bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Herpes Simplex Virus Glycoprotein-Induced Cascade of Events Governing Cell-Cell Fusion
Authors: Atanasiu Doina , Saw Wan Ting , Eisenberg Roselyn J. , Cohen Gary H. 
Published: September 2016

ABSTRACT

Receptor-dependent herpes simplex virus (HSV)-induced cell-cell fusion requires glycoproteins gD, gH/gL, and gB. Our current model posits that during fusion, receptor-activated conformational changes in gD activate gH/gL, which subsequently triggers the transformation of the prefusion form of gB into a fusogenic state. To examine the role of each glycoprotein in receptor-dependent cell-cell fusion, we took advantage of our discovery that fusion by wild-type herpes simplex virus 2 (HSV-2) glycoproteins occurs twice as fast as that achieved by HSV-1 glycoproteins. By sequentially swapping each glycoprotein between the two serotypes, we established that fusion speed was governed by gH/gL, with gH being the main contributor. While the mutant forms of gB fuse at distinct rates that are dictated by their molecular structure, these restrictions can be overcome by gH/gL of HSV-2 (gH
2
/gL
2
), thereby enhancing their activity. We also found that deregulated forms of gD of HSV-1 (gD
1
) and gH
2
/gL
2
can alter the fusogenic potential of gB, promoting cell fusion in the absence of a cellular receptor, and that deregulated forms of gB can drive the fusion machinery to even higher levels. Low pH enhanced fusion by affecting the structure of both gB and gH/gL mutants. Together, our data highlight the complexity of the fusion machinery, the impact of the activation state of each glycoprotein on the fusion process, and the critical role of gH/gL in regulating HSV-induced fusion.

IMPORTANCE
Cell-cell fusion mediated by HSV glycoproteins requires gD, gH/gL, gB, and a gD receptor. Here, we show that fusion by wild-type HSV-2 glycoproteins occurs twice as fast as that achieved by HSV-1 glycoproteins. By sequentially swapping each glycoprotein between the two serotypes, we found that the fusion process was controlled by gH/gL. Restrictions imposed on the gB structure by mutations could be overcome by gH
2
/gL
2
, enhancing the activity of the mutants. Under low-pH conditions or when using deregulated forms of gD
1
and gH
2
/gL
2
, the fusogenic potential of gB could only be increased in the absence of receptor, underlining the exquisite regulation that occurs in the presence of receptor. Our data highlight the complexity of the fusion machinery, the impact of the activation state of each glycoprotein on the fusion process, and the critical role of gH/gL in regulating HSV-induced fusion.
HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation
Authors: Deng Jing , Mitsuki Yu-ya , Shen Guomiao , Ray Jocelyn C. , Cicala Claudia , Arthos James , Dustin Michael L. , Hioe Catarina E. 
Published: September 2016

ABSTRACTHIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells.IMPORTANCEThere are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells.
Hepatitis C Virus Is Released via a Noncanonical Secretory Route
Authors: Bayer Karen , Banning Carina , Bruss Volker , Wiltzer-Bach Linda , Schindler Michael 
Published: September 2016

ABSTRACTWe analyzed hepatitis C virus (HCV) morphogenesis using viral genomes encoding a mCherry-tagged E1 glycoprotein. HCV-E1-mCherry polyprotein expression, intracellular localization, and replication kinetics were comparable to those of untagged HCV, and E1-mCherry-tagged viral particles were assembled and released into cell culture supernatants. Expression and localization of structural E1 and nonstructural NS5A followed a temporospatial pattern with a succinct decrease in the number of replication complexes and the appearance of E1-mCherry punctae. Interaction of the structural proteins E1, Core, and E2 increased at E1-mCherry punctae in a time-dependent manner, indicating that E1-mCherry punctae represent assembled or assembling virions. E1-mCherry did not colocalize with Golgi markers. Furthermore, the bulk of viral glycoproteins within released particles revealed an EndoH-sensitive glycosylation pattern, indicating an absence of viral glycoprotein processing by the Golgi apparatus. In contrast, HCV-E1-mCherry trafficked with Rab9-positive compartments and inhibition of endosomes specifically suppressed HCV release. Our data suggest that assembled HCV particles are released via a noncanonical secretory route involving the endosomal compartment.IMPORTANCEThe goal of this study was to shed light on the poorly understood trafficking and release routes of hepatitis C virus (HCV). For this, we generated novel HCV genomes which resulted in the production of fluorescently labeled viral particles. We used live-cell microscopy and other imaging techniques to follow up on the temporal dynamics of virus particle formation and trafficking in HCV-expressing liver cells. While viral particles and viral structural protein were found in endosomal compartments, no overlap of Golgi structures could be observed. Furthermore, biochemical and inhibitor-based experiments support a HCV release route which is distinguishable from canonical Golgi-mediated secretion. Since viruses hijack cellular pathways to generate viral progeny, our results point toward the possible existence of a not-yet-described cellular secretion route.
Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C
Authors: Gaido Cibele M. , Stone Shane , Chopra Abha , Thomas Wayne R. , Le Souëf Peter N. , Hales Belinda J. 
Published: September 2016

