bluuebunny/crossref_metadata_2025 huggingface dataset:
Supply Chain Structure Incentives for Corporate Social Responsibility: An Incomplete Contracting Analysis
Authors: Letizia Paolo , Hendrikse George
Published: June 2016

Downstream firms increasingly recognize the importance of integrating social and environmental concerns with their businesses. As a consequence, they urge to create incentives for their suppliers to invest in corporate social responsibility (CSR) activities. Contracts to provide these incentives are rarely observed in practice. If not totally absent, contracts may be incomplete, in that unforeseen contingencies or some CSR attributes that are difficult to measure may not be included in the contract. We show that incentives for CSR investments can also be provided through the supply chain structure, which consists of the distribution of ownership rights over the firms' assets of production, and involves horizontal and/or vertical alliances among supply chain members. Motivated by examples in agricultural contexts, this study adopts the property rights approach to study the impact of supply chain structures on the adoption of CSR activities. We show that the structure that best incentivizes CSR investments depends on the interaction between CSR vertical synergy, free‐riding, and countervailing power. One of the main findings is that the alliance between suppliers is beneficial only if the revenues generated by a downstream investment are sufficiently high. In fact, only in this case, the suppliers can appropriate a sufficiently large stake of the revenues generated downstream, thanks to their countervailing power. When the upstream investment costs become high, however, the suppliers will invest in CSR only if the downstream distributor is vertically integrated. The resulting structure of a cooperative will best incentivize CSR investments only if the CSR vertical synergy between the two tiers of the supply chain is sufficiently high.
New Product Design under Channel Acceptance: Brick‐and‐Mortar, Online‐Exclusive, or Brick‐and‐Click
Authors: Luo Lan , Sun Jiong
Published: June 2016

In recent years, an increasing number of brick‐and‐mortar retailers have entered into the new brick‐and‐click era. Within this context, when a manufacturer presents a new product offering to a retailer, the ultimate decision is often made by the retailer regarding (1) whether to carry the new product, and (2) the channel outlet the product will be carried in (i.e., in‐store only, online‐exclusive, or brick‐and‐click). In response to this trend, we examine how a manufacturer may use product design to influence a dual‐channel retailer's outlet designation decision. This is the first study to investigate a manufacturer's optimal product design strategy when a brick‐and‐mortar retailer expands online. We demonstrate that, to induce the retailer to carry a new product both offline and online, it may not always be optimal for the manufacturer to enhance product quality (compared with when the retailer only operates offline). With the online store addition, the retailer may also be incentivized to adjust his participation criterion to a level less than what is determined by his outside option.
Brain correlates of the orientation of auditory spatial attention onto speaker location in a “cocktail‐party” situation
Authors: Lewald Jörg , Hanenberg Christina , Getzmann Stephan
Published: June 2016

Successful speech perception in complex auditory scenes with multiple competing speakers requires spatial segregation of auditory streams into perceptually distinct and coherent auditory objects and focusing of attention toward the speaker of interest. Here, we focused on the neural basis of this remarkable capacity of the human auditory system and investigated the spatiotemporal sequence of neural activity within the cortical network engaged in solving the “cocktail‐party” problem. Twenty‐eight subjects localized a target word in the presence of three competing sound sources. The analysis of the ERPs revealed an anterior contralateral subcomponent of the N2 (N2ac), computed as the difference waveform for targets to the left minus targets to the right. The N2ac peaked at about 500 ms after stimulus onset, and its amplitude was correlated with better localization performance. Cortical source localization for the contrast of left versus right targets at the time of the N2ac revealed a maximum in the region around left superior frontal sulcus and frontal eye field, both of which are known to be involved in processing of auditory spatial information. In addition, a posterior‐contralateral late positive subcomponent (LPCpc) occurred at a latency of about 700 ms. Both these subcomponents are potential correlates of allocation of spatial attention to the target under cocktail‐party conditions.
Overexpression of C/EBPβ Affects The Cell Cycle Regulators and Spermatogenesis Related Genes Expression And Function of Bovine Sertoli Cells
Authors: Tang K , Jin Y , Chen F , Wang L
Published: June 2016

Contents

CCAAT/enhancer‐binding protein beta (C/EBPβ), an important transcriptional factor, plays a pivotal role in the regulation of female germ cell development. However, the role of C/EBPβ on the development of male germ cells has not been reported. In this study, we constructed the recombinant adenovirus plasmids of bovine C/EBPβ gene and harvested the subsequent adenoviruses, and then assessed the mRNA levels of spermatogenesis‐related genes (real‐time PCR) and secretion of inhibin B after 48 h of Ad‐C/EBPβ recombinant adenovirus infection in bovine sertoli cells (SCs). We found that overexpression of exogenous C/EBPβ gene upregulated the mRNA expressions of spermatogenesis‐related genes, including Pdgfa, Claudin, Caspase‐3, Occludin, kit1 and Cyclin E, and decreased the mRNA levels of Cyclin D1. Meanwhile, overexpression of exogenous C/EBPβ gene significantly increases the amounts of secreted inhibin B. In conclusion, the results indicate that the C/EBPβ gene plays an important regulatory role in regulation of the cell cycle regulators and spermatogenesis‐related genes expression and function of bovine SCs.
Factors associated with abnormal pulmonary function test among subjects with normal chest radiography: The Korean National Health and Nutrition Examination Survey
Authors: Chae Kum Ju , Kwon Keun‐Sang , Jin Gong Yong , Bang Heejung , Lee Juhyung
Published: June 2016

Determinants of abnormal lung function among subjects with normal chest radiography have not been widely evaluated. We investigated 12 109 participants with normal chest radiographs from the Korean National Health and Nutrition Examination Survey. Factors associated with abnormal pulmonary function were male gender, age ≥50, smoking history and a clinical history of cough or sputum production. Pulmonary function tests should be considered in population‐based screening, especially in men over 50 years old with a smoking history.
Effects of positive end expiratory pressure administration during non‐invasive ventilation in patients affected by amyotrophic lateral sclerosis: A randomized crossover study
Authors: Crescimanno Grazia , Greco Francesca , Arrisicato Salvo , Morana Noemi , Marrone Oreste
Published: June 2016

Background and objective

No studies have evaluated the impact of different settings of non‐invasive ventilation (NIV) in patients affected by amyotrophic lateral sclerosis (ALS). We explored consequences of positive end‐expiratory pressure (PEEP) application on effectiveness of ventilation, sleep architecture and heart rate variability (HRV) in patients with ALS naïve to ventilatory treatment.

Methods

In two consecutive nights, 25 patients received in random order 0 or 4 cm H20 of PEEP during nocturnal NIV administration (Idea Ultra ResMed) with the same level of total positive inspiratory pressure. Polysomnographies were performed to evaluate sleep and NIV quality, as well as HRV. HRV was analyzed on 4‐h periods and on 5‐min segments of stable NREM sleep.

Results

We did not observe differences in gas exchanges during NIV with and without PEEP. Conversely, during PEEP application increases in leaks (41.4 ± 29.3% vs 31.0 ± 25.7%, P = 0.0007) and in autotriggerings (4.2 (IQR 1.3–10.0) vs 0.9 (IQR 0.0–3.0) events/h, P < 0.001, PEEP vs no PEEP, respectively) occurred. Besides, N3 sleep stage duration decreased (2.5% (IQR 0.0–18.0) vs 0.0% (IQR0.0–12.1), P = 0.001) and arousal/awakening index increased (16.9 ± 7.4 vs 13.4 ± 5.0 events/h, P = 0.01). Data on HRV were available in 15 patients. A higher low/high frequency ratio, either in the 4‐h (3.8 ± 2.6 vs 2.9 ± 1.7, P = 0.04, PEEP vs no PEEP, respectively) or in the 5‐min segments (2.6 ± 1.8 vs 1.45 ± 0.9 P = 0.01) was found during PEEP administration.

Conclusion

In ALS patients, PEEP application during NIV was associated with worse NIV and sleep quality and with higher sympathetic activity.
How Do Exporters React to Changes in Cost Competitiveness?
Authors: Decramer Stefaan , Fuss Catherine , Konings Jozef
Published: June 2016

Various international institutions such as the European Commission, the ECB and the OECD often use unit labour costs as a measure of international competitiveness. The goal of this paper was to examine how well this measure is related to international export performance at the firm level. To this end, we use Belgian firm‐level data for the period 1999 to 2010 to analyse the impact of unit labour costs on exports. We find an estimated elasticity of the intensive margin of exports with respect to unit labour costs between −0.2 and −0.4. This elasticity varies between sectors and between firms, with more labour‐intensive firms having a higher elasticity. The microdata also enable us to analyse the impact of unit labour costs on the extensive margin. Our results show that higher unit labour costs reduce the probability of starting to export for non‐exporters and increase the probability of exporters stopping. While our results show that unit labour costs have an impact on the intensive margin and extensive margin of firm‐level exports, the effect is rather low, suggesting that pass‐through of costs into prices is limited. The latter is consistent with recent trade models emphasising that not only relative costs, but also demand factors such as quality and taste matter for explaining firm‐level exports.
Arteriolar oxygen reactivity: where is the sensor and what is the mechanism of action?
Authors: Jackson William F.
Published: June 2016

Arterioles in the peripheral microcirculation are exquisitely sensitive to changes in in their environment: increases in cause vasoconstriction while decreases in result in vasodilatation. However, the cell type that senses O2 (the O2 sensor) and the signalling pathway that couples changes in to changes in arteriolar tone (the mechanism of action) remain unclear. Many (but not all) ex vivo studies of isolated cannulated resistance arteries and large, first‐order arterioles support the hypothesis that these vessels are intrinsically sensitive to with the smooth muscle, endothelial cells, or red blood cells serving as the O2 sensor. However, in situ studies testing these hypotheses in downstream arterioles have failed to find evidence of intrinsic O2 sensitivity, and instead have supported the idea that extravascular cells sense O2. Similarly, ex vivo studies of isolated, cannulated resistance arteries and large first‐order arterioles support the hypotheses that O2‐dependent inhibition of production of vasodilator cyclooxygenase products or O2‐dependent destruction of nitric oxide mediates O2 reactivity of these upstream vessels. In contrast, most in vivo studies of downstream arterioles have disproved these hypotheses and instead have provided evidence supporting the idea that O2‐dependent production of vasoconstrictors mediates arteriolar O2 reactivity, with significant regional heterogeneity in the specific vasoconstrictor involved. Oxygen‐induced vasoconstriction may serve as a protective mechanism to reduce the oxidative burden to which a tissue is exposed, a process that is superimposed on top of the local mechanisms which regulate tissue blood flow to meet a tissue's metabolic demand.

image
China overtakes U.S. supercomputing lead
Authors: Service Robert F.
Published: June 2016

A new machine propels China to first place in combined supercomputing power.
Polar explorer
Authors: Hand Eric
Published: June 2016

Joe Kirschvink thinks he has found a magnetic sixth sense in humans.
Allosteric initiation and regulation of catalysis with a molecular knot
Authors: Marcos Vanesa , Stephens Alexander J. , Jaramillo-Garcia Javier , Nussbaumer Alina L. , Woltering Steffen L. , Valero Alberto , Lemonnier Jean-François , Vitorica-Yrezabal Iñigo J. , Leigh David A.
Published: June 2016

Catalysis gets all tied up in knots

Over the past decade, chemists have used metal ion templating to prepare a wide variety of knotted molecular strands. Marcos
et al.
now show that one such pentafoil knot can be applied to catalysis. When held taut by zinc ions, the knot can capture a chloride or bromide ion from a halocarbon, thereby unleashing the reactivity of the residual cation for applications such as Lewis acid catalysis. Removing the zinc ions lowers the knot's affinity for the halides, offering a reversible modulation mechanism for the catalysis.

Science
, this issue p.
1555
When the universe became dusty
Authors: Breuck Carlos De
Published: June 2016

Observations from high-redshift galaxies reveal details of early universe evolution
Fast horses
Authors: McNutt Marcia
Published: June 2016

Those who know me well appreciate my passion for fast horses—those with spirit and stamina, as well as speed. And thus I devote my final words as editor-in-chief of the
Science
journals to the incredible team of thoroughbreds who accomplished more in a short time than I ever thought was possible. The changes that have come to the publishing enterprise at the American Association for the Advancement of Science (AAAS, the publisher of
Science
journals) have touched all facets of what we do and how we deliver it to our readers.
Spoligotyping of Mycobacterium tuberculosis Complex Isolates by Use of Ligation-Based Amplification and Melting Curve Analysis
Authors: Zeng Xiaohong , Li Hui , Zheng Rongrong , Kurepina Natalia , Kreiswirth Barry N. , Zhao Xilin , Xu Ye , Li Qingge
Published: June 2016

We report here a ligation-based spoligotyping that can identify unamplified spacers in membrane-based spoligotyping due to asymmetric insertion of IS
6110
in the direct repeat locus. Our typing yielded 84.4% (411/487) concordance with traditional typing and 100% (487/487) accuracy when confirmed by DNA sequencing.
Duplex Quantitative PCR Assay for Detection of Haemophilus influenzae That Distinguishes Fucose- and Protein D-Negative Strains
Authors: de Gier Camilla , Pickering Janessa L. , Richmond Peter C. , Thornton Ruth B. , Kirkham Lea-Ann S.
Published: June 2016

We have developed a specificHaemophilus influenzaequantitative PCR (qPCR) that also identifies fucose-negative and protein D-negative strains. Analysis of 100H. influenzaeisolates, 28Haemophilus haemolyticusisolates, and 14 other bacterial species revealed 100% sensitivity (95% confidence interval [CI], 96% to 100%) and 100% specificity (95% CI, 92% to 100%) for this assay. The evaluation of 80 clinical specimens demonstrated a strong correlation between semiquantitative culture and the qPCR (P< 0.001).
Protein-Protein Interactions Suggest Novel Activities of Human Cytomegalovirus Tegument Protein pUL103
Authors: Ortiz Daniel A. , Glassbrook James E. , Pellett Philip E.
Published: June 2016

Human cytomegalovirus (HCMV) is an enveloped double-stranded DNA virus that causes severe disease in newborns and immunocompromised patients. During infection, the host cell endosecretory system is remodeled to form the cytoplasmic virion assembly complex (cVAC). We and others previously identified the conserved, multifunctional HCMV virion tegument protein pUL103 as important for cVAC biogenesis and efficient secondary envelopment. To help define its mechanisms of action and predict additional functions, we used two complementary methods, coimmunoprecipitation (co-IP) and proximity biotinylation (BioID), to identify viral and cellular proteins that interact with pUL103. By using the two methods in parallel and applying stringent selection criteria, we identified potentially high-value interactions of pUL103 with 13 HCMV and 18 cellular proteins. Detection of the previously identified pUL103-pUL71 interaction, as well as verification of several interactions by reverse co-IP, supports the specificity of our screening process. As might be expected for a tegument protein, interactions were identified that suggest distinct roles for pUL103 across the arc of lytic infection, including interactions with proteins involved in cellular antiviral responses, nuclear activities, and biogenesis and transport of cytoplasmic vesicles. Further analysis of some of these interactions expands our understanding of the multifunctional repertoire of pUL103: we detected HCMV pUL103 in nuclei of infected cells and identified an ALIX-binding domain within the pUL103 sequence.

IMPORTANCE
Human cytomegalovirus (HCMV) is able to reconfigure the host cell machinery to establish a virion production factory, the cytoplasmic virion assembly complex (cVAC). cVAC biogenesis and operation represent targets for development of novel HCMV antivirals. We previously showed that the HCMV tegument protein pUL103 is required for cVAC biogenesis. Using pUL103 as bait, we investigated viral and cellular protein-protein interactions to identify and understand the range of pUL103 functions. We found that pUL103 interacts with cellular antiviral defense systems and proteins involved in organelle biogenesis and transport of cytoplasmic vesicles and is present in infected cell nuclei. These results expand our understanding of the functional repertoire of pUL103 to include activities that extend from the earliest stages of infection through virion assembly and egress.
MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency
Authors: Crepeau Rebecca L. , Zhang Peisheng , Usherwood Edward J.
Published: June 2016

MicroRNA-155 (miR-155) has been shown to play significant roles in the immune response, including in the formation of germinal centers (GC) and the development and maturation of T follicular helper (Tfh) cells. There is
in vitro
evidence to support a critical role for cellular miR-155 and viral miR-155 homologs in the establishment of gammaherpesvirus latency in B cells. We sought to determine the contribution of miR-155 to the establishment and maintenance of latency
in vivo
using murine gammaherpesvirus (MHV-68) infection. MHV-68-infected mice deficient in miR-155 exhibited decreases in GC B cells and Tfh cells. However, the frequencies of spleen cells harboring latent MHV-68 genomes were the same in both miR-155-deficient and wild-type (WT) mice. Similar latent loads were also observed in mixed bone marrow chimeric mice, where B cell-extrinsic effects of miR-155 deficiency were normalized. Interestingly, we observed markedly lower efficiency of reactivation from latency in miR-155-deficient cells, indicating an important role for miR-155 in this process. These
in vivo
data complement previous
in vitro
studies and lead to the conclusion that miR-155 is not necessary for the establishment or maintenance of gammaherpesvirus latency but that it does affect reactivation efficiency.

IMPORTANCE
Gammaherpesvirus infection leads to severe disease in immunosuppressed populations. miR-155 has been shown to play important roles in many pathological processes, including tumorigenesis and diseases caused by an overly aggressive immune response. Our work provides valuable
in vivo
data showing that miR-155 is dispensable for gammaherpesvirus latency but that it is critical for reactivation from latency, which is a crucial step in the viral life cycle.
DC-SIGN and L-SIGN Are Attachment Factors That Promote Infection of Target Cells by Human Metapneumovirus in the Presence or Absence of Cellular Glycosaminoglycans
Authors: Gillespie Leah , Gerstenberg Kathleen , Ana-Sosa-Batiz Fernanda , Parsons Matthew S. , Farrukee Rubaiyea , Krabbe Mark , Spann Kirsten , Brooks Andrew G. , Londrigan Sarah L. , Reading Patrick C.
Published: June 2016

It is well established that glycosaminoglycans (GAGs) function as attachment factors for human metapneumovirus (HMPV), concentrating virions at the cell surface to promote interaction with other receptors for virus entry and infection. There is increasing evidence to suggest that multiple receptors may exhibit the capacity to promote infectious entry of HMPV into host cells; however, definitive identification of specific transmembrane receptors for HMPV attachment and entry is complicated by the widespread expression of cell surface GAGs. pgsA745 Chinese hamster ovary (CHO) cells are deficient in the expression of cell surface GAGs and resistant to HMPV infection. Here, we demonstrate that the expression of the Ca2+-dependent C-type lectin receptor (CLR) DC-SIGN (CD209L) or L-SIGN (CD209L) rendered pgsA745 cells permissive to HMPV infection. Unlike infection of parental CHO cells, HMPV infection of pgsA745 cells expressing DC-SIGN or L-SIGN was dynamin dependent and inhibited by mannan but not by pretreatment with bacterial heparinase. Parental CHO cells expressing DC-SIGN/L-SIGN also showed enhanced susceptibility to dynamin-dependent HMPV infection, confirming that CLRs can promote HMPV infection in the presence or absence of GAGs. Comparison of pgsA745 cells expressing wild-type and endocytosis-defective mutants of DC-SIGN/L-SIGN indicated that the endocytic function of CLRs was not essential but could contribute to HMPV infection of GAG-deficient cells. Together, these studies confirm a role for CLRs as attachment factors and entry receptors for HMPV infection. Moreover, they define an experimental system that can be exploited to identify transmembrane receptors and entry pathways where permissivity to HMPV infection can be rescued following the expression of a single cell surface receptor.

IMPORTANCEOn the surface of CHO cells, glycosaminoglycans (GAGs) function as the major attachment factor for human metapneumoviruses (HMPV), promoting dynamin-independent infection. Consistent with this, GAG-deficient pgaA745 CHO cells are resistant to HMPV. However, expression of DC-SIGN or L-SIGN rendered pgsA745 cells permissive to dynamin-dependent infection by HMPV, although the endocytic function of DC-SIGN/L-SIGN was not essential for, but could contribute to, enhanced infection. These studies provide direct evidence implicating DC-SIGN/L-SIGN as an alternate attachment factor for HMPV attachment, promoting dynamin-dependent infection via other unknown receptors in the absence of GAGs. Moreover, we describe a unique experimental system for the assessment of putative attachment and entry receptors for HMPV.
Analysis of
cis
and
trans
Requirements for DNA Replication at the Right-End Hairpin of the Human Bocavirus 1 Genome
Authors: Shen Weiran , Deng Xuefeng , Zou Wei , Engelhardt John F. , Yan Ziying , Qiu Jianming
Published: June 2016

Parvoviruses are single-stranded DNA viruses that use the palindromic structures at the ends of the viral genome for their replication. The mechanism of parvovirus replication has been studied mostly in the dependoparvovirus adeno-associated virus 2 (AAV2) and the protoparvovirus minute virus of mice (MVM). Here, we used human bocavirus 1 (HBoV1) to understand the replication mechanism of bocaparvovirus. HBoV1 is pathogenic to humans, causing acute respiratory tract infections, especially in young children under 2 years old. By using the duplex replicative form of the HBoV1 genome in human embryonic kidney 293 (HEK293) cells, we identified the HBoV1 minimal replication origin at the right-end hairpin (OriR). Mutagenesis analyses confirmed the putative NS1 binding and nicking sites within the OriR. Of note, unlike the large nonstructural protein (Rep78/68 or NS1) of other parvoviruses, HBoV1 NS1 did not specifically bind OriR
in vitro
, indicating that other viral and cellular components or the oligomerization of NS1 is required for NS1 binding to the OriR.
In vivo
studies demonstrated that residues responsible for NS1 binding and nicking are within the origin-binding domain. Further analysis identified that the small nonstructural protein NP1 is required for HBoV1 DNA replication at OriR. NP1 and other viral nonstructural proteins (NS1 to NS4) colocalized within the viral DNA replication centers in both OriR-transfected cells and virus-infected cells, highlighting a direct involvement of NP1 in viral DNA replication at OriR. Overall, our study revealed the characteristics of HBoV1 DNA replication at OriR, suggesting novel characteristics of autonomous parvovirus DNA replication.

IMPORTANCE
Human bocavirus 1 (HBoV1) causes acute respiratory tract infections in young children. The duplex HBoV1 genome replicates in HEK293 cells and produces progeny virions that are infectious in well-differentiated airway epithelial cells. A recombinant AAV2 vector pseudotyped with an HBoV1 capsid has been developed to efficiently deliver the cystic fibrosis transmembrane conductance regulator gene to human airway epithelia. Here, we identified both
cis
-acting elements and
trans
-acting proteins that are required for HBoV1 DNA replication at the right-end hairpin in HEK293 cells. We localized the minimal replication origin, which contains both NS1 nicking and binding sites, to a 46-nucleotide sequence in the right-end hairpin. The identification of these essential elements of HBoV1 DNA replication acting both in
cis
and in
trans
will provide guidance to develop antiviral strategies targeting viral DNA replication at the right-end hairpin and to design next-generation recombinant HBoV1 vectors, a promising tool for gene therapy of lung diseases.
ICAM-1 Binding Rhinoviruses A89 and B14 Uncoat in Different Endosomal Compartments
Authors: Conzemius Rick , Ganjian Haleh , Blaas Dieter , Fuchs Renate
Published: June 2016

Human rhinovirus A89 (HRV-A89) and HRV-B14 bind to and are internalized by intercellular adhesion molecule 1 (ICAM-1); as demonstrated earlier, the RNA genome of HRV-B14 penetrates into the cytoplasm from endosomal compartments of the lysosomal pathway. Here, we show by immunofluorescence microscopy that HRV-A89 but not HRV-B14 colocalizes with transferrin in the endocytic recycling compartment (ERC). Applying drugs differentially interfering with endosomal recycling and with the pathway to lysosomes, we demonstrate that these two major-group HRVs productively uncoat in distinct endosomal compartments. Overexpression of constitutively active (Rab11-GTP) and dominant negative (Rab11-GDP) mutants revealed that uncoating of HRV-A89 depends on functional Rab11. Thus, two ICAM-1 binding HRVs are routed into distinct endosomal compartments for productive uncoating.

IMPORTANCE
Based on similarity of their RNA genomic sequences, the more than 150 currently known common cold virus serotypes were classified as species A, B, and C. The majority of HRV-A viruses and all HRV-B viruses use ICAM-1 for cell attachment and entry. Our results highlight important differences of two ICAM-1 binding HRVs with respect to their intracellular trafficking and productive uncoating; they demonstrate that serotypes belonging to species A and B, but entering the cell via the same receptors, direct the endocytosis machinery to ferry them along distinct pathways toward different endocytic compartments for uncoating.
Mutagenesis of Paramyxovirus Hemagglutinin-Neuraminidase Membrane-Proximal Stalk Region Influences Stability, Receptor Binding, and Neuraminidase Activity
Authors: Adu-Gyamfi Emmanuel , Kim Lori S. , Jardetzky Theodore S. , Lamb Robert A.
Published: June 2016

Paramyxoviridae
consist of a large family of enveloped, negative-sense, nonsegmented single-stranded RNA viruses that account for a significant number of human and animal diseases. The fusion process for nearly all paramyxoviruses involves the mixing of the host cell plasma membrane and the virus envelope in a pH-independent fashion. Fusion is orchestrated via the concerted action of two surface glycoproteins: an attachment protein called hemagglutinin-neuraminidase (HN [also called H or G depending on virus type and substrate]), which acts as a receptor binding protein, and a fusion (F) protein, which undergoes a major irreversible refolding process to merge the two membranes. Recent biochemical evidence suggests that receptor binding by HN is dispensable for cell-cell fusion. However, factors that influence the stability and/or conformation of the HN 4-helix bundle (4HB) stalk have not been studied. Here, we used oxidative cross-linking as well as functional assays to investigate the role of the structurally unresolved membrane-proximal stalk region (MPSR) (residues 37 to 58) of HN in the context of headless and full-length HN membrane fusion promotion. Our data suggest that the receptor binding head serves to stabilize the stalk to regulate fusion. Moreover, we found that the MPSR of HN modulates receptor binding and neuraminidase activity without a corresponding regulation of F triggering.

IMPORTANCE
Paramyxoviruses require two viral membrane glycoproteins, the attachment protein variously called HN, H, or G and the fusion protein (F), to couple host receptor recognition to virus-cell fusion. The HN protein has a globular head that is attached to a membrane-anchored flexible stalk of ∼80 residues and has three activities: receptor binding, neuraminidase, and fusion activation. In this report, we have identified the functional significance of the membrane-proximal stalk region (MPSR) (HN, residues 37 to 56) of the paramyxovirus parainfluenza virus (PIV5), a region of the HN stalk that has not had its structure determined by X-ray crystallography. Our data suggest that the MPSR influences receptor binding and neuraminidase activity via an indirect mechanism. Moreover, the receptor binding head group stabilizes the 4HB stalk as part of the general mechanism to fine-tune F-activation.
Herpes Simplex Virus 2 Virion Host Shutoff Endoribonuclease Activity Is Required To Disrupt Stress Granule Formation
Authors: Finnen Renée L. , Zhu Mingzhao , Li Jing , Romo Daniel , Banfield Bruce W.
Published: June 2016

We previously established that cells infected with herpes simplex virus 2 (HSV-2) are disrupted in their ability to form stress granules (SGs) in response to oxidative stress and that this disruption is mediated by virion host shutoff protein (vhs), a virion-associated endoribonuclease. Here, we test the requirement for vhs endoribonuclease activity in disruption of SG formation. We analyzed the ability of HSV-2 vhs carrying the point mutation D215N, which ablates its endoribonuclease activity, to disrupt SG formation in both transfected and infected cells. We present evidence that ablation of vhs endoribonuclease activity results in defects in vhs-mediated disruption of SG formation. Furthermore, we demonstrate that preformed SGs can be disassembled by HSV-2 infection in a manner that requires vhs endoribonuclease activity and that, befitting this ability to promote SG disassembly, vhs is able to localize to SGs. Together these data indicate that endoribonuclease activity must be maintained in order for vhs to disrupt SG formation. We propose a model whereby vhs-mediated destruction of SG mRNA promotes SG disassembly and may also prevent SG assembly.

IMPORTANCE
Stress granules (SGs) are transient cytoplasmic structures that form when a cell is exposed to stress. SGs are emerging as potential barriers to viral infection, necessitating a more thorough understanding of their basic biology. We identified virion host shutoff protein (vhs) as a herpes simplex virus 2 (HSV-2) protein capable of disrupting SG formation. As mRNA is a central component of SGs and the best-characterized activity of vhs is as an endoribonuclease specific for mRNA
in vivo
, we investigated the requirement for vhs endoribonuclease activity in disruption of SG formation. Our studies demonstrate that endoribonuclease activity is required for vhs to disrupt SG formation and, more specifically, that SG disassembly can be driven by vhs endoribonuclease activity. Notably, during the course of these studies we discovered that there is an ordered departure of SG components during their disassembly and, furthermore, that vhs itself has the capacity to localize to SGs.
Adeno-associated Virus Vectors Efficiently Transduce Mouse and Rabbit Sensory Neurons Coinfected with Herpes Simplex Virus 1 following Peripheral Inoculation
Authors: Watson Zachary L. , Ertel Monica K. , Lewin Alfred S. , Tuli Sonal S. , Schultz Gregory S. , Neumann Donna M. , Bloom David C.
Published: June 2016

Following infection of epithelial tissues, herpes simplex virus 1 (HSV-1) virions travel via axonal transport to sensory ganglia and establish a lifelong latent infection within neurons. Recent studies have revealed that, following intraganglionic or intrathecal injection, recombinant adeno-associated virus (rAAV) vectors can also infect sensory neurons and are capable of stable, long-term transgene expression. We sought to determine if application of rAAV to peripheral nerve termini at the epithelial surface would allow rAAV to traffic to sensory ganglia in a manner similar to that seen with HSV. We hypothesized that footpad or ocular inoculation with rAAV8 would result in transduction of dorsal root ganglia (DRG) or trigeminal ganglia (TG), respectively. To test this, we inoculated the footpads of mice with various amounts of rAAV as well as rAAV capsid mutants. We demonstrated that this method of inoculation can achieve a transduction rate of >90% of the sensory neurons in the DRG that innervate the footpad. Similarly, we showed that corneal inoculation with rAAV vectors in the rabbit efficiently transduced >70% of the TG neurons in the optic tract. Finally, we demonstrated that coinfection of mouse footpads or rabbit eyes with rAAV vectors and HSV-1 resulted in colocalization in nearly all of the HSV-1-positive neurons. These results suggest that rAAV is a useful tool for the study of HSV-1 infection and may provide a means to deliver therapeutic cargos for the treatment of HSV infections or of dysfunctions of sensory ganglia.

IMPORTANCE
Adeno-associated virus (AAV) has been shown to transduce dorsal root ganglion sensory neurons following direct intraganglionic sciatic nerve injection and intraperitoneal and intravenous injection as well as intrathecal injection. We sought to determine if rAAV vectors would be delivered to the same sensory neurons that herpes simplex virus (HSV-1) infects when applied peripherally at an epithelial surface that had been treated to expose the underlying sensory nerve termini. For this study, we chose two well-established HSV-1 infection models: mouse footpad infection and rabbit ocular infection. The results presented here provide the first description of AAV vectors transducing neurons following delivery at the skin/epithelium/eye. The ability of AAV to cotransduce HSV-1-infected neurons in both the mouse and the rabbit provides an opportunity to experimentally explore and disrupt host and viral proteins that are integral to the establishment of HSV-1 latency, to the maintenance of latency, and to reactivation from latency
in vivo
.
Human T
h
17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection
Authors: Christensen-Quick Aaron , Lafferty Mark , Sun Lingling , Marchionni Luigi , DeVico Anthony , Garzino-Demo Alfredo
Published: June 2016

Human immunodeficiency virus (HIV) infects and depletes CD4
+
T cells, but subsets of CD4
+
T cells vary in their susceptibility and permissiveness to infection. For example, HIV preferentially depletes interleukin-17 (IL-17)-producing T helper 17 (T
h
17) cells and T follicular helper (T
fh
) cells. The preferential loss of T
h
17 cells during the acute phase of infection impairs the integrity of the gut mucosal barrier, which drives chronic immune activation—a key determinant of disease progression. The preferential loss of T
h
17 cells has been attributed to high CD4, CCR5, and CXCR4 expression. Here, we show that T
h
17 cells also exhibit heightened permissiveness to productive HIV infection. Primary human CD4
+
T cells were sorted, activated under T
h
17- or T
h
0-polarizing conditions and infected, and then analyzed by flow cytometry. T
h
17-polarizing cytokines increased HIV infection, and HIV infection was disproportionately higher among T
h
17 cells than among IL-17
−
or gamma interferon-positive (IFN-γ
+
) cells, even upon infection with a replication-defective HIV vector with a pseudotype envelope. Further, T
h
17-polarized cells produced more viral capsid protein. Our data also reveal that T
h
17-polarized cells have diminished expression of RNase A superfamily proteins, and we report for the first time that RNase 6 inhibits HIV. Thus, our findings link T
h
17 polarization to increased HIV replication.

IMPORTANCE
Our study compares the intracellular replicative capacities of several different HIV isolates among different T cell subsets, providing a link between the differentiation of T
h
17 cells and HIV replication. T
h
17 cells are of key importance in mucosal integrity and in the immune response to certain pathogens. Based on our findings and the work of others, we propose a model in which HIV replication is favored by the intracellular environment of two CD4
+
T cell subsets that share several requirements for their differentiation: T
h
17 and T
fh
cells. Characterizing cells that support high levels of viral replication (rather than becoming latently infected or undergoing cell death) informs the search for new therapeutics aimed at manipulating intracellular signaling pathways and/or transcriptional factors that affect HIV replication.
Injury risk and a tackle ban in youth Rugby Union: reviewing the evidence and searching for targeted, effective interventions. A critical review
Authors: Tucker Ross , Raftery Martin , Verhagen Evert
Published: June 2016

It has recently been proposed that the tackle, an integral part of Rugby Union, be banned in school rugby, as a means to reduce the risk of injury. This proposal held that harmful contact should be removed in response to what was termed an unacceptably high-injury risk. Such a ban would represent a significant intervention that could change the nature of Rugby Union. As such, the basis and rationale for such a ban is worthy of critical evaluation. This review aims to describe the research on which such a ban is proposed. It does so through an assessment (identification), estimation (understanding of the magnitude and occurrence) and evaluation (determining acceptability) of the risk before decisions can be made about implementing any risk mitigation strategies. The body of literature describing injury risk, particularly among youths, is indeed thin and fraught with methodological differences that makes definitive conclusions impossible. We describe these, and their implications, arguing that the complete ban on the tackle may be unnecessary in young children, in whom injury risk may not be as high as is often argued, but also that it may have detrimental consequences. Finally, we propose alternative strategies and research questions which must be pursued to effectively reduce risk without creating unintended consequences or changing the nature of the sport.
Perceptions and culture of safety among helicopter emergency medical service personnel in the UK
Authors: Chesters Adam , Grieve Philip H , Hodgetts Timothy J
Published: June 2016

Background

The use of helicopter emergency medical services (HEMS) has increased significantly in the UK since 1987. To date there has been no research that addresses HEMS pilots and medical crews' own ideas on the risks that they view as inherent in their line of work and how to mitigate these risks. The aim of this survey is to describe and compare the attitudes and perceptions towards risk in HEMS operations of these staff.

Methods

A questionnaire was administered electronically to a representative selection of HEMS doctors, paramedics and pilots in the UK. A number of questions were grouped into common themes, and presented as Likert scales and ranking where appropriate. Descriptive and comparative results were presented and statistically analysed.

Results

The target sample of 100 consecutive respondents was achieved. All questionnaires were entirely completed. Respondents attributed the most risk to night HEMS operations without the use of night vision goggles, commercial pressure and mechanical aircraft failure. There was no statistical difference in overall perception of safety and years of experience (p=0.58) or between professions (p=0.08). Those who had experienced a crash were more likely to believe that HEMS operations are not inherently safe (p=0.05).

Conclusions

We have surveyed a cross-section of the HEMS operational community in the UK in order to describe their perceptions of safety and risk within their professional life. Two-thirds of respondents believed that HEMS operations were inherently safe. Those who did not seemed to be influenced by personal experience of a crash or serious incident. We support increased operational training for clinical crewmembers, an increased emphasis on incident reporting and a culture of safety, and careful attention to minimum training and equipment requirements for all HEMS missions.
Diary of a parliamentary intern
Authors: Ridge Anthony
Published: June 2016

Anthony Ridge, parliamentary intern to Lord Trees, witnesses the State Opening of Parliament for the first time and realises it carries a lot more significance than he had previously thought.
Regulation of expression of the p21CIP1 gene by the transcription factor ZNF217 and MDM2
Authors: Mantsou Aglaia , Koutsogiannouli Evangelia , Haitoglou Costas , Papavassiliou Athanasios G. , Papanikolaou Nikolaos A.
Published: June 2016

Using mouse double minute 2 (MDM2) protein-specific affinity chromatography and mass spectrometry, we have isolated the protein product of the oncogene znf217, which is a transcription factor and a component of a Hela-S-derived HDAC1 complex, as a novel MDM2-interacting protein. When co-expressed in cultured cancer cells, ZNF217 forms a complex with MDM2 and its ectopic over-expression reduces the steady-state levels of acetylated p53 in cell lines, suppressing its ability to activate the expression of a p21 promoter construct. In-silico analysis of the p21 promoter revealed the presence of several ZNF217-binding sites. These findings suggest that MDM2 controls p21 expression by at least 2 mechanisms: through ZNF217-mediated recruitment of HDAC1/MDM2 activity, which inhibits p53 acetylation; and through direct interaction with its binding site(s) on the p21 promoter.
Population decline of endangered lichen Erioderma pedicellatum in Nova Scotia, Canada
Authors: Cameron Robert P. , Toms Brad
Published: June 2016

Erioderma pedicellatum (Hue) P.M. Jørg. (1972) is a globally endangered lichen known from only four countries worldwide. The Atlantic population in Nova Scotia, Canada, has been declining for at least the last few decades. The population was closely monitored between 2003 and 2012 to determine mortality rates by life stage and population growth. A population viability model was created to assess the future viability of this population. The population declined by 12.8% over the 10 year monitoring period. Mortality rates for juveniles were significantly lower than for adults. The population viability model suggests the population in Nova Scotia will decline by 49% within 25 years. Conservation measures aimed at prolonging adult survival or increasing juvenile survival is, according to the model, the best way to maintain the population.
On the quantum mechanical solutions with minimal length uncertainty
Authors: Shababi Homa , Pedram Pouria , Chung Won Sang
Published: June 2016

In this paper, we study two generalized uncertainty principles (GUPs) including [Formula: see text] and [Formula: see text] which imply minimal measurable lengths. Using two momentum representations, for the former GUP, we find eigenvalues and eigenfunctions of the free particle and the harmonic oscillator in terms of generalized trigonometric functions. Also, for the latter GUP, we obtain quantum mechanical solutions of a particle in a box and harmonic oscillator. Finally we investigate the statistical properties of the harmonic oscillator including partition function, internal energy, and heat capacity in the context of the first GUP.
Alteration in non-classicality of light on passing through a linear polarization beam splitter
Authors: Shukla Namrata , Prakash Ranjana
Published: June 2016

We observe the polarization squeezing in the mixture of a two mode squeezed vacuum and a simple coherent light through a linear polarization beam splitter. Squeezed vacuum not being squeezed in polarization, generates polarization squeezed light when superposed with coherent light. All the three Stokes parameters of the light produced on the output port of polarization beam splitter are found to be squeezed and squeezing factor also depends upon the parameters of coherent light.
High energy particle collisions and geometry of horizon
Authors: Zaslavskii O. B.
Published: June 2016

We consider collision of two geodesic particles near the lightlike surface (black hole horizon or naked singularity) of such an axially symmetric rotating or static metric that the coefficient [Formula: see text] on this surface. It is shown that the energy in the center of mass frame [Formula: see text] is indefinitely large even without fine-tuning of particles’ parameters. Kinematically, this is the collision between two rapid particles that approach the horizon almost with the speed of light but at different angles (or they align along the normal to the horizon too slowly). The latter is the reason why the relative velocity tends to that of light, hence to high [Formula: see text]. Our approach is model-independent. It relies on general properties of geometry and is insensitive to the details of material source that supports the geometries of the type under consideration. For several particular models (the stringy black hole, the Brans–Dicke analogue of the Schwarzschild metric and the Janis–Newman–Winicour one) we recover the results found in literature previously.
INFLUENCE OF ION BEAM IRRADIATION ON STRUCTURAL, MAGNETIC AND ELECTRICAL CHARACTERISTICS OF Ho-DOPED AlN THIN FILMS
Authors: HASSAN NAJAM UL , HUSSAIN ZAHID , NAEEM M. , SHAH ISHFAQ AHMAD , HUSNAIN G. , AHMAD ISHAQ , ULLAH ZAKA
Published: June 2016

Holmium (Ho)-doped AlN thin films of thicknesses 60, 90 and 300 nm were grown in pure nitrogen atmosphere via RF magnetron sputtering. The deposited thin films were irradiated with protons at a dose of 5[Formula: see text]10[Formula: see text] ions/cm2 and the effects of irradiation on structural, magnetic and electrical characteristics of thin films were investigated. Rutherford backscattering spectroscopy (RBS) confirmed the presence of Al, N and Ho in prepared samples. X-ray diffraction analysis showed that crystallinity of the thin films was enhanced after irradiation and thicker films were more crystalline. Atomic force microscopy (AFM) revealed that the surface roughness and porosity of the thin films were increased after irradiation. Magnetic measurements showed that diamagnetic AlN:Ho thin films can be transformed into paramagnetic and ferromagnetic ones via suitable irradiation. The increase in carrier concentrations after irradiation was responsible for tuning the electrical and magnetic characteristics of thin films for applications in various high voltage microelectronic and magnetic devices.