impulsivity in the context of negative affect) predicted an increased ERN; at high levels of conscientiousness, the effect of negative urgency was not significant. This relationship was driven specifically by the conscientiousness facets of competence, order, and deliberation. Links between personality measures and error positivity amplitude were weaker and nonsignificant. Post‐error slowing was also related to conscientiousness, as well as a different facet of impulsivity: lack of perseverance. These findings suggest that, in the general population, error processing is modulated by the joint combination of negative affect, impulsivity, and conscientiousness (i.e., the profile across traits), perhaps more so than any one dimension alone. This work may inform future research concerning aberrant error processing in clinical populations.
Opportunity recognition and SME performance: the mediating effect of business model innovation
Authors: Guo Hai , Tang Jintong , Su Zhongfeng , Katz Jerome A.
Published: May 2016

Opportunity recognition is vital for small and medium‐sized enterprises (SMEs), but SMEs face challenges in capturing recognized opportunities. Given that opportunity recognition does not automatically lead to higher SME performance and that SMEs need to take appropriate actions to exploit recognized opportunities to achieve better performance, it is imperative to explore the mediators that enable SMEs to translate opportunity recognition into higher performance. This study proposes that business model innovation may be a key conduit through which opportunity recognition affects SME performance. Based on a dataset of 155 SMEs, we find that the positive relationship between opportunity recognition and SME performance is mediated by business model innovation. These findings not only aid SMEs in accomplishing the performance effect of opportunity recognition, but also provide some insights into the implications of business model innovation.
Transverse Orbital Stability of Periodic Traveling Waves for Nonlinear Klein–Gordon Equations
Authors: Angulo Pava Jaime , Plaza Ramón G.
Published: May 2016

In this paper, we establish the orbital stability of a class of spatially periodic wave train solutions to multidimensional nonlinear Klein–Gordon equations with periodic potential. We show that the orbit generated by the one‐dimensional wave train is stable under the flow of the multidimensional equation under perturbations which are, on one hand, coperiodic with respect to the translation or Galilean variable of propagation, and, on the other hand, periodic (but not necessarily coperiodic) with respect to the transverse directions. That is, we show their transverse orbital stability. The class of periodic wave trains under consideration is the family of subluminal rotational waves, which are periodic in the momentum but unbounded in their position.
Forum of Tactics for Teaching the Materiality of Scripture
Authors: Plate S. Brent , Parmenter Dorina Miller , Dault David , Lee Song‐Chong , Larson Jason , Schwarz Sarah L.
Published: May 2016

S. Brent Plate's introductory essay orients the reader to the academic move toward material text studies, a wide range of research questions and pedagogical practices that includes attention to the history of the book, book technologies, the social habits of readership especially in relation to print culture, and issues raised in media studies about differences in verbal communication. This introduction is followed by a series of one‐page Teaching Tactics that prompt students to ask about the material conditions in and through which scriptures acquire meaning. Students are challenged to become aware of the sensorial nature of sacred texts, and of communication itself. They touch, see, and hear in new ways, learning with their bodies.
An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques
Authors: Schwartz Jennifer A. , Prado Ilia , Misamore Johnathan , Weiss Deborah , Francis Jesse , Pal Ranajit , Huaman Maria , Cristillo Anthony , Lewis George K. , Gallo Robert C. , DeVico Anthony L. , Fouts Timothy R.
Published: May 2016

A promising concept for human immunodeficiency virus (HIV) vaccines focuses immunity on the highly conserved transition state structures and epitopes that appear when the HIV glycoprotein gp120 binds to its receptor, CD4. We are developing chimeric antigens (full-length single chain, or FLSC) in which gp120 and CD4 sequences are flexibly linked to allow stable intrachain complex formation between the two moieties (A. DeVico et al., Proc Natl Acad Sci U S A 104:17477–17482, 2007, doi:10.1073/pnas.0707399104; T. R. Fouts et al., J Virol 74:11427–11436, 2000,doi:10.1128/JVI.74.24.11427-11436.2000). Proof of concept studies with nonhuman primates show that FLSC elicited heterologous protection against simian-human immunodeficiency virus (SHIV)/simian immunodeficiency virus (SIV) (T. R. Fouts et al., Proc Natl Acad Sci U S A 112:E992–E999, 2016,doi:10.1073/pnas.1423669112), which correlated with antibodies against transition state gp120 epitopes. Nevertheless, advancement of any vaccine that comprises gp120-CD4 complexes must consider whether the CD4 component breaks tolerance and becomes immunogenic in the autologous host. To address this, we performed an immunotoxicology study with cynomolgus macaques vaccinated with either FLSC or a rhesus variant of FLSC containing macaque CD4 sequences (rhFLSC). Enzyme-linked immunosorbent assay (ELISA) binding titers, primary CD3+T cell staining, and temporal trends in T cell subset frequencies served to assess whether anti-CD4 autoantibody responses were elicited by vaccination. We find that immunization with multiple high doses of rhFLSC did not elicit detectable antibody titers despite robust responses to rhFLSC. In accordance with these findings, immunized animals had no changes in circulating CD4+T cell counts or evidence of autoantibody reactivity with cell surface CD4 on primary naive macaque T cells. Collectively, these studies show that antigens using CD4 sequences to stabilize transition state gp120 structures are unlikely to elicit autoimmune antibody responses, supporting the advancement of gp120-CD4 complex-based antigens, such as FLSC, into clinical testing.
Follow-Up of External Quality Controls for PCR-Based Diagnosis of Whooping Cough in a Hospital Laboratory Network (Renacoq) and in Other Hospital and Private Laboratories in France
Authors: Guillot Sophie , Guiso Nicole
Published: May 2016

The French National Reference Centre (NRC) for Whooping Cough carried out an external quality control (QC) analysis in 2010 for the PCR diagnosis of whooping cough. The main objective of the study was to assess the impact of this QC in the participating laboratories through a repeat analysis in 2012.
Comparison of Virulence Gene Identification, Ribosomal Spacer PCR, and Pulsed-Field Gel Electrophoresis for Typing of Staphylococcus aureus Strains Isolated from Cases of Subclinical Bovine Mastitis in the United States
Authors: Adkins Pamela R. F. , Middleton John R. , Fox Lawrence K.
Published: May 2016

Staphylococcus aureus
is one of the most important pathogens causing contagious mastitis in dairy cattle worldwide. The objectives of this study were to determine if recently described
S. aureus
genotype B was present among previously characterized isolates from cases of bovine intramammary infection in the United States and to compare pulsed-field gel electrophoresis (PFGE) to the combination of ribosomal spacer PCR (RS-PCR) and virulence gene identification for typing of
S. aureus
strains. The hypothesis was that isolates that were previously characterized as contagious would be identified as genotype B and that the results of the two strain-typing methods would be comparable. Isolates were selected from a collection of
S. aureus
isolates from eight dairy farms. Mammary quarter milk somatic cell count (SCC) and
N
-acetyl-β-
d
-gluconaminidase (NAGase) activity data were known and used to evaluate strain pathogenicity. RS-PCR was performed with conventional gel electrophoresis, and PCR was used for toxin gene identification. RS-PCR patterns were associated with a specific virulence gene pattern, as previously reported. Five RS-PCR banding patterns were identified. None of the isolates were characterized as genotype B. No association between RS-PCR types and milk SCC was found; however, NAGase activity was significantly higher in milk from mammary glands infected with RS-PCR banding type 1 (RSP type 1) than in milk from those infected with RSP type 2. The discriminatory power values were 1.0 and 0.46 for PFGE and RS-PCR, respectively. These data suggest that genotype B may have a limited geographic distribution and that PFGE is more discriminatory than RS-PCR performed with conventional gel electrophoresis for typing of
S. aureus
isolates of bovine origin.
Uukuniemi Virus as a Tick-Borne Virus Model
Authors: Mazelier Magalie , Rouxel Ronan Nicolas , Zumstein Michael , Mancini Roberta , Bell-Sakyi Lesley , Lozach Pierre-Yves
Published: May 2016

In the last decade, novel tick-borne pathogenic phleboviruses in the family
Bunyaviridae
, all closely related to Uukuniemi virus (UUKV), have emerged on different continents. To reproduce the tick-mammal switch
in vitro
, we first established a reverse genetics system to rescue UUKV with a genome close to that of the authentic virus isolated from the
Ixodes ricinus
tick reservoir. The IRE/CTVM19 and IRE/CTVM20 cell lines, both derived from
I. ricinus
, were susceptible to the virus rescued from plasmid DNAs and supported production of the virus over many weeks, indicating that infection was persistent. The glycoprotein G
C
was mainly highly mannosylated on tick cell-derived viral progeny. The second envelope viral protein, G
N
, carried mostly
N
-glycans not recognized by the classical glycosidases peptide-
N
-glycosidase F (PNGase F) and endoglycosidase H (Endo H). Treatment with β-mercaptoethanol did not impact the apparent molecular weight of G
N
. On viruses originating from mammalian BHK-21 cells, G
N
glycosylations were exclusively sensitive to PNGase F, and the electrophoretic mobility of the protein was substantially slower after the reduction of disulfide bonds. Furthermore, the amount of viral nucleoprotein per focus forming unit differed markedly whether viruses were produced in tick or BHK-21 cells, suggesting a higher infectivity for tick cell-derived viruses. Together, our results indicate that UUKV particles derived from vector tick cells have glycosylation and structural specificities that may influence the initial infection in mammalian hosts. This study also highlights the importance of working with viruses originating from arthropod vector cells in investigations of the cell biology of arbovirus transmission and entry into mammalian hosts.

IMPORTANCE
Tick-borne phleboviruses represent a growing threat to humans globally. Although ticks are important vectors of infectious emerging diseases, previous studies have mainly involved virus stocks produced in mammalian cells. This limitation tends to minimize the importance of host alternation in virus transmission to humans and initial infection at the molecular level. With this study, we have developed an
in vitro
tick cell-based model that allows production of the tick-borne Uukuniemi virus to high titers. Using this system, we found that virions derived from tick cells have specific structural properties and
N
-glycans that may enhance virus infectivity for mammalian cells. By shedding light on molecular aspects of tick-derived viral particles, our data illustrate the importance of considering the host switch in studying early virus-mammalian receptor/cell interactions. The information gained here lays the basis for future research on not only tick-borne phleboviruses but also all viruses and other pathogens transmitted by ticks.
ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway
Authors: Xue Binbin , Yang Darong , Wang Jingjing , Xu Yan , Wang Xiaohong , Qin Yuwen , Tian Renyun , Chen Shengwen , Xie Qinya , Liu Nianli , Zhu Haizhen
Published: May 2016

Interferons (IFNs) restrict various kinds of viral infection via induction of hundreds of IFN-stimulated genes (ISGs), while the functions of the majority of ISGs are broadly unclear. Here, we show that a high-IFN-inducible gene, ISG12a (also known as IFI27), exhibits a nonapoptotic antiviral effect on hepatitis C virus (HCV) infection. Viral NS5A protein is targeted specifically by ISG12a, which mediates NS5A degradation via a ubiquitination-dependent proteasomal pathway. K374R mutation in NS5A domain III abrogates ISG12a-induced ubiquitination and degradation of NS5A. S-phase kinase-associated protein 2 (SKP2) is identified as an ubiquitin E3 ligase for NS5A. ISG12a functions as a crucial adaptor that promotes SKP2 to interact with and degrade viral protein. Moreover, the antiviral effect of ISG12a is dependent on the E3 ligase activity of SKP2. These findings uncover an intriguing mechanism by which ISG12a restricts viral infection and provide clues for understanding the actions of innate immunity.

IMPORTANCE
Upon virus invasion, IFNs induce numerous ISGs to control viral spread, while the functions of the majority of ISGs are broadly unclear. The present study shows a novel antiviral mechanism of ISGs and elucidated that ISG12a recruits an E3 ligase, SKP2, for ubiquitination and degradation of viral protein and restricts viral infection. These findings provide important insights into exploring the working principles of innate immunity.
Both
cis
and
trans
Activities of Foot-and-Mouth Disease Virus 3D Polymerase Are Essential for Viral RNA Replication
Authors: Herod Morgan R. , Ferrer-Orta Cristina , Loundras Eleni-Anna , Ward Joseph C. , Verdaguer Nuria , Rowlands David J. , Stonehouse Nicola J.
Published: May 2016

The
Picornaviridae
is a large family of positive-sense RNA viruses that contains numerous human and animal pathogens, including foot-and-mouth disease virus (FMDV). The picornavirus replication complex comprises a coordinated network of protein-protein and protein-RNA interactions involving multiple viral and host-cellular factors. Many of the proteins within the complex possess multiple roles in viral RNA replication, some of which can be provided in
trans
(i.e., via expression from a separate RNA molecule), while others are required in
cis
(i.e., expressed from the template RNA molecule).
In vitro
studies have suggested that multiple copies of the RNA-dependent RNA polymerase (RdRp) 3D are involved in the viral replication complex. However, it is not clear whether all these molecules are catalytically active or what other function(s) they provide. In this study, we aimed to distinguish between catalytically active 3D molecules and those that build a replication complex. We report a novel nonenzymatic
cis
-acting function of 3D that is essential for viral-genome replication. Using an FMDV replicon in complementation experiments, our data demonstrate that this
cis
-acting role of 3D is distinct from the catalytic activity, which is predominantly
trans
acting. Immunofluorescence studies suggest that both
cis
- and
trans
-acting 3D molecules localize to the same cellular compartment. However, our genetic and structural data suggest that 3D interacts in
cis
with RNA stem-loops that are essential for viral RNA replication. This study identifies a previously undescribed aspect of picornavirus replication complex structure-function and an important methodology for probing such interactions further.

IMPORTANCE
Foot-and-mouth disease virus (FMDV) is an important animal pathogen responsible for foot-and-mouth disease. The disease is endemic in many parts of the world with outbreaks within livestock resulting in major economic losses. Propagation of the viral genome occurs within replication complexes, and understanding this process can facilitate the development of novel therapeutic strategies. Many of the nonstructural proteins involved in replication possess multiple functions in the viral life cycle, some of which can be supplied to the replication complex from a separate genome (i.e., in
trans
) while others must originate from the template (i.e., in
cis
). Here, we present an analysis of
cis
and
trans
activities of the RNA-dependent RNA polymerase 3D. We demonstrate a novel
cis
-acting role of 3D in replication. Our data suggest that this role is distinct from its enzymatic functions and requires interaction with the viral genome. Our data further the understanding of genome replication of this important pathogen.
Small-Molecule Fusion Inhibitors Bind the pH-Sensing Stable Signal Peptide-GP2 Subunit Interface of the Lassa Virus Envelope Glycoprotein
Authors: Shankar Sundaresh , Whitby Landon R. , Casquilho-Gray Hedi E. , York Joanne , Boger Dale L. , Nunberg Jack H.
Published: May 2016

Arenavirus species are responsible for severe life-threatening hemorrhagic fevers in western Africa and South America. Without effective antiviral therapies or vaccines, these viruses pose serious public health and biodefense concerns. Chemically distinct small-molecule inhibitors of arenavirus entry have recently been identified and shown to act on the arenavirus envelope glycoprotein (GPC) to prevent membrane fusion. In the tripartite GPC complex, pH-dependent membrane fusion is triggered through a poorly understood interaction between the stable signal peptide (SSP) and the transmembrane fusion subunit GP2, and our genetic studies have suggested that these small-molecule inhibitors act at this interface to antagonize fusion activation. Here, we have designed and synthesized photoaffinity derivatives of the 4-acyl-1,6-dialkylpiperazin-2-one class of fusion inhibitors and demonstrate specific labeling of both the SSP and GP2 subunits in a native-like Lassa virus (LASV) GPC trimer expressed in insect cells. Photoaddition is competed by the parental inhibitor and other chemically distinct compounds active against LASV, but not those specific to New World arenaviruses. These studies provide direct physical evidence that these inhibitors bind at the SSP-GP2 interface. We also find that GPC containing the uncleaved GP1-GP2 precursor is not susceptible to photo-cross-linking, suggesting that proteolytic maturation is accompanied by conformational changes at this site. Detailed mapping of residues modified by the photoaffinity adducts may provide insight to guide the further development of these promising lead compounds as potential therapeutic agents to treat Lassa hemorrhagic fever.

IMPORTANCE
Hemorrhagic fever arenaviruses cause lethal infections in humans and, in the absence of licensed vaccines or specific antiviral therapies, are recognized to pose significant threats to public health and biodefense. Lead small-molecule inhibitors that target the arenavirus envelope glycoprotein (GPC) have recently been identified and shown to block GPC-mediated fusion of the viral and cellular endosomal membranes, thereby preventing virus entry into the host cell. Genetic studies suggest that these inhibitors act through a unique pH-sensing intersubunit interface in GPC, but atomic-level structural information is unavailable. In this report, we utilize novel photoreactive fusion inhibitors and photoaffinity labeling to obtain direct physical evidence for inhibitor binding at this critical interface in Lassa virus GPC. Future identification of modified residues at the inhibitor-binding site will help elucidate the molecular basis for fusion activation and its inhibition and guide the development of effective therapies to treat arenaviral hemorrhagic fevers.