ABSTRACT

Rhinovirus (RV) species A and C are the most frequent cause of respiratory viral illness worldwide, and RV-C has been linked to more severe exacerbations of asthma in young children. Little is known about the immune responses to the different RV species, although studies comparing IgG1 antibody titers found impaired antibody responses to RV-C. Therefore, the aim of this study was to assess whether T-cell immunity to RV-C is similarly impaired. We measured T-cell proliferation to overlapping synthetic peptides covering the entire VP1 capsid protein of an RV-A and RV-C genotype for 20 healthy adult donors. Human leukocyte antigen (HLA) was typed in all the donors in order to investigate possible associations between the HLA type and RV peptide recognition. Total and specific IgG1 antibody titers to the VP1 proteins of both RV-A and RV-C were also measured to examine associations between the antibody and T-cell responses. We identified T-cell epitopes that are specific to and representative of each RV-A and RV-C species. These epitopes stimulated CD4
+
-specific T-cell proliferation, with similar magnitudes of response for both RV species. All the donors, independent of their HLA-DR or -DQ type, were able to recognize the immunodominant RV-A and -C regions of VP1. Furthermore, the presence or absence of specific antibody titers was not related to changes in T-cell recognition. Our results indicate a dissociation between the antibody and T-cell responses to rhinoviruses. The species-representative T-cell epitopes identified in this study are valuable tools for future studies investigating T-cell responses to the different RV species.

IMPORTANCE
Rhinoviruses (RVs) are mostly associated with the common cold and asthma exacerbations, although their contributions to most upper and lower respiratory tract diseases have increasingly been reported. Species C (RV-C) has been associated with more frequent and severe asthma exacerbations in young children and, along with RV-A, is the most clinically relevant species. Little is known about how our immune system responds to rhinoviruses, and there are limited tools to study specific adaptive immunity against each rhinovirus species. In this study, we identified immunodominant T-cell epitopes of the VP1 proteins of RV-A and RV-C, which are representative of each species. The study found that T-cell responses to RV-A and RV-C were of similar magnitudes, in contrast with previous findings showing RV-C-specific antibody responses were low. These findings will provide the basis for future studies on the immune response to rhinoviruses and can help elucidate the mechanisms of severity of rhinovirus-induced infections.
SUMO Modification Stabilizes Enterovirus 71 Polymerase 3D To Facilitate Viral Replication
Authors: Liu Yan , Zheng Zhenhua , Shu Bo , Meng Jin , Zhang Yuan , Zheng Caishang , Ke Xianliang , Gong Peng , Hu Qinxue , Wang Hanzhong 
Published: September 2016

ABSTRACT

Accumulating evidence suggests that viruses hijack cellular proteins to circumvent the host immune system. Ubiquitination and SUMOylation are extensively studied posttranslational modifications (PTMs) that play critical roles in diverse biological processes. Cross talk between ubiquitination and SUMOylation of both host and viral proteins has been reported to result in distinct functional consequences. Enterovirus 71 (EV71), an RNA virus belonging to the family
Picornaviridae
, is a common cause of hand, foot, and mouth disease. Little is known concerning how host PTM systems interact with enteroviruses. Here, we demonstrate that the 3D protein, an RNA-dependent RNA polymerase (RdRp) of EV71, is modified by small ubiquitin-like modifier 1 (SUMO-1) both during infection and
in vitro
. Residues K159 and L150/D151/L152 were responsible for 3D SUMOylation as determined by bioinformatics prediction combined with site-directed mutagenesis. Also, primer-dependent polymerase assays indicated that mutation of SUMOylation sites impaired 3D polymerase activity and virus replication. Moreover, 3D is ubiquitinated in a SUMO-dependent manner, and SUMOylation is crucial for 3D stability, which may be due to the interplay between the two PTMs. Importantly, increasing the level of SUMO-1 in EV71-infected cells augmented the SUMOylation and ubiquitination levels of 3D, leading to enhanced replication of EV71. These results together suggested that SUMO and ubiquitin cooperatively regulated EV71 infection, either by SUMO-ubiquitin hybrid chains or by ubiquitin conjugating to the exposed lysine residue through SUMOylation. Our study provides new insight into how a virus utilizes cellular pathways to facilitate its replication.

IMPORTANCE
Infection with enterovirus 71 (EV71) often causes neurological diseases in children, and EV71 is responsible for the majority of fatalities. Based on a better understanding of interplay between virus and host cell, antiviral drugs against enteroviruses may be developed. As a dynamic cellular process of posttranslational modification, SUMOylation regulates global cellular protein localization, interaction, stability, and enzymatic activity. However, little is known concerning how SUMOylation directly influences virus replication by targeting viral polymerase. Here, we found that EV71 polymerase 3D was SUMOylated during EV71 infection and
in vitro
. Moreover, the SUMOylation sites were determined, and
in vitro
polymerase assays indicated that mutations at SUMOylation sites could impair polymerase synthesis. Importantly, 3D is ubiquitinated in a SUMOylation-dependent manner that enhances the stability of the viral polymerase. Our findings indicate that the two modifications likely cooperatively enhance virus replication. Our study may offer a new therapeutic strategy against virus replication.
HIV testing history and preferences for future tests among gay men, bisexual men and other MSM in England: results from a cross-sectional study
Authors: Witzel T Charles , Melendez-Torres G J , Hickson Ford , Weatherburn Peter 
Published: September 2016

ObjectivesThe British HIV Association's (BHIVA) testing guidelines recommend men who have sex with men (MSM) test annually or more frequently if ongoing risk is present. We identify which groups of MSM in England are less likely to have tested for HIV and their preferences for future tests by testing model, in order to inform health promotion programmes.MethodsData come from the Gay Men's Sex Survey 2014, a cross-sectional survey of MSM, aged 16 years or older and living in the UK. Only men who did not have diagnosed HIV and were living in England were included in this analysis. We used logistic regression models to understand how social determinants of health were associated with not testing for HIV in the past 12 months, and never having tested. We then cross-tabulated preferred testing location by demographic characteristics.ResultsYounger men, older men and men who were not gay identified were least likely to have tested for HIV. Higher educational attainment, migrancy, Black ethnicity and being at higher of risk were associated with greater levels of HIV testing. Men who were less likely to have tested for HIV preferred a wider range of options for future HIV testing.ConclusionsIf the BHIVA's HIV testing policy of 2008 was used to guide testing priorities among MSM focus would be on increasing the rate of annual testing among MSM at less risk of HIV (ie, younger men, older men and non-gay identified MSM). Instead the promotion of more frequent testing among the groups most at risk of infection should be prioritised in order to reduce the time between infection and diagnosis.
Investigating the feasibility of an enhanced contact intervention in self-harm and suicidal behaviour: a protocol for a randomised controlled trial delivering a Social support and Wellbeing Intervention following Self Harm (SWISH)
Authors: Ahmed Nilufar , John Ann , Islam Saiful , Jones Richard , Anderson Pippa , Davies Charlotte , Khanom Ashra , Harris Shaun , Huxley Peter 
Published: September 2016

IntroductionSelf-harm is a strong predictor for suicide. Risks for repeat behaviour are heightened in the aftermath of an index episode. There is no consensus on the most effective type of intervention to reduce repetition. Treatment options for patients who do not require secondary mental health services include no support, discharge to general practitioner or referral to primary care mental health support services. The aim of this study is to assess whether it is feasible to deliver a brief intervention after an episode and whether this can reduce depressive symptoms and increase the sense of well-being for patients who self-harm.MethodsThis is a non-blinded parallel group randomised clinical trial. 120 patients presenting with self-harm and/or suicidal ideation to mental health services over a 12-month period who are not referred to secondary services will be randomised to either intervention plus treatment as usual (TAU), or control (TAU only). Patients are assessed at baseline, 4 and 12 weeks with standardised measures to collect data on depression, well-being and service use. Primary outcome is depression scores and secondary outcomes are well-being scores and use of services. The findings will indicate whether a rapid response brief intervention is feasible and can reduce depression and increase well-being among patients who self-harm and do not require secondary services.Ethics and disseminationEthical approval was granted by the UK National Health Service (NHS) Ethics Committee process (REC 6: 14/WA/0074). The findings of the trial will be disseminated through presentations to the participating Health Board and partners, peer-reviewed journals and national and international conferences.Trial registration numberISRCTN76914248; Pre-results.
Health system barriers and facilitators to medication adherence for the secondary prevention of cardiovascular disease: a systematic review
Authors: Banerjee Amitava , Khandelwal Shweta , Nambiar Lavanya , Saxena Malvika , Peck Victoria , Moniruzzaman Mohammed , Faria Neto Jose Rocha , Quinto Katherine Curi , Smyth Andrew , Leong Darryl , Werba José Pablo 
Published: September 2016

BackgroundSecondary prevention is cost-effective for cardiovascular disease (CVD), but uptake is suboptimal. Understanding barriers and facilitators to adherence to secondary prevention for CVD at multiple health system levels may inform policy.ObjectivesTo conduct a systematic review of barriers and facilitators to adherence/persistence to secondary CVD prevention medications at health system level.MethodsIncluded studies reported effects of health system level factors on adherence/persistence to secondary prevention medications for CVD (coronary artery or cerebrovascular disease). Studies considered at least one of β blockers, statins, angiotensin–renin system blockers and aspirin. Relevant databases were searched from 1 January 1966 until 1 October 2015. Full texts were screened for inclusion by 2 independent reviewers.ResultsOf 2246 screened articles, 25 studies were included (12 trials, 11 cohort studies, 1 cross-sectional study and 1 case–control study) with 132 140 individuals overall (smallest n=30, largest n=63 301). 3 studies included upper middle-income countries, 1 included a low middle-income country and 21 (84%) included high-income countries (9 in the USA). Studies concerned established CVD (n=4), cerebrovascular disease (n=7) and coronary heart disease (n=14). Three studies considered persistence and adherence. Quantity and quality of evidence was limited for adherence, persistence and across drug classes. Studies were concerned with governance and delivery (n=19, including 4 trials of fixed-dose combination therapy, FDC), intellectual resources (n=1), human resources (n=1) and health system financing (n=4). Full prescription coverage, reduced copayments, FDC and counselling were facilitators associated with higher adherence.ConclusionsHigh-quality evidence on health system barriers and facilitators to adherence to secondary prevention medications for CVD is lacking, especially for low-income settings. Full prescription coverage, reduced copayments, FDC and counselling may be effective in improving adherence and are priorities for further research.
Evolving data access policy: The Canadian context
Authors: Dyke Stephanie O.M. , Saulnier Katie M. , Pastinen Tomi , Bourque Guillaume , Joly Yann 
Published: September 2016

In setting up a data access policy to share controlled access data from the McGill Epigenomics Mapping Centre (EMC), an International Human Epigenome Consortium (IHEC) partner project, we encountered ethical and legal challenges that are likely to be relevant to other researchers sharing data, especially from Canadian projects. We discuss our solutions to the following data-sharing challenges, based on comparative legal and policy analysis: (1) providing access to data to a growing number of researchers; (2) maintaining Canadian privacy standards while sharing controlled access data internationally; (3) freedom of information requests; and (4) providing more incentives for researchers to share pre-publication data.
Protective Effects on Central Nervous System by Acidic Polysaccharide of Panax ginseng in Relapse-Remitting Experimental Autoimmune Encephalomyelitis-Induced SJL/J Mice
Authors: Bing So Jin , Ha Danbee , Hwang Insun , Park Eunjin , Ahn Ginnae , Song Jie-Young , Jee Youngheun 
Published: September 2016

Bearing pathologic and clinical similarities to human multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) is used as a murine model to test potential therapeutic agents for MS. Recently, we reported the protective effects of an acidic polysaccharide of Panax ginseng (APG) in C57BL/6 strain-dependent EAE, a model of primary progressive MS. In this study, we extend our previous findings on the therapeutic capacity of APG in relapsing-remitting EAE (rr-EAE), the animal model to closely mimic recurrent inflammatory demyelination lesions of relapsing-remitting MS. Treatments with APG led to a significant reduction of clinical symptoms and the relapse rate of EAE than vehicle treatments. Consistent with this, histological examination revealed that APG markedly modulated the infiltration of CD4[Formula: see text] T cells and CD11b[Formula: see text] macrophages into the spinal cord and the APG-treated CNS was devoid of demyelination and axonal damages. In addition, APG decreased the proliferation of peripheral PLP-reactive T cells and the production of pro-inflammatory factors such as IFN-[Formula: see text], IL-17 and TNF-[Formula: see text]. The fact that APG can induce clinically beneficial effects to distinct types of EAE furthers our understanding on the basis of its immunosuppression in EAE and, possibly, in MS. Our results suggest that APG may serve as a new therapeutic agent for MS as well as other human autoimmune diseases, and warrants continued evaluation for its translation into therapeutic application.
Perspectives from CTA in relativistic astrophysics
Authors: Hofmann Werner 
Published: September 2016

The Cherenkov telescope array (CTA) is a next-generation observatory for very high energy (VHE) gamma-ray astronomy. With one array of imaging atmospheric Cherenkov telescopes each in the Northern and Southern Hemispheres, CTA will provide full-sky coverage, enhance flux sensitivity by one order of magnitude compared to current instruments, cover gamma-ray energies from 20 GeV to 300 GeV, and provide a wide field of view with angular resolution of a few arc-minutes. Science themes to be addressed by the CTA observatory include (i) understanding the origin of relativistic cosmic particles, and the role these play in the evolution of star forming systems and galaxies, (ii) probing extreme environments such as neutron stars and black holes, but also the cosmic voids, and (iii) exploring frontiers in physics such as the nature of dark matter. With its superior performance, the prospects for CTA combine guaranteed science — the in-depth understanding of known objects and mechanisms — with anticipated detection of new classes of gamma-ray emitters and new phenomena, and a very significant potential for fundamentally new discoveries